CN116600789A - Polymeric bile acid ester nanoparticles for inducing tolerance - Google Patents
Polymeric bile acid ester nanoparticles for inducing tolerance Download PDFInfo
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- CN116600789A CN116600789A CN202180055989.4A CN202180055989A CN116600789A CN 116600789 A CN116600789 A CN 116600789A CN 202180055989 A CN202180055989 A CN 202180055989A CN 116600789 A CN116600789 A CN 116600789A
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Abstract
Polymeric bile acid (pBA) nanoparticles and tolerogenic formulations containing polymeric bile acid nanoparticles for oral delivery and induction of antigen-specific tolerance in a subject may comprise immunosuppressants and/or disease-specific antigens. Oral delivery causes local organ accumulation and systemic delivery of these nanoparticles. Early intervention using these nanoparticles induces antigen-specific tolerance and prevents the development of autoimmune disorders. In autoimmune diseases, treatment with nanoparticles causes long-term antigen-specific immune tolerance, even after cessation of treatment.
Description
Cross Reference to Related Applications
The present application claims priority from U.S. application Ser. No. 16/907,055 to Jung Seok Lee, tarek M.Fahmy and Dorgin Kim, filed by the university of Yersinia at 19, 6, 2020 to the United states patent and trademark office.
Statement regarding federally sponsored research
The present application was completed with government support under 0747577 awarded by the national science foundation and under AI056363, CA199004 and CA026412 awarded by the national institutes of health. The government has certain rights in this application.
Technical Field
The present invention relates generally to polymeric bile acid ester nanocompositions containing immunomodulators and/or antigens that can be used to induce antigen-specific immune tolerance.
Background
Direct priming of Dendritic Cells (DCs) with antigen and adjuvant is a well-established powerful vaccination method for eliciting immunity. Biodegradable nanoparticles are therefore a promising vaccine vehicle, with proven applications in infections and cancers. One particular property of nanoparticles that are attractive for immunotherapy is their propensity to be taken up by antigen presenting cells and the possibility to preferentially target professional antigen presenting cell DCs to deliver protein antigens as well as immunogenic adjuvants.
However, nanoparticle-mediated tolerance induction is not well understood due to nanoparticle-mediated inflammatory responses. While previous work has demonstrated the promise of nanoparticle-mediated delivery of antigens and immunosuppressants for immune tolerance in allergies, little is known about the mechanisms how these systems function at the cellular and tissue level and thus how they can be adapted to develop new autoimmune therapeutic options.
Another challenge is to achieve antigen-specific immune tolerance induction by oral delivery rather than injection. Delivery of active agents and/or imaging agents to internal organs following oral administration remains a challenge because the harsh biochemical environment inherent to the stomach, particularly the high acidic pH and the presence of proteolytic enzymes, can degrade and inactivate many therapeutic agents. The materials used to form the oral drug delivery vehicle are carefully selected to protect the active agent from the harsh conditions in the stomach and for the particular desired agent release pattern. In general, the materials that exert a therapeutic effect on the target organ or cell are not selected other than the effect of the therapeutic agent.
There remains a need for improved oral delivery systems that utilize a delivery vehicle as a therapeutic agent and increase the bioavailability and/or efficacy of the orally delivered agent to induce antigen-specific tolerance.
It is therefore an object of the present invention to provide a highly efficient oral delivery system for inducing antigen-specific immune tolerance.
It is yet another object of the present invention to provide a method of preparing a high efficiency oral delivery system.
It is yet another object of the present invention to provide a method of using a high efficiency oral delivery system.
Disclosure of Invention
Polymeric bile acid ester (pBA) nanoparticles and tolerogenic formulations containing polymeric bile acid ester nanoparticles for inducing antigen-specific tolerance in a subject are typically formed from bile acid esterified polymers (pBA) having a molecular weight between about 800-1,000 (two monomers) and 240,000 daltons (Da), preferably about 400 monomers. The bile acid ester polymers are typically formed from one or more of polymeric ursodeoxycholic acid (pUDCA), polymeric lithocholic acid (pLCA), polymeric deoxycholic acid (pDCA), polymeric chenodeoxycholic acid (pCDCA) and polymeric cholic acid (pCA). The bile acid ester polymer may be a linear and/or branched polymer. References to pUDCA are generally applicable to other bile acid ester polymers. The diameter of the nanoparticles formed from pBA may be between 60nm and 600nm, more preferably between 100nm and 400nm, with a typical average geometric diameter of 350nm. The polymer nanoparticles may comprise other biocompatible polymers, such as blends or copolymers. In some embodiments, the nanoparticle is formed from pUDCA having a molecular weight between about 800 and 5,000Da and having about two to 20 UDCA monomer units per polymer.
Typically, the bile acid ester polymer forms a surface on a nanoparticle containing 100 to 5000 bile acid monomer units. The nanoparticle typically has at least 1.5 times and at most about 50 times the affinity for the bile acid receptor than the corresponding monomer that forms the bile acid ester polymer. Bile acid receptors include G protein-coupled bile acid receptor 1 (GPBAR 1 or Takeda G protein receptor 5 (TGR 5)) and Farnesol X Receptor (FXR). These receptors are placed at the interface of the host immune system and intestinal microbiota and are highly expressed in innate immune cells such as intestinal and hepatic macrophages, with dendritic cells and natural killer T cells typically located on the surface of the innate immune cells such as macrophages.
Typically, the nanoparticle and/or the formulation contains one or more immunosuppressants, such as rapamycin (sirolimus) and analogues of rapamycin, such as everolimus (everolimus), everolimus (ridaforolimus), lei Xiluo limus (remsirolimus), umirolimus (umirolimus), and zotarolimus (zotarolimus). The immunostimulant may be blocked, encapsulated and/or associated with the nanoparticle. The nanoparticles and/or formulations typically also contain a disease or disorder specific antigen. The disease-specific antigen may be blocked, encapsulated, and/or associated with the nanoparticle.
Methods of inducing antigen-specific tolerance in a subject suffering from an autoimmune or allergic disease with a nanoparticle generally comprise orally administering to the subject an effective amount of the nanoparticle. Typically, following oral administration, the nanoparticles are distributed to internal organs such as heart, kidney, spleen, lung, liver, colon and pancreas. This distribution is typically mediated by intestinal transport of the particles and infiltration through the intestinal epithelium aided by macrophage phagocytosis (by binding to TGR-5, endocytosis, exocytosis) and intestinal hepatic circulation (gallbladder accumulation and pancreatic duct entry). Such distribution is typically achieved in the absence of tissue or organ specific targeting agents.
Representative autoimmune and allergic diseases include type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, food allergy, environmental allergy, and diseases with anti-drug antibodies (ADA). A method of treating type 1 diabetes is illustrated, the method comprising orally administering to a subject in need thereof a formulation containing an effective amount of pBA nanoparticles containing an anti-inflammatory agent and/or an immunosuppressant such as rapamycin.
The method generally comprises administering the formulation for a period of at least one week, at least two weeks, or at least three weeks. In some embodiments, the formulation may be administered three times a week, twice a week, or once a day. Following treatment, the diabetic animal model can maintain healthy blood glucose for at least about three days, about five days, about one week, about two weeks, about one month or more after discontinuing administration of the formulation, and exhibit an increase in the number of regulatory T cells (tregs) relative to the control. The subject may develop a tolerogenic phenotype.
The nanoparticle selectively accumulates in the pancreas, liver, and colon, and delivers 0.1ng to 200pg of the agent/NP of the agent to the target tissue such that the total dose depends on the administered volume of the NP. Nanoparticles may release the agent over time by sustained release and/or in a single burst. For example, one or more agents encapsulated in the nanoparticle may be released over a period of time between one hour and several weeks, or may be released within the first 24 hours of reaching the target organ. Typical dosages for the treatment of inflammatory and/or autoimmune diseases are between 0.1mg/Kg and 1000mg/Kg, such as between about 0.4mg/Kg and about 400mg/Kg, between about 50mg/Kg and 1000mg/Kg or between about 100mg/Kg and 500 mg/Kg.
Methods have been developed for the preparation of NPs using self-assembly and aggregation of bile acid ester polymers. Two methods of preparing a bile acid assembly include the manufacture of branched polymeric bile acid units (as opposed to linear) and encapsulation by guest/host interactions in cavities formed by such branched building units; and supramolecular self-assembly by fluorinated bile acid units. Fluorination introduces a "fluorine-thinning effect". This is clearly different from hydrophobic or hydrophilic interactions and results in self-assembly into complex larger structures without the need for special formulations.
NPs can exhibit therapeutic and/or prophylactic effects on inflammation (e.g., for the treatment of autoimmune diseases) and/or metabolic regulation (e.g., for controlling blood glucose levels and body weight). This is believed to be due to the binding of pBA, and more preferably pUDCA, to the TGR5 bile acid receptor. The binding affinity and affinity of NPs for bile acid receptors is enhanced when compared to the corresponding bile acid monomers. The enhancement of affinity and avidity is due to the polymerization of bile acids and the surface properties of NPs that are exposed to 100 to 5000 bile acid monomer units. This allows the use of NPs as therapeutic agents with increased potency and efficacy when compared to the use of bile acid monomers.
Inclusion of therapeutic agents, such as anti-inflammatory agents or immunosuppressants, typically results in exceeding additive therapeutic effects, as the effects of pBA, and preferably pucca, increase with the effect of encapsulating the drug. The results of examples of prevention and treatment of type 1 diabetes demonstrate this not just additive effect.
PBA binding to bile acid receptors activates intracellular pathways that promote endogenous insulin secretion, energy metabolism, endogenous insulin receptor expression, and many other functions, such as reduction of reactive oxygen species and reduction of pro-inflammatory signals. In the embodiment where the particles encapsulate insulin, this anti-inflammatory effect on the cells occurs before the insulin is released from the particles and binds its receptor and modulates glucose.
Thus, bile acid particles naturally mimic physiological processes, and it is due to this bio-mimicking that they are able to achieve more than additive effects with encapsulated insulin. Because pBA NPs first engage bile acid receptors and initiate intracellular signaling, and then release the encapsulated agents, pBA NPs generally increase and potentiate the effects of the encapsulated agents.
Thus, the polymerization of bile acids significantly increases their binding affinity and avidity for bile acid receptors and enhances the therapeutic efficacy of bile acids. pBA NP alone showed therapeutic anti-inflammatory and immunosuppressive effects. Encapsulation of the therapeutic agent enhances the therapeutic effect of the agent because this effect increases with the effect of pBA. As shown in the examples, NPs have broad-spectrum therapeutic properties, manage T1D in the short term, and are used in the long term to reverse pathology and restore endogenous insulin secretion and regulate immunity.
Drawings
FIGS. 1A-1E are schematic illustrations of the formulation of bile acid monomers and polymeric BA (pBA) into NPs under emulsifying conditions.
FIGS. 1A-1E are structures of Cholic Acid (CA) (FIG. 1A), chenodeoxycholic acid (CDCA) (FIG. 1B), deoxycholic acid (DCA) (FIG. 1C), lithocholic acid (ECA) (FIG. 1D) and ursodeoxycholic acid (UDCA) (FIG. 1E).
Figures 2A-2E illustrate the polymerization and formation of nanoparticles. The monomer was esterified at the carbon-24 position of monomer BA (fig. 2A) to produce a hydrolyzable ester linkage BA (pBA) (fig. 2B). The schematic representation of the polymerization step shows the positioning of the reactive end groups forming the polymer. Emulsification of pBA (FIG. 2C) in the presence of drug resulted in drug entrapped in solid pBA NP (FIG. 2D) having an average diameter of 344.3.+ -. 4.7nm (FIG. 2E).
FIGS. 3A-3E are graphs showing distribution and uptake of polymeric bile acids (pBA) in vitro and in vivo.
FIG. 3A is a graph of the biodistribution in the non-gastrointestinal organs, heart, kidney, spleen, lung, liver and pancreas (pUDCA and total NPs of control PLGA NPs as% initial dose/cn).
FIG. 3B is a graph of dye-independent localization of NPs in the pancreas. When coumarin 6 is used as a tracer, the pancreatic accumulation of NPs is quantified to confirm that the level of pancreatic accumulation of NPs is not dependent on the physicochemical properties of the loaded agent, but rather on the particle composition. Dispersing free coumarin in a solution containing 1% 20 in brine.
FIG. 3C is a graph of CD11C-F4/80+ macrophages associated with pUDCA NP loaded with coumarin 6 in the pancreas, liver, lung and spleen obtained using a flow cytometer 4 hours after oral ingestion in a mouse.
FIG. 3D is a graph of competitive binding of pUDCA and UDCA to TGR5 on macrophages as a function of concentration (micrograms/ml) of pUDCA, UDCA and PLGA at 4 ℃.
FIG. 3E is the number of particles in the cell (x 10 5 ) The plot of change over time (in hours) shows the endocytosis rate at 37℃and the exocytosis rate at 4℃for pUDCA, PLGA/pUDCA and PLGA. (XP)<0.01 and***P<0.001)。
FIG. 3F is a graph showing insulin production (ng/ml) induced from pancreatic beta cells by pUDCA and UDCA.
FIG. 3G is a graph showing IFN-. Gamma.production by CD4+ T cells treated directly with pUDCA (50 and 5 micrograms/ml) and stimulated with anti-CD 3 and anti-CD 28.
Fig. 4A-4I are graphs showing comparative prevention of T1D.
Fig. 4A shows an experimental scheme. Pancreatic inflammation was induced by IP injection of Cyclophosphamide (CY) on day 0.
FIG. 4B is a graph showing comparative evaluation of formulations in prevention T1D as blood glucose (mg/dl) as empty pUDCA (pUDCA after oral gavage EMPTR ) Monomeric UDCA (UDCA) EMPTR )、pLCA(pLCA EMPTR ) And pDCA (pDCA) EMPTR ) The number of days after CY treatment was performed.
FIG. 4C is a graph of percent diabetic animals (glucose >200 mg/dL) after CY treatment.
FIG. 4D is pUDCA RAPA Graph of the effect on blood glucose levels.
Fig. 4E is a graph of the percentage of animals with diabetes. The single dose on day 1 is referred to as dose I, and the two doses on consecutive 2 days are referred to as dose II.
FIG. 4F is a graph of the saline and pUDCA RAPA Dose I and dose II, decrease after administration of cd8+ T cell frequency over 5 days.
Fig. 4G is a graph of% comparison of CD 8T cells normalized at day 5 at saline, dose I and dose II.
Fig. 4H is a graph showing post-dose boost in Treg% (cd4+cd25+foxp3+) frequency over 5 days.
Fig. 4I is a graph indicating a normalized comparison at day 5 post-inflammation. All experiments were performed with 10 samples per group per animal and repeated twice. P <0.05, < P <0.01, and 0.001).
FIGS. 5A and 5B are diagrams showing the use of rapamycin loaded pUDCA NP (pUDCA) RAPA ) Graph of dose-dependent efficacy of prevention T1D. In CY-induced T1D animal models, the prophylactic effect of Rapa-loaded pucca was tested as a function of doseAnd (5) fruits. The dosage is as follows: 50. 100 and 500mg/kg pUDCA. On the first day after CY induction (day 0, CY arrow), pUDCA was orally administered for two days (NP arrow). The results indicate that the prophylactic effect (i.e., preventing onset of disease) is dose dependent as assessed by the extent of blood glucose reduction (fig. 5A) and the percentage of non-diabetic animals after 30 days (fig. 5B). The indication of onset of diabetes is a blood glucose level greater than 200mg/dL.
FIGS. 6A-6O are diagrams showing oral ingestion of pUDCA INS Short-term and long-term regression of T1D after NP, TGR 5-induced activation of endogenous GLP-1 and insulin secretion, and anti-inflammatory effects of pucca.
FIG. 6A is a graph of short term blood glucose (mg/dL) over time following treatment with UDCA-insulin (500 mg/kg), pUDCA-insulin (100 mg/kg), pUDCA-null (500 mg/kg) and pUDCA-insulin (500 mg/kg).
FIG. 6B is a graph of short-term blood glucose (mg/dl) versus UDCA (n=10) over time (days). Oral treatment was started after glucose ≡ 200mg/dL and the dose was 100 or 500mg/kg, 1 dose per day for seven doses.
FIG. 6C is a graph of long-term blood glucose (mg/dL) versus time (days). Long-term reversal of spontaneous T1D disease following oral treatment with insulin loaded NP (n=6).
FIG. 6D is a graph of body weight (grams) versus time (days), saline, soluble insulin, PLGA insulin, and pUDCA insulin.
FIG. 6E is a graph of percent survival in diabetic mice over time (in days) showing the test with log rank and χ 2 Statistical analysis (up to 90 days) survival curves after pUDCA treatment.
FIG. 6F is a T1D blood glucose (mg/dl) plot of time (days) for saline, soluble oral, soluble insulin (subcutaneous), soluble insulin (intraperitoneal), and pUDCA insulin (oral).
FIG. 6G is a graph of blood glucose (mg/dl) in pigs over time (days). T1D induction in Ossabaw pigs by treatment with tetraoxypyrimidine followed by animals pUDCA INS The oral administration was performed 7 times. Blood glucose levels were measured every 5 minutes in three pigs and averaged with saline-receiving control pigsA comparison is made. Arrows indicate oral administration and food recovery.
FIGS. 6H and 6I are graphs of serum insulin concentrations (ng/ml) (FIG. 6H) and pancreatic insulin (FIG. 6I) at 4, 8 and 24 hours after oral ingestion for saline, free insulin, PLGA-insulin, pUDCA-insulin.
FIGS. 6J and 6K are graphs of GLP-1 secretion (pmol/L) (FIG. 6J) and insulin production (FIG. 6K), which are the results of pUDCA activating TGR 5.
FIGS. 6L and 6M are graphs of CD44+CD8+ T cells (FIG. 6L) and Foxp3+CD25+CD4+ Treg (FIG. 6M) following administration of saline and pUDCA-insulin. Pancreatic lymph node cd8+ T cell frequency and fig. 6m, cd4+ treg (n=10).
FIG. 6N is a graph of IL-10 levels (pg/ml) and CCL1 (pg/ml) of pUDCA, UDCA, PLGA showing the production of anti-inflammatory cytokines (IL 10) and chemokines (CCL 1).
FIG. 6O is a graph of M1/M2 ratio of pUDCA, UDCA, PLGA, saline showing pUDCA-induced macrophage phenotype bias from Ml (CD 86) to M2 (CD 206). All experiments were performed with more than 6 samples per animal, except for the pig study, and repeated twice (< 0.05, <0.01 and < 0.001).
Fig. 7A and 7B are experimental protocols for two groups of mice: group a was used to test efficacy with OTii adoptive transfer (fig. 7A), and group B was used to evaluate efficacy in OTii mice (no cell transfer, fig. 7B). FIG. 7C is a graph showing the CD25+Foxp3+ percentages of OTii cells obtained from animals treated with vehicle, pUDCA-OVA NP (OVA NP) OR pUDCA-OVA-RAPA NP (OR NP).
Fig. 8A is an experimental protocol for inducing therapeutic antigen-specific tolerance in a mouse model of type 1 diabetes.
FIGS. 8B and 8C show the change in blood glucose (mg/dL) of mice orally administered with seven doses of saline, empty pUDCA NP, pUDCA-BDC or pUDCA-BDC-RAPA daily at either high dose (10 mg/dose, FIG. 8B) or low dose (2 mg/dose, FIG. 8C).
FIGS. 8D and 8E are graphs showing the change in CD44+CD8+ T cell percentage (FIG. 8D) or CD4+CD25+FoxP3+ Treg percentage (FIG. 8E) in untreated diabetic mice or mice treated with BDC/pUDCA-RAPA.
Fig. 9A and 9B are bar graphs showing fasting blood glucose levels (mg/dL) for one month (fig. 9A) and six months (fig. 9B) following administration of tetraoxamidine to young and adult pigs.
FIG. 10A is a graph showing the change in blood glucose levels (mg/dL) of a tetraoxapyrimidine-induced diabetic pig following seven days of cumulative daily administration of pUDCA and 0.01% insulin, 6.4mg/kg dose (each daily dose delivering 6.4mg/kg of particles containing 0.01% insulin).
FIG. 10B is a graph showing the change in blood glucose levels (mg/dL) in a tetraoxamidine-induced diabetic pig following a single dose of water gavage, pUDCA-insulin or subcutaneous insulin 70/30. pUDCA-insulin particles produced a broader trough and reduced postprandial effects, with an average blood glucose level of 65mg/dL.
FIG. 10C is a graph showing the change in blood glucose levels (mg/dL) in a tetraoxamidine-induced diabetic pig following repeated daily subcutaneous administration of insulin for four days, followed by a single dose of pUDCA (up arrow). The bottom arrow shows the possible postprandial effect without any external insulin. A single administration of pucca eliminates the need for insulin for the next three days.
FIG. 10D is a bar graph showing baseline fasting glucose (mg/dL) versus time (days) for adult tetraoxypyrimidine-induced diabetic pigs two weeks or one month after pUDCA treatment. Insulin loaded pUDCA NP rapidly reversed tetraoxypyrimidine-induced diabetes in adult Ossabaw pigs.
FIG. 10E is a graph showing the effect of pUDCA NP in diabetes therapy. NP provides diabetes care and treatment from three aspects: oral delivery with good bioavailability for the treatment of late T1D and T2D, for the treatment of metabolic recovery of early T1D, and for the reduction of autoimmune reactivity of early T1D.
Fig. 11A is an experimental protocol for inducing therapeutic antigen-specific tolerance in a mouse model of multiple sclerosis.
FIG. 11B is a graph showing clinical scores over time (days) for mice untreated or treated with soluble MOG, pUDCA-MOG, soluble MOG/Rapa or pUDCA-MOG/Rapa.
Fig. 12A is an experimental protocol for inducing therapeutic antigen-specific tolerance in a collagen-induced arthritis (CIA) mouse model.
Fig. 12B is a graph showing the change in clinical score over time (days) for mice with CIA: untreated (vehicle), or treated with soluble MOG, empty pucca, pucca-Rapa, pucca-collagen, or pucca-collagen-Rapa.
Detailed Description
I. And (5) defining.
As used herein, the term "nanoparticle" generally refers to particles having a diameter of about 10nm to but not including about 1000nm, preferably about 60nm to about 450 nm. The particles may have any shape. Typically, the nanoparticles are spherical and the size is expressed as the geometric average of the diameters measured in nm.
As used herein, the term "encapsulated" refers to an agent, such as a therapeutic agent and/or imaging agent, encapsulated within, surrounded by, and/or dispersed throughout the polymer matrix of the nanoparticle. Alternatively or additionally, the agent may be associated with the polymer matrix by hydrophobic interactions, charge interactions, van der waals forces, and the like.
As used herein, the term "non-targeted" refers to nanoparticles formed from polymers such as pucca or PLGA that have increased affinity for a particular cell type or organ without additional elements such as targeting moieties. As used herein, the term "targeting moiety" refers to any molecule, such as an antibody, ligand, receptor binding moiety or active fragment thereof, or agonist, antagonist or tissue or cell specific targeting molecule, which is used to attach the nanoparticle to a cell in a target organ.
As used herein, the term "active agent" or "bioactive agent" is used interchangeably herein to refer to a chemical or biological compound that induces a desired pharmacological and/or physiological effect, wherein the effect may be prophylactic, therapeutic and/or diagnostic. The term also encompasses pharmaceutically acceptable pharmacologically active derivatives of the active agents, including but not limited to salts, esters, amides, prodrugs, active metabolites and analogues.
As used herein, the term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmacologically inactive substance that is added to a composition to further facilitate administration of the composition.
As used herein, "oral administration" refers to delivering the composition to a subject by the oral route. Oral administration may be achieved by oral gavage or by swallowing a composition in liquid or solid form. The liquid form of the orally administered composition may be in the form of a solution, emulsion, suspension, liquid capsule or gel. Solid forms of compositions for oral administration include capsules, tablets, pills, powders and granules.
As used herein, the term "therapeutically effective amount" means an amount of a therapeutic, prophylactic, and/or diagnostic agent that, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, is sufficient to treat, alleviate, ameliorate, alleviate symptoms of, prevent, delay onset of, inhibit progression of, reduce severity of, and/or reduce incidence of the disease, disorder, and/or condition.
As used herein, the term "treatment" refers to the partial or complete alleviation, amelioration, alleviation, delay of onset, inhibition of progression, reduction of severity, and/or reduction of incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. For example, "treating" a microbial infection may refer to inhibiting the survival, growth, and/or spread of a microorganism. For the purpose of reducing the risk of developing a pathology associated with a disease, disorder and/or condition, the treatment may be administered to a subject that does not exhibit signs of the disease, disorder and/or condition and/or to a subject that exhibits only early signs of the disease, disorder and/or condition.
As used herein, the term "prevention" or "prophylaxis" refers to administration of a composition to a subject or system at risk of, or having a predisposition to, one or more symptoms caused by a disease or disorder to cause cessation of a particular symptom of the disease or disorder, reduction or prevention of one or more symptoms of the disease or disorder, reduction in the severity of the disease or disorder, complete elimination of the disease or disorder, stabilization or delay of progression or progress of the disease or disorder.
As used herein, "tolerability" refers to a reduced ability of the immune system to mount an adaptive (T or B mediated) response to a given antigen.
As used herein, "tolerogenic" means a condition or ability to stimulate or increase tolerance.
As used herein, "Treg" includes any T cell that confers inhibition. Thus, the term encompasses traditional CD4, foxp3+ tregs, as well as other CD4 cells that do not express Foxp3 but can be regulated by secretion of IL-10 (Tr 1 cells) and other signals, as well as CD8 tregs (foxp3+ and-) that have also been identified.
II, composition.
The composition comprises nanoparticles formed from poly (bile acid) ester polymers. These particles are administered without the incorporation of therapeutic, prophylactic and/or diagnostic agents therein or thereon, and optionally pharmaceutically acceptable excipients.
Bile acids have been used for decades to enhance the oral intake of drugs. See, e.g., samstein et al Biomaterials (Biomaterials) 29 (2008) 703-708. Bile salts are used to improve the bioavailability of poly (lactide-co-glycolide) (PLGA) nanoparticles by protecting them and enhancing their absorption by intestinal epithelial cells during their transport through the gastrointestinal tract. Deoxycholic acid emulsions have been shown to protect PLGA nanoparticles from degradation under acidic conditions and to enhance their permeability through the human epithelial model. The loaded PLGA nanoparticles were orally administered to mice using deoxycholic acid emulsion, producing sustained levels of the encapsulant in the blood over 24-48 hours, with a relative bioavailability of 1.81. The highest concentration of the encapsulating agent in the liver demonstrated targeted delivery to the liver by the oral route.
It has now been demonstrated that the use of bile acid ester polymers, such as pUDCA, not only significantly improves oral intake, but also that the empty particles have anti-inflammatory properties. This is believed to be achieved by binding of the polymer (e.g., pUDCA) to the TGR5 receptor. The hollow pUDCA NPs (i.e., not containing added therapeutic or prophylactic agents) are effective in reducing inflammation, e.g., for treating diabetes, due to enhanced surface affinity due to the polymeric and spherical forms. Studies have shown that GLP-1 is upregulated by TGR5 binding in the ileum. The anti-inflammatory aspects of UDCA are also amplified in a similar manner.
Based on these findings, pUDCA NP is expected and shown to be useful for the treatment of autoimmune and inflammatory diseases and disorders of the pancreas, liver and colon, including diabetes, pancreatitis, primary Biliary Cirrhosis (PBC), nonalcoholic steatohepatitis (NASH), IBD and rCDI (Clostridium difficile). Typically, pUDCA NP provides sustained release of UDCA from pUDCA as the ester linkage is degraded.
A. Polymer
Generally, bile acid monomers suitable for forming poly (bile acid) polymers are defined by formula I:
wherein:
R 1 、R 2 and R is 3 Independently hydrogen or hydroxy, and
x is a hydroxyl group at low pH (2-5), which is deprotonated at a pH above 5.5. Optionally, X is NHCH 2 COOH、NHCH 2 COO - 、NHCH 2 CH 2 SO 3 H or NHCH 2 CH 2 SO 3 - Represents glycine or taurine conjugates (also known as bile salts) of the corresponding bile acids.
The hydroxyl groups fully protonated at position X render the monomer insoluble in water, and the loss of protons improves the water solubility of the monomer.
The structure of the bile acid monomer Cholic Acid (CA) is shown in formula II:
the structure of the bile acid monomer lithocholic acid (LCA) is shown in formula III:
the structure of the bile acid monomer deoxycholic acid (DCA) is shown in formula IV:
the structure of the bile acid monomer chenodeoxycholic acid (CDCA) is shown in formula V:
the structure of the bile acid monomer ursodeoxycholic acid (UDCA) is shown in formula VI:
Other suitable bile acids include, but are not limited to, glycocholic acid, taurocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, ethoxycholic acid, glycoursodeoxycholic acid, and taurine conjugates of 3-alpha-7-alpha-12-alpha-22-xi-tetrahydroxy-5-beta-cholestane-26-carboxylic acid (tetrahydroxycholanic acid) and 3-alpha-12 alpha-22-xi-trihydroxy-5-beta-cholestane-26-carboxylic acid.
Other suitable bile acids also include murine cholic acid (e.g., alpha-murine cholic acid, beta-murine cholic acid, gamma-murine cholic acid, and omega-murine cholic acid), hyodeoxycholic acid, ursolic acid, iso-cholic acid, iso-deoxycholic acid, iso-lithocholic acid, iso-phenyldeoxycholic acid, iso-ursodeoxycholic acid, norcholic acid, nordeoxycholic acid, norchenodeoxycholic acid, norursodeoxycholic acid, apocholic acid, allocholic acid, and taurine or glycine conjugates thereof.
Further suitable bile acids are described in Heinken et al, microbiome 2019,7:75; schmidt et al, J journal of biochemistry (J Biol Chem), 2010,285 (19): 14486-94; chiang, comparative physiology (Compr Physiol), 2013,3 (3): 1191-1212; sarenac and Mikov, front pharmacological (Front Pharmacol), 2018,9:939; de Haan et al, J.clinical transformation study (J Clin Transl Res), 2018,4 (1): 1-46; LIPID MAPS structural database: bile acids and derivatives thereof (https:// www.lipidmaps.org/data/structure/lmsdsearch. Phpmode= Process ClassSearch & lmid=lmst 04).
The monomers listed above are esterified to produce a poly (bile acid) (PBA) polymer having a molecular weight of between about 800 (at least two monomers) and 250,000 daltons, more preferably between 800 and 50,000 daltons. In some embodiments, the pUDCA polymer has a Mw value of between about 1000 and about 10,000 daltons, or between about 1200 and about 5,000 daltons. Room temperature polymerization of bile acids can be performed using a mixture of Diisopropylcarbodiimide (DIC), dimethylaminopyridine and 1:1 salt of p-toluenesulfonic acid (DMAP/PTSA) under mild reaction conditions and without significant crosslinking. Carbodiimide activation results in preferential esterification of carbon 3 and the linear polymer chains. Applied to UDCA, the aggregated UDCA may be defined by formula VII:
where n is a number ranging from 2 to 600, preferably from 2 to 100, corresponding to an average value of the Mw of the polymer ranging from 800 to 240,000 daltons.
The degree of branching may vary from generation 0 (no branching) to the higher infinite generation. An exemplary polymeric UDCA with branching is shown in formula VIII:
the polymers may be formed from the same monomers such as UDCA, forming poly (UDCA), or PUDCA. In other embodiments, the polymer may be formed from a mixture of bile acid monomers, forming a copolymer or monomer that encapsulates the polymer bile acid core. In these embodiments, the monomers or polymers may be mixed in any combination and in any ratio to form a polymeric blend of bile acid ester polymers having a molecular weight ranging between 800 and 250,000 daltons. Typically, the polymer is linear, but other structures, such as branched or bifurcated or dendritic, may be used. Dendrimers of poly (bile acids) (e.g., dendritic PUDCA) will have a pH stimulation response similar to that of the linear counterpart. Such dendritic systems will be in an expanded or open state at physiological pH or pH above 6.0. Thus, it can be easily loaded with drug by non-covalent association with the dendritic polymer or by entrapment in interstitial cavities formed in the branched system. Low pH may shrink the system, protect the encapsulant and/or make its release slower. Thus, the dendritic bile acid ester polymer itself can act as a nanoparticle without the formulation conditions used for the linear polymer.
The pUDCA polymer can be formed from ursodeoxycholic acid, glycoursodeoxycholic acid, tauroursodeoxycholic acid, or a combination thereof.
In some embodiments, the monomer or formed polymeric chain may comprise a moiety having one or more radionuclides or optical tracers (bioluminescence, chemiluminescence, fluorescence, or other high extinction coefficient or high quantum yield optical tracers). Similarly, non-invasive contrast agents such as heavy metal-based T1 MR agents (gadolinium, dysprosium, etc.) or T2 contrast agents (iron oxide, manganese oxide, etc.), iodizing agents for X-ray attenuation (CT) and other forms. The inherent ability of these systems to respond to changes in the pH range of 7 to 2 is of significant interest for delivering therapeutic agents to both the low pH endocytic compartment within the cell and/or the site of inflammation characterized by a low pH microenvironment or tumor surrounding environment. The polymeric chains of these embodiments can be used to form trackable pUDCA nanoparticles, eliminating the need to encapsulate the imaging/tracking agent, and enhancing the imaging modality due to the localized retention of the imaging agent in this region (confinement of the probe).
The pUDCA nanoparticles were pH responsive. Under low pH microenvironments (pH 2-5), the polymer backbone shrinks and the nanoparticles aggregate and expand at higher pH (pH 6-7.5) to release the encapsulated agent. The pUDCA polymer allows encapsulation of both hydrophilic and hydrophobic drugs, peptides, proteins and oligonucleotides. In the higher pH microenvironment of the intestinal lumen, or generally in organs with a pH above 5.5-6.0, the encapsulated agent is released over time.
The aqueous solubility of bile acids increases exponentially with increasing pH (Hoffman et al, J. Lipid Res.) (1992) J. Lipid. J. 617-626). The polymeric chains of pucca and nanoparticles made therefrom aggregate at low pH and become increasingly soluble/dispersible as the pH increases above 5.5. These polymers and nanoparticles are particularly suitable for oral drug delivery because they can protect the agent encapsulated with the nanoparticles from the damaging environment of the stomach. Then, when the polymer begins to dissolve to release the agent, the agent can be safely released in the intestine (typically 6-7.4) and the target organ at neutral pH.
The average geometric diameter of the nanoparticles may be between 50 and 500 nm. In some embodiments, the average geometric diameter of the population of nanoparticles is about 60nm, 75nm, 100nm, 125nm, 150nm, 175nm, 200nm, 225nm, 250nm, 275nm, 300nm, 325nm, 350nm, 375nm, 400nm, 425nm, 450nm, or 475nm. In some embodiments, the average geometric diameter is between 100-400nm, 100-300nm, 100-250nm, or 100-200 nm. In some embodiments, the average geometric diameter is between 60-400nm, 60-350nm, 60-300nm, 60-250nm, or 60-200 nm. In some embodiments, the average geometric diameter is between 75 and 250 nm. In some embodiments, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of the nanoparticles in the population of nanoparticles have a diameter between 50 and 500 nm. In a preferred embodiment, the average particle size is 350nm. The size is measured by conventional techniques such as optical microscopy.
B. Tolerogenic compositions
Compositions for inducing tolerance typically contain, or are formulated with, tolerogenic (tolerogenic) antigens, immunosuppressants (e.g., rapamycin), or combinations thereof, or for co-administration therewith to dendritic cells or Antigen Presenting Cells (APCs). In some embodiments, the tolerogenic antigen and the immunosuppressive agent are co-delivered to the same cell. APCs can then become tolerogenic and migrate to peripheral lymphoid lymph nodes where they are believed to activate tregs such as cd4+foxp3+ cells, induce their proliferation, induce their differentiation, or a combination thereof. These tregs can then inhibit activation of B cells and antibody production specific for tolerogenic antigens. It is desirable that the antigen and immunosuppressive drug be spatially localized to the same hepatic dendritic cell or hepatic endothelial cell to initiate tolerogenic procedures. Thus, in a most preferred embodiment, the antigen and the immunosuppressive drug are loaded into, dispersed within, conjugated to, or otherwise displayed on or in the same particle. Co-delivery of immunosuppressants with antigens in the same particle can have two effects: 1) Concentrate antigen and drug doses in the same cell, and 2) ensure that the same antigen presenting cell is inhibited. Such a strategy may reduce or prevent extensive immunosuppression or antigen-specific immunogenicity.
Immunosuppressants are delivered to the same antigen presenting cell along with the antigen to enhance the immunosuppressive effects (e.g., tolerance induction) of the drug. In some embodiments, the two immunosuppressants are co-delivered, such as mycophenolic acid and rapamycin. Preferably, the particles accumulate in the liver. In some embodiments, the particle comprises a targeting moiety, e.g., a targeting moiety that increases (or further increases) the accumulation of the particle in the liver or directs the particle to a specific cell (e.g., a dendritic cell in the liver).
In alternative embodiments, the antigen and immunosuppressive drug are loaded into, dispersed within, conjugated to, or otherwise displayed on or in the individual particles.
C. Antigens
The particles may comprise one or more antigens to be induced to tolerance. The appropriate antigen is selected based on the desired therapeutic outcome and the disease, disorder or condition being treated. Exemplary antigens are known in the art. See, for example, U.S. published application No. 2014/0356384, which discusses:
tolerogenic antigens may be derived from therapeutic proteins for which tolerance is desired. Examples are protein drugs of their wild type, e.g. human factor VIII or factor IX, to which the patient has not established central tolerance, as they lack these proteins, protein drugs of non-human origin, for administration to humans. Examples are protein drugs that are glycosylated in a non-human form as a result of production, or engineered protein drugs, e.g., having non-native sequences that can elicit an unwanted immune response. Examples of tolerogenic antigens that are not engineered therapeutic proteins naturally occurring in humans include human proteins with engineered mutations, such as mutations for improving pharmacological properties. Examples of tolerogenic antigens containing non-human glycosylation include proteins produced in yeast or insect cells.
Tolerogenic antigens may be derived from proteins administered to a protein-deficient human. Lack means that patients receiving the protein cannot naturally produce enough protein. The protein may be a protein that is defective or dysfunctional in a gene of the patient. Such proteins include, for example, antithrombin-III, protein C, factor VIII, factor IX, growth hormone, somatostatin, insulin, pramlintide acetate, mecamylin (IGF-1), beta-glucocerebrosidase, arabinase-a, la Luo Naide enzyme (alpha-L-iduronidase), iduronidase (idursucase) (idursucase-2-sulfatase), galactosidase, agarase-beta (alpha-galactosidase), alpha-1 protease inhibitors, and Willebrand factor (von Willebrands factor).
Tolerogenic antigens may be derived from therapeutic antibodies and antibody-like molecules, including antibody fragments and fusion proteins having antibodies and antibody fragments. These include non-human antibodies, chimeric antibodies and humanized antibodies. Immune responses to humanized antibodies have been observed in humans (Getts D R, getts M T, mcCarthy D P, chapain E L and Miller S D (2010), "mAbs", 2 (6): 682-694.). Thus, embodiments comprise fusion molecules for tolerogenic comprising a red blood cell binding moiety and at least one antigen, antigen fragment or antigen mimotope of one or more of these proteins, wherein the red blood cell binding moiety specifically binds to, for example, glycophorin a or a target selected from the group consisting of: band 3, glycophorin B, glycophorin C or other member of the red blood cell target group. The red blood cell binding moiety may, for example, be selected from the group consisting of: antibodies, antibody fragments, scFv, peptide ligands and aptamers.
Tolerogenic antigens may be derived from human allograft antigens. Examples of such antigens are subunits of various MHC class I and MHC class II haplotype proteins, as well as single amino acid polymorphisms on minor blood group antigens comprising RhCE, kell, kidd, duffy and Ss.
The tolerogenic antigen may be an autoantigen against which the patient has developed an autoimmune response or may develop an autoimmune response. Examples are proinsulin (diabetes), collagen (rheumatoid arthritis) and myelin basic protein (multiple sclerosis).
For example, type 1 diabetes (T1D) is an autoimmune disease in which T cells that recognize islet proteins have been shed from immune regulation and signal the immune system to destroy pancreatic tissue. Many protein antigens have been found as targets for such diabetogenic T cells, including insulin, GAD65, chromogranin-a, and the like. In the treatment or prevention of T1D, it would be useful to induce antigen specific immune tolerance against defined diabetogenic antigens to functionally inactivate or delete the diabetogenic T-cell clones.
The tolerogenic antigen may be one or more of the following proteins, or fragments or peptides derived therefrom. In type 1 diabetes, several autoantigens have been identified: insulin, proinsulin, preproinsulin, glutamate decarboxylase-65 (GAD-65), GAD-67, insulinoma-related protein 2 (IA-2) and insulinoma-related protein 2β (IA-213); other antigens include ICA69, ICA12 (SOX-13), carboxypeptidase H, imogen, GLIMA 38, chromogranin-A, FISP-60, carboxypeptidase E, peripherin, glucose transporter 2, liver cancer-entero-pancreas/pancreas related protein, S100P, glial fiber Acid protein, regeneration gene II, pancreas duodenum homologous box 1, myotonic kinase of muscular dystrophy, islet-specific glucose-6-phosphatase catalysis subunit related protein and SST G protein coupled receptor 1-5. Among autoimmune diseases of the thyroid gland, including Hashimoto's thyroiditis and Graves' disease, autoantigens include Thyroglobulin (TG), thyroperoxidase (TPO) and thyrotropin receptor (TSHR); other antigens include sodium-iodine transporter (NIS) and megalin (megalin). In thyroid-related eye and skin diseases, the antigen is the insulin-like growth factor 1 receptor in addition to the thyroid autoantigen, which comprises TSHR. In hypoparathyroidism, the autoantigen is a calcium sensitive receptor. In Edison's disease (Addison's disease), autoantigens include 21-hydroxylase, 17 a-hydroxylase and P450 side chain cleaving enzyme (P450 scc); other antigens include ACTH receptor, P450c21 and P450cl7. In premature ovarian failure, the autoantigen comprises the FSH receptor and alpha-enolase. In autoimmune pituitary inflammation or autoimmune disease, the autoantigen comprises pituitary-specific protein factors (PGSF) la and 2; another antigen is iodothyronine deiodinase type 2. In multiple sclerosis, autoantigens include myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein. In rheumatoid arthritis, the autoantigen is type II collagen. In immune gastritis, the autoantigen is H + 、K + -atpase. In pernicious anaemia, autoantigens are internal factors. In celiac disease, autoantigens are tissue transglutaminase and prolamin. In vitiligo, the autoantigens are tyrosinase, and tyrosinase-related proteins 1 and 2. In myasthenia gravis, the autoantigen is the acetylcholine receptor. In pemphigus vulgaris and variants, the autoantigens are desmoglein 3, 1 and 4; other antigens include annexin (pephaxin), desmoglein, plakoglobin, peplatin (perplatin), desmoplakin and acetylcholine receptors. In bullous pemphigoid, autoantigens include BP180 and BP230; other antigens include plexin and laminin 5. In dermatitis herpetiformis, autoantigens include endometrium and tissue transferGlutaminase. In acquired epidermolysis bullosa, the autoantigen is collagen type VII. In systemic sclerosis, autoantigens comprise matrix metalloproteinases 1 and 3, collagen specific chaperone heat shock protein 47, fibrillin-1 and PDGF receptors; other antigens include Scl-70, U1 RNP, th/To, ku, jo1, NAG-2, centromere protein, topoisomerase I, nucleolin, RNA polymerase I, II and III, PM-Slc, filamin and B23. In mixed connective tissue diseases, the autoantigen is ulsnrp. In Sjogren's syndrome, autoantigens are nuclear antigens SS-A and SS-B; other antigens include cytosolic proteins, poly (ADP-ribose) polymerase and topoisomerase. In systemic lupus erythematosus, autoantigens include nucleoprotein, including SS-se:Sup>A, high mobility group 1 protein (HMGB 1), nucleosomes, histones and double-stranded dnse:Sup>A. In Goodpasture's syndrome, the autoantigen comprises glomerular basement membrane protein, comprising type IV collagen. In rheumatic heart disease, the autoantigen is cardiac myoglobin. Other autoantigens found in autoimmune polyadenopathy type 1 syndrome include aromatic L-amino acid decarboxylase, histidine decarboxylase, cysteine sulfinic acid decarboxylase, tryptophan hydroxylase, tyrosine hydroxylase, phenylalanine hydroxylase, liver P450 cytochrome P4501A2 and 2A6, SOX-9, SOX-10, calcium sensitive receptor protein and type 1 interferons α, β and ω.
The tolerogenic antigen may be a foreign antigen to which the patient has developed an unwanted immune response. Examples are food antigens. Examples include testing a patient to identify a foreign antigen and produce a molecular fusion containing the antigen, and treating the patient to develop immune tolerance to the antigen or food. Examples of such foods and/or antigens are provided. Examples are from peanuts: concanavalin (Ara h 1), allergen II (Ara h 2), peanut lectin, concanavalin (Ara h 6); from apple: 31kda major allergen/antiviral protein homologue (Mal D2), lipid transfer protein precursor (Mal D3), major allergen Mal D1.03D (Mal D1); from milk: alpha-lactalbumin (ALA), lactoferrin; from kiwi fruit: actinidin (Act c 1, act d 1), plant cystatin, kiwi protein-like protein (Act d 2), kiwilin (kiwellin) (Act d 5); from mustard: 2S albumin (Sin a 1), 11S globulin (Sin a 2), lipid transfer protein (Sin a 3), profilin (Sin a 4); from celery: an inhibitor protein (Api g 4), a high molecular weight glycoprotein (Api g 5); from shrimp: pen a 1 allergen (Pen a 1), allergen Pen m 2 (Pen in 2), tropomyosin rapid isoforms; from wheat and/or other grains: high molecular weight glutenins, low molecular weight glutenins, alpha-and gamma-gliadins, hordeins, secalins and avenins; from strawberry: main strawberry allergy Fra a 1-E (Fra a 1), from banana: inhibitor protein (musxp 1).
D. Immunomodulators
The particles may comprise one or more immunomodulators, immunosuppressants or immunostimulants comprising regulatory T cells. Immunosuppressants are known in the art and comprise glucocorticoids, cytostatics (such as alkylating agents, antimetabolites and cytotoxic antibodies), antibodies (such as antibodies to T cell receptors or 11-2 receptors), drugs acting on immunophilins (such as cyclosporin, tacrolimus and sirolimus) and other drugs (such as interferons, opioids, TNF binding proteins, mycophenolate and other small molecules such as fingolimod). Immunosuppressants include, but are not limited to FK506, prednisone, methylprednisolone, cyclophosphamide, thalidomide, azathioprine and daclizumab, physalin B, physalin F, physalin G, purified split steroids from physalin, 15-deoxyspergualin, MMF, rapamycin and its derivatives, CCI-779, FR 900520, FR 900523, NK86-1086, depsipeptide mycin, kang Le Meisu-C, spegulin, lingcin 25-C, carbomycin (cammunomicin), demethomycin, tetramycin, tranilast (tranilast), stent (stevantelins), myricetin, gliotoxin, FR 651814, SDZ214-104, bricillin, WS9482, mycophenolic acid, polymyxin mizoribine, misoprost, OKT3, anti-IL-2 receptor antibody, azasporine, leflunomide, mizoribine, azaspirane, paclitaxel, octreotide, busulfan, chlorambucil, ifosfamide, mechlorethamine, melphalane, thiophanan, thiotepa, fluxuridine, gemcitabine, thiotepa, prastatin, methotrexate, 6-mercaptopurine, and azastatin, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, isoplatin, tetraclatin, lobaplatin, JM216, 335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate (megestrol acetate), cyproterone acetate (cyproterone acetate), tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, bleomycin, fludarabine, leuprolide, and cyproterone acetate (cyproterone acetate) dacarbazine (dactinomycin), daunorubicin (daunorubicin), doxorubicin (doxorubicin), idarubicin (idarubicin), mitoxantrone (mitoxantrone), rosemary (losoxantrone), mitomycin-c, prazizanol (paclitaxel), docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), 9-aminocamptothecin, 9-nitrocamptothecin, GS-211, etoposide (etoposide), teniposide (teniposide), vinorelbine (vinorelbine), procarbazine (procarbazine), asparaginase, aspartic acid, octreotide (octreotide), estramustine (estramustine) and hydroxyurea.
As used herein, the term "rapamycin compound" encompasses the neutral tricyclic compounds rapamycin, rapamycin derivatives, rapamycin analogs, and other macrolide compounds that are believed to have the same mechanism of action as rapamycin (e.g., inhibition of cytokine function). The term "rapamycin compound" encompasses compounds having structural similarity to rapamycin, e.g., compounds having a similar macrocyclic structure, which have been modified to enhance their therapeutic effect. Exemplary rapamycin compounds and other methods of administering rapamycin are known in the art (see, e.g., WO 95/22972, WO 95/16691, WO 95/04738, U.S. Pat. No. 6,015,809; 5,989,591; 5,567,709; 5,559,112; 5,530,006; 5,484,790; 5,385,908; 5,202,332; 5,162,333; 5,780,462; 5,120,727). Rapamycin analogues include, for example, everolimus, ridaforolimus (ridaforolimus), lei Xiluo limus, lamimus and zotarolimus. The following agents may be used in combination with an antigen and an immunosuppressant such as rapamycin, alone or in combination with an antigen that does not contain an immunosuppressant for immunomodulation. In one embodiment, the immunosuppressant is a TNF- α blocker. In another embodiment, the immunosuppressant increases the amount of adenosine in the serum, see for example WO 08/147482.
The composition may be used in combination or in succession with a compound that increases Treg activity or yield. Exemplary Treg enhancers include, but are not limited to, the glucocorticoids fluticasone, salmeterol, antibodies to IL-12, IFN- γ and IL-4; vitamin D3 and dexamethasone, and combinations thereof. These compounds may increase or promote the activity of tregs, increase the production of cytokines such as IL-10 by tregs, increase the differentiation of tregs, increase the number of tregs, or increase the survival of tregs. See also U.S. published application 2012/0276095.
Antibodies, small molecules, and other compounds that reduce the biological activity of pro-inflammatory cytokines may also be used. In some embodiments, these compounds reduce the biological activity of IL-1, IL-6, IL-8, TNF- α (tumor necrosis factor α), TNF- β (lymphotoxin α, LT), or a combination thereof.
Another major class in biology is Tumor Necrosis Factor (TNF) blockers, which combat high levels of inflammatory proteins. The most widely used are etanercept (Enbrel), infliximab (infliximab) (like gram (Remicade)) and adalimumab (adalimumab) (trimara). Another group of promising interleukin-1 (IL-1) blockers, such as anakinra (Kineret).
In some embodiments, the agent is an anti-inflammatory cytokine or chemokine, such as transforming growth factor-beta (TGF-beta), interleukin (IL) -l receptor antagonist, IL-4, IL-6, IL-10, IL-11, and IL-13. Specific cytokine receptors for IL-1, tumor necrosis factor-alpha and IL-18 also act as pro-inflammatory cytokine inhibitors. The properties of anti-inflammatory cytokines and soluble cytokine receptors are known in the art and are described in Opal and DePalo, chest 117 (4): 1162-72 (2000).
Retinoic acid is another therapeutic compound that may be used as an anti-inflammatory agent. See, for example, capurso et al, self/non-Self (Self/Nonself), 1:4,335-340 (2010).
Mycophenolate Mofetil (MMF) and mycophenolic acid (MPA), the active metabolites thereof, are very potent immunosuppressants. MMF has been used to treat autoimmune and inflammatory skin disorders. Lipsky, lancet 348:L1357-1359 (1996) and has become a valuable therapeutic option for children with autoimmune diseases. Filler et al, 8:1 (2010) Pediatric rheumatology (Pediatric Rheumatoid.). Mycophenolic acid (MPA) is a relatively new adjuvant drug that selectively inhibits T and B lymphocyte proliferation by re-inhibiting purine synthesis. Other steroid-sparing immunosuppressants include azathioprine, methotrexate, and cyclophosphamide.
MPA is an active form of mycophenolate mofetil, which is currently used as an immunosuppressant for the treatment of lupus and other autoimmune diseases in humans (Ginzler et al, J Engl J Med, new England, 353 (21): 2219-28 (2005)). MPA has a broad immunosuppressive effect on several immune cell types. MPA blocks the de novo synthesis pathway of guanine nucleotides. T and B cell proliferation are severely impaired by MPA because these cells lack biosynthetic salvage pathways that can avoid the production of damaged neonatal guanine (Jonsson et al, clinical and experimental immunology (Clin Exp Immunol.) 124 (3) 486-91 (2001), quemeeur et al, J Immunol. 169 (5) 2747-55 (2002), jonsson et al, international immunopharmacol (Int Immunopharmacol), 3 (l) 31-7 (2003), and Karnel et al, journal of immunology 187 (7) 3603-12 (2011) furthermore, MPA can impair the activation of dendritic cells and its stimulated alloantigen responses (Mehling et al), 165 (5) 2374-81 (2000), lagaraine et al, international immunopharmacol, 17 (4) 351-63 (2005), wanec et al, lca (2005) and human biological journal of 4 (35) can be assigned a biological factor of biological resistance values (e.g., lv. 35, lv. In. 35 (35) in the same manner as in the journal of human clinical laboratory, E.J.3-12 (2011) and E.J.p.m.p.p.p.p.E.m., 859 (2):276-81 (2007)).
An immunosuppressant may be any small molecule that inhibits immune system function or increases susceptibility to infectious diseases. In certain embodiments, the immunosuppressant is a T cell proliferation inhibitor, a B cell proliferation inhibitor, or a T cell and B cell proliferation inhibitor. In certain embodiments, the T cell or B cell proliferation inhibitor inhibits or modulates guanine monophosphate synthesis. For example, the immunosuppressant may be mycophenolic acid.
Alternatively, the immunosuppressant is a prodrug of mycophenolic acid, including but not limited to mycophenolate esters (commercially available from Swedish company F. Hoffmann-La Roche Ltd., swedish company, inc.)Sales).
Salts of immunosuppressants may also be used, such as salts of mycophenolic acid including, but not limited to, sodium mycophenolate (sold under the trade name Novartis by Novartis)Sales). In some embodiments, the immunosuppressant is a purine analog, including but not limited to azathioprine (to include the amino acids expressed by Salix alba (Salix) to +.>And by the company Glaxo (Glaxo)SmithKline) to +.>Sold under the trade names of (a) or mercaptopurine (sold under the trade name +.>Sales (mercaptopurine)). In some embodiments, the immunosuppressant is an antimetabolite that inhibits the use and/or synthesis of a purine, such as a purine nucleoside phosphorylase inhibitor.
Additionally or alternatively, anti-inflammatory agents may be used. The anti-inflammatory agent may be a non-steroid, a steroid, or a combination thereof. Representative examples of non-steroidal anti-inflammatory agents include, but are not limited to, oxicams (oxicam), such as piroxicam (piroxicam), isoxicam (isoxicam), tenoxicam (tenoxicam), sudoxicam (sudoxicam); salicylates, such as aspirin (aspirin), bissalicylic acid, benorilate (benorilate), trisalicylate, salfapraline (safapryn), sorpraline (solprin), diflunisal and Fender willow; acetic acid derivatives such as diclofenac (dichlofenac), diclofenac (fenloconac), indomethacin (indomethacin), sulindac (sulindac), tolmetin (tolmetin), isopipacane (isoxepa), furanphenolic acid (furofonac), thiapipacane (tiopinac), zidometacin (zidometacin), acemetacin (aceatacin), fentizac, zomefenac (zomepirac), gram Lin Shansuan (clindanac), oxepinic acid (oxepinic), felbinac, and ketorolac; fenamic acid salts such as mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid; propionic acid derivatives such as ibuprofen (ibuprofen), naproxen (naproxen), benoxaprofen (benoxaprofen), flurbiprofen (flurbiprofen), ketoprofen (ketoprofen), fenoprofen (fenoprofen), fenbufen (fenbufen), indomethacin (indoprofen), pirprofen (pirprofen), carprofen (carprofen), oxaprozin (oxaprozin), praprofen (pranoprofen), mi Luofen (miroprofen), thiooxaprofen (tioxaprofen), suprofen (suprofen), amoprofen (alminoprofen) and thiaprofen (tiaprofen); pyrazoles (pyrazole) such as phenylbutazone, hydroxyphenylbutazone, nonproprione, azapropanone and triazolone. Mixtures of these non-steroidal anti-inflammatory agents may also be employed.
Representative examples of steroidal anti-inflammatory drugs include, but are not limited to, corticosteroids such as hydrocortisone (hydroortisone), hydroxytriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionate (beclomethasone), dipropionate (diprionate), clobetasol valerate (clobetasol valerate), desonide (desonide), desobetamethasone (desoxymethyl) acetate, deoxycorticosterone (desoxycorticosterone acetate), dexamethasone (desomethasone), dichlorotriamcinolone (dichloromethyl), diflupresone (diflorasone diacetate), difluosal valerate (diflucortolone valerate), fludrolone (fludrolone), fludrolone (fluclorolone acetonide), fludrocortisone (393), terfenazone (2), fluocinolone acetate (fluosinolone acetonide), fluocinolone (fluocinolone) and flubutyl acetate (desonide), desoxymethasone (desoxymethyl), difluozone (43), fludrolone (35), fludrolone (43), fludrolone (prednisone (7452), fludrolone (43), fludrolone (prednisone (7452), fludrolone (prednisone) and fludrolone (fluclorolone acetonide) Fludrocortisone (fludrocortisone), (diflurosone diacetate), difluocortisone diacetate (fluradrenolone acetonide), meflozone (medysone), amprenavine (amicinafel), amprenavide (amicinafide), betamethasone (betamethasone) and its ester balance, methylprednisone (chloroprednisone), methylprednisone acetate (chlorprednisone acetate), clocortolone (clodronate), chloro Xin Nuolong, (clecinolone), dichloropine (dichlorsonne), difluprednate (difluprednate), fludrolone (fludrolide), ai Fulong (fludrolone), fludrolone (fludronate), hydrocortisone acetate (hydrocortisone valerate), hydrocortisone (35 67), hydrocortisone (hydrogen carbonate), fludronate (fludronate), and prednisolone (fludronate), and mixtures thereof.
More commonly used corticosteroids include prednisolone, hydrocortisone, methylprednisolone, dexamethasone, cortisone, triamcinolone acetonide, and betamethasone.
E. Targeting moiety
In some embodiments, one or more targeting moieties (also referred to herein as targeting molecules and targeting signals) may be loaded onto, attached to, and/or enclosed within the surface of the particle. These are generally not necessary. Exemplary target molecules include proteins, peptides, nucleic acids, lipids, carbohydrates or polysaccharides that bind to one or more targets associated with the tissue, cells or extracellular matrix of the liver. Preferably, the targeting moiety is displayed on the outer surface of the particle, and preferably is conjugated to the outer surface of the particle. Preferably, the targeting moiety increases or enhances targeting of the particle to the liver or tissues or cells thereof (including hepatocytes and endothelial cells).
The surface of the particles can be engineered using various techniques, such as covalent attachment of molecules (ligands) to nanosystems (polymers or lipids) (Tosi et al, san diego neuroscience (SfN Neurosci San Diego) (U.S. a), 1:84 (2010)).
The degree of specificity targeted by the particles can be modulated by selecting targeting molecules with the appropriate affinity and specificity. For example, antibodies are very specific. These may be polyclonal, monoclonal fragments, recombinant or single stranded, many of which are commercially available or readily available using standard techniques. The targeting molecule may be conjugated to the end of one or more PEG chains present on the surface of the particle.
In some embodiments, the targeting moiety is an antibody or antigen binding fragment thereof that specifically recognizes a liver cell or tissue marker. Fragments are preferred because antibodies are very large and can be limited in diffusion through tissues. Suitable targeting molecules that can be used to direct the particles to cells and tissues of interest and methods of conjugating target molecules to nanoparticles are known in the art.
A particularly preferred target is dec205+. The DEC205+ cell receptor (DEC 205) at 205kDa m.w. (Ring et al J.Immunol. 10.4049/jimmunol.1202592 (page 11) (2013)). It is expressed by epithelial cells and Dendritic Cells (DCs) and promotes antigen presentation. Compositions for targeting dec205+ are known in the art and comprise, for example, anti-dec205+ antibodies and fragments and fusions thereof (see, e.g., silva-Sanchez, public science library-complex (PLoS ONE) 10 (4): e0124828.Doi:10.1371/joumal. Fine. 0124528; spring et al, J.Immunol. 194 (10): 4804-13 (2015): doi:10.4049/jimmunol.1400986, electronic edition 2015, 4 month 10). It is believed that nanoparticles targeting DEC205 utilize DEC 205-mediated endocytosis into target cells, which reduces their ability to activate antigen-specific CD 4T cells. DCs that ingest antigen through DEC205 are known to cross exist through class I MHC, which may promote CD 8T cell depletion tolerance in autoimmune diabetes and EAE mouse models.
In some embodiments, the density of the targeting ligand is adjusted to modulate the tolerance-inducing effect of the vector.
F. Pharmaceutical composition dosage unit
Nanoparticles may be formulated in liquid or solid form for oral administration as single or multiple dose units.
For ease of administration and uniformity of dosage, the compositions are typically formulated in dosage unit form. However, it will be appreciated that the total daily amount of the composition will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular active ingredient employed; the specific composition employed; age, body weight, general health, sex, and diet of the subject; the time of administration, the route of administration and the rate of excretion of the particular active ingredient employed; duration of treatment; a medicament for use in combination or simultaneously with the particular active ingredient employed; as well as other factors well known in the medical arts.
In certain embodiments, the dosage unit contains PBA nanoparticles encapsulating between about 1 microgram/kg and 5 grams/kg of total dose of active agent and/or imaging agent, based on the species, route of administration, number of doses, and condition to be treated. Representative ranges include from 0.001mg/kg to about 1000mg/kg, from about 0.01mg/kg to about 500mg/kg, from about 0.1mg/kg to about 500mg/kg, from about 0.5mg/kg to about 500mg/kg, from about 1mg/kg to about 5000mg/kg, from about 0.1mg/kg to about 100mg/kg, or from about 1mg/kg to about 100mg/kg of subject body weight per day, one or more times per day, to achieve the desired therapeutic effect. The desired dose may be delivered three times a day, twice a day, once a day, every other day, weekly, biweekly, every three weeks, or every four weeks. In certain embodiments, multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, twelve, thirteen, fourteen or more administrations) may be used to deliver the desired dose.
Excipient
Nanoparticles may be formulated in liquid or solid form for oral administration as single or multiple dose units.
The effective dose may depend on the concentration of the excipient and the manner in which it is added. TGR5 activation results in anti-inflammatory immunity, anti-fibrotic activity, induction and secretion of enteroendocrine L-cell GLP-1 and an increase in energy expenditure of adipose tissue 32. pUDCA can not only significantly reduce the dose, but also expand the range of action of UDCA, since its monomeric counterpart UDCA is an intrinsically weaker TGR5 agonist.
For ease of administration and uniformity of dosage, the compositions are typically formulated in dosage unit form. However, it will be appreciated that the total daily amount of the composition will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular active ingredient employed; the specific composition employed; age, body weight, general health, sex, and diet of the subject; the time of administration, the route of administration and the rate of excretion of the particular active ingredient employed; duration of treatment; a medicament for use in combination or simultaneously with the particular active ingredient employed; as well as other factors well known in the medical arts.
Excipients and/or carriers may be selected based on the dosage form to be administered, the active agent to be delivered, and the like. Suitable excipients include surfactants, emulsifiers, emulsion stabilizers, antioxidants, emollients, humectants, chelating agents, suspending agents, thickeners, occlusion agents, preservatives, stabilizers, pH adjusting agents, solubilizing agents, solvents, flavoring agents, coloring agents and other excipients. As used herein, "excipient" does not include any bile acid or polymer thereof.
Suitable emulsifiers include, but are not limited to, linear or branched fatty acids, polyoxyethylene sorbitan fatty acid esters, propylene glycol stearates, glyceryl stearate, polyethylene glycols, fatty alcohols, polymeric ethylene oxide-propylene oxide block copolymers, and combinations thereof.
Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants.
Suitable suspending agents include, but are not limited to, alginic acid, bentonite, carbomers, carboxymethyl cellulose and salts thereof, colloidal oatmeal, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, triglycerides, methyl cellulose, polyoxyethylene fatty acid esters, polyvinylpyrrolidone, propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, tragacanth, and combinations thereof.
Suitable antioxidants include, but are not limited to, butylated hydroxytoluene, alpha tocopherol, ascorbic acid, fumaric acid, malic acid, butylated hydroxyanisole, propyl gallate, sodium ascorbate, sodium metabisulfite, ascorbyl palmitate, ascorbyl acetate, ascorbyl phosphate, vitamin a, folic acid, flavone or flavonoid, histidine, glycine, tyrosine, tryptophan, carotenoids, carotenes, alpha-carotene, beta-carotene, uric acid, pharmaceutically acceptable salts thereof, derivatives thereof, and combinations thereof.
Suitable chelating agents include, but are not limited to, EDTA and combinations thereof.
Suitable humectants include, but are not limited to, glycerin, butylene glycol, propylene glycol, sorbitol, triacetin, and combinations thereof.
Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenethyl alcohol, thimerosal, and combinations thereof.
Excipients may include suspending agents, such as sterile water, phosphate buffered saline, or non-aqueous solutions such as glycerol.
The particles may be provided in dry powder form after spray drying or freeze drying.
The granules can be compressed into tablets, for exampleTo prevent release of the particles after passage through the stomach.
The particles may also be encapsulated in a hard gel or a soft gel, such as gelatin and alginate capsules as sold by banna pharmaceutical company (Banner Pharmaceuticals) and enteric soft capsules.
The particles may also be formulated for mucosal surface administration, such as oral, nasal, oral, pulmonary, rectal or vaginal surfaces.
The particles may also be provided in a kit wherein the material to be delivered is provided separately from the dosage units and then combined in powder or dry form or in solution prior to use. The drug to be delivered may be entrapped, encapsulated or chemically or physically bound to the bile salt polymer.
And III, a method for preparing the nano particles.
The pUDCA nanoparticles described herein can be prepared by a variety of methods. The following is a representative method.
A. Solvent evaporation microencapsulation
In solvent evaporation microencapsulation, the polymer is typically dissolved in a water-immiscible organic solvent, and the material to be encapsulated is added to the polymer solution as a suspension or solution in the organic solvent. An emulsion is formed by adding this suspension or solution to a beaker of vigorously stirred water (typically containing a surfactant, such as polyethylene glycol or polyvinyl alcohol, to stabilize the emulsion). The organic solvent was evaporated while stirring was continued. Evaporation causes precipitation of the polymer, forming solid nanoparticles containing the core material.
The polymer or copolymer is dissolved in a miscible mixture of solvent and non-solvent at a concentration just below that which would result in phase separation (i.e., cloud point). The liquid core material is added to the solution while stirring to form an emulsion and disperse the material into droplets. The solvent and non-solvent are evaporated, wherein the solvent evaporates at a faster rate, causing the polymer or copolymer to phase separate and migrate towards the surface of the core material droplets. This phase separated solution is then transferred to a stirred volume of non-solvent to precipitate any residual dissolved polymer or copolymer and extract any residual solvent from the formed film. The result is a nanoparticle consisting of a polymer or copolymer shell and a core of liquid material.
In solvent-removal microencapsulation, the polymer is typically dissolved in an oil-miscible organic solvent, and the material to be encapsulated is added to the polymer solution as a suspension or solution in the organic solvent. Surfactants may be added to improve the dispersion of the material to be encapsulated. An emulsion is formed by adding this suspension or solution to a vigorously stirred oil, where the oil is a non-solvent for the polymer and the polymer/solvent solution is not miscible in the oil. While continuing to stir, the organic solvent is removed by diffusion into the oil phase. Removal of the solvent causes precipitation of the polymer, forming solid particles containing the core material.
B. Phase separation microencapsulation
In phase separation microencapsulation, the material to be encapsulated is dispersed in the polymer solution with stirring. While continuing to stir to uniformly suspend the material, a non-solvent for the polymer is slowly added to the solution to reduce the solubility of the polymer. Depending on the solubility of the polymer in the solvent and non-solvent, the polymer precipitates or phase separates into a polymer-rich phase and a polymer-lean phase. Under the appropriate conditions, the polymer in the polymer-rich phase will migrate to the interface with the continuous phase, encapsulating the core material in droplets with the outer polymer shell.
C. Spontaneous emulsification
Spontaneous emulsification involves curing emulsified liquid polymer droplets by changing temperature, evaporating solvent, or adding chemical cross-linking agents. The physical and chemical properties of the encapsulant and the material to be encapsulated determine the appropriate encapsulation method. Factors such as hydrophobicity, molecular weight, chemical stability, and thermal stability can affect encapsulation.
D. Agglomeration
In the prior art, for example, in GB-B-929 406; GB-B-929 401; U.S. patent No. 3,266,987; 4,794,000; and 4,460,563, a procedure for encapsulating various substances using coacervation techniques has been described. Coagulation is a process involving separation of a colloidal solution into two or more immiscible liquid layers (Dowben, r. (n.) general physiology (General Physiology), haper & Row, new York, 1969, pages 142-143). By the coacervation process, a composition comprising two or more phases and referred to as coacervate can be produced. The component comprising a two-phase coacervate system is present in both phases; however, the rich colloid has a higher concentration of components than the lean colloid phase.
E. Spray drying
In this method, the polymer is dissolved in an organic solvent. A known amount of active drug is suspended (insoluble drug) or co-dissolved (soluble drug) in the polymer solution. The solution or dispersion is then spray dried. Typical processing parameters for a small spray dryer (Buchi) are as follows: polymer concentration = 0.04g/mL, inlet temperature = -24 ℃, outlet temperature = -13-15 ℃, aspirator setting = 15, pump setting = 10 mL/min, spray flow = 600 Nl/hour, nozzle diameter = 0.5mm. Particles in the range of 1-10 microns are obtained, the morphology of which depends on the type of polymer used.
F. Fluorine mediated supramolecular assembly
Fluorinated bile acid units (linear or branched) can be synthesized by reacting terminal carboxylic acid esters or hydroxyl groups with Alkyl Fluoroanhydrides (AFAA). The product can be extracted into water, causing a fluorophilic effect in which spontaneous aggregation of fluorinated building blocks preferentially occurs, unlike a hydrophobic effect. Such assembly depends on the thermal energy, the degree of fluorination, enabling some thermodynamic and kinetic control of the final morphology. Phosphor-mediated self-assembly will provide cohesion for aggregation and can be an inherently imageable system by 19F NMR. Fluorinated bile acids will also have significantly different biodistribution and clearance times, which may help increase the residence time of the system in the GI tract or pancreatic region.
IV, using method:
A. route of administration
These particles are preferably administered orally and exhibit enhanced uptake by target organs such as pancreas, liver or colon. Oral administration may be achieved by oral gavage or by swallowing a composition in liquid or solid form. The liquid form of the orally administered composition may be in the form of a solution or a liquid gel. Solid forms of compositions for oral administration may be in the form of capsules, soft and hard gels, tablets, pills, powders and granules.
Although described with reference to oral administration, it is understood that the same delivery may be achieved by delivery to mucosal surfaces such as the oral cavity, nasal cavity, lung, rectum or vagina, or by intravenous (i.v.) injection.
The desired dose may be delivered orally once a day, or multiple times a day. For example, the desired dose may be delivered orally three times a day, twice a day, once a day, every other day, weekly, every other week, every third week, or every fourth week. In certain embodiments, multiple daily administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, twelve, thirteen, fourteen or more administrations) may be used to deliver the desired dose.
B. Disorders to be treated
Methods of preventing, inhibiting, or treating a disease or condition may comprise administering to a subject in need thereof an oral dosage unit containing a pharmaceutical composition comprising non-targeted PBA nanoparticles encapsulating one or more agents; optionally delivering an effective amount of one or more agents to a targeted tissue, such as the pancreas, liver, or colon; wherein the agent is released from the PBA nanoparticles at the target tissue, resulting in the prevention, inhibition or treatment of the disease.
These formulations are particularly useful for treating tumors of the colon, liver, spleen, pancreas or adjacent regions. These formulations are also well suited for the treatment of gastrointestinal disorders, including ulcers, irritable Bowel Disease (IBD) and colon cancer. These formulations are useful for the treatment of inflammatory, autoimmune and allergic diseases. These formulations are also effective in treating diseases such as diabetes.
1. Autoimmune and inflammatory diseases and conditions
It is to be understood that the compositions and methods disclosed herein have a wide range of applications, including but not limited to the treatment of autoimmune diseases, the treatment of transplant rejection, adjuvants for enhancing immunosuppressive function, and cell therapies involving tregs or tolerogenic DCs.
In some embodiments, these compositions and methods are used to treat chronic and persistent inflammation, which may be the primary cause of pathogenesis and progression of autoimmune diseases or inflammatory conditions. Thus, methods of treating inflammatory and autoimmune diseases and disorders may comprise administering to a subject in need thereof an effective amount of a particulate formulation or pharmaceutical composition thereof to alleviate or ameliorate one or more symptoms of the disease or condition. Some applications are discussed in more detail below.
Representative inflammatory or autoimmune diseases and conditions that can be treated using the disclosed compositions and methods include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (alps), autoimmune Thrombocytopenic Purpura (ATP), behcet's disease, bullous pemphigoid, cardiomyopathy, celiac dermatitis, chronic fatigue syndrome, immunodeficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, condensed set disease, crohn's disease Dego's disease), dermatomyositis, juvenile dermatomyositis, discoid lupus, primary mixed cryoglobulinemia, fibromyalgia-fibromyositis, graves ' disease, guillain-barre syndrome, hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic Thrombocytopenic Purpura (ITP), igA nephropathy, insulin dependent diabetes mellitus (type I), juvenile arthritis, meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis syndrome, polymyositis rheumatica, polymyositis and dermatomyositis, primary agarop globulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon (rayn's phenomenons), lyter's syndrome, rheumatic fever, sarcoidosis, scleroderma, sjogren's syndrome, stiff person syndrome, takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo and Wegener's granulomatosis.
2. Inhibiting epitope diffusion
Epitope spreading refers to the ability of B and T cell immune responses to be diversified at the level of specificity (from a single determinant to many sites on self-antigens) and at the level of V gene usage (Monneaux, F. Et al, arthritis and Rheumatism (Arthritis & Rheumatoid), 46 (6): 1430-1438 (2002)). Epitope spreading is not limited to systemic autoimmune diseases. Have been described in T cell dependent organ specific diseases such as IDDM and multiple sclerosis in humans and EAE experimental animals induced with various myelin proteins.
Epitope diffusion involves the acquired recognition of a neoepitope in the same self molecule and an epitope in a related protein residing in the same macromolecular complex. Epitope spreading can be assessed by measuring Delayed Type Hypersensitivity (DTH), methods of which are known in the art.
Thus, in some embodiments, a method for inhibiting or reducing epitope spreading in a subject comprises administering to the subject an effective amount of a nanocarrier. In a preferred embodiment, the particle formulation inhibits epitope spreading in an individual with multiple sclerosis.
3. Allergy to humans
Similar methods can be used to treat allergies, substituting the allergen of interest for autoimmune stimulation. Typically, the particles are administered to the subject in an amount effective to reduce or inhibit the allergy or allergic response.
Allergy is an abnormal reaction of the immune system in response to otherwise harmless substances. Allergy is one of the most common medical conditions. It is estimated that 6000 ten thousand americans, or more than one fifth, suffer from some form of allergy, with similar proportions in the rest of the world. Allergy is the biggest cause of the open class and is also the main cause of the decline of productivity in workplaces.
Allergy is a type of immune response. Typically, the immune system responds to foreign microorganisms or particles by producing specific proteins called antibodies. These antibodies are capable of binding to recognition molecules or antigens on foreign particles. This reaction between antibodies and antigens initiates a series of chemical reactions that aim to protect the body from infection. Sometimes, this same series of reactions is caused by innocuous daily substances such as pollen, dust and animal dander. When this occurs, the allergy is directed to an offensive substance (allergen).
Mast cells are one of the major participants in allergic reactions, and capture and display a specific type of antibody that binds to allergens, known as type E immunoglobulins (IgE). Inside the mast cells is a small chemical filled package, called a pellet. The particles contain a variety of potent chemicals, including histamine.
Immunologists divide allergic reactions into two main types: immediate hypersensitivity reactions, mediated primarily by mast cells, occur within minutes after exposure to allergens; and delayed type hypersensitivity mediated by T cells (an leukocyte) occurs within hours to days after exposure.
Inhaled or ingested allergens often cause immediate allergic reactions. The allergen binds to IgE antibodies on the surface of mast cells that spill the contents of their granules into adjacent cells, including blood vessels and nerve cells. Histamine binds to the surface of these other cells via a specific protein called the histamine receptor. The interaction of histamine with receptors on blood vessels causes increased leakage, resulting in increased fluid collection, swelling and redness. Histamine also stimulates pain receptors, making the tissue more sensitive and allergic. Symptoms last for one to several hours after contact. In the upper respiratory tract and eyes, immediate hypersensitivity reactions can lead to runny nose and itching, and congestion of the eyes, which are typical symptoms of allergic rhinitis. In the gastrointestinal tract, these reactions lead to swelling and inflammation of the intestinal wall, causing cramps and diarrhea, which are typical of food allergies. Allergens entering the circulation may cause urticaria, angioedema, allergic reactions or atopic dermatitis.
Allergens on the skin typically cause delayed hypersensitivity reactions. The mobilized T cells contact the allergen, initiating an extended immune response. This type of allergic response may occur within days after exposure to the allergen and symptoms may last for a week or more.
Allergens enter the human body through four main pathways: airway, skin, gastrointestinal tract, and circulatory system. Airborne allergens can cause hay fever (allergic rhinitis) causing sneezing, runny nose and itchy eyes with congestion. Airborne allergens can also affect the membranes of the lungs, leading to asthma or conjunctivitis (pinkeye). Contact cockroach allergens are associated with the development of asthma. Airborne allergens from domestic pets are another common source of environmental exposure. Allergens in the food can cause itching, swelling, cramping and diarrhea in the lips and throat. When absorbed into the blood, they may cause urticaria or a more severe response involving recurrent non-inflammatory swelling of the skin, mucous membranes, organs and brain (angioedema). Some food allergens may cause allergic reactions, a potentially life threatening disease manifested by swelling of tissues, airway constriction and blood pressure drop. Allergy to foods such as milk, eggs, nuts, fish and beans (peanuts and soybeans) is common. Allergy to fruits and vegetables may also occur. Upon contact with the skin, allergens cause reddening, itching and foaming of the skin, known as contact dermatitis. Skin reactions may also be caused by allergens introduced through the airways or gastrointestinal tract. This type of reaction is known as atopic dermatitis. Dermatitis may be caused by allergic dermatitis, which may be caused by allergic reactions (e.g., poison ivy), or exposure to irritants (e.g., soaps, colds, and chemicals) that cause non-immune damage to skin cells. Allergen injections from insect bites or drug administration can introduce allergens directly into the circulation where they can cause systemic responses (including allergic reactions), as well as localized swelling and irritation of the injection site.
These may be treated by administration of anti-inflammatory agents or by inducing tolerance to antigens, as discussed in more detail below.
4. Diabetes mellitus
Diabetes (diabetes) or diabetes (diabetes mellitus) is due to insufficient insulin production by the pancreas or the inability of cells of the body to respond appropriately to the insulin produced. There are three main types of diabetes:
type 1 diabetes is due to the inability of the pancreas to produce sufficient insulin or active insulin; this form was previously referred to as "insulin dependent diabetes mellitus" (IDDM) or "juvenile diabetes",
type 2 diabetes begins with insulin resistance, a condition in which cells fail to respond appropriately to insulin. Insulin deficiency may also occur as the disease progresses; this form has previously been referred to as "non-insulin dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes.
Gestational diabetes is the third major form, which occurs when pregnant women without a history of diabetes develop high blood glucose levels.
Type 1 diabetes must be managed by insulin injection. Type 2 diabetes can be treated with insulin-containing or insulin-free drugs. Gestational diabetes generally disappears after birth of the infant.
People with type 1 diabetes require insulin therapy to survive. Insulin therapy is also required for many people with type 2 diabetes or gestational diabetes. Medicaments for the treatment of T2D include 20 or more insulin injections and orally administered medicaments such as meglitinides (meglitinides), sulfonylureas (sulfourea), metformin (metaformin), canagliflozin (canaglizin), dapagliflozin (dapagliflozin), thiazolidinediones (thiazolizidine), pioglitazone (pioglitazone), rosiglitazone (rosiglitazone), acarbose (acarbose), pramlintides (pramlintide), exenatide (exenatide), liraglutide (liraglutide), long acting exenatide, albiclutide (albiclutide), dullupeptide (dulaglutinide) and dipeptidyl peptidase-4 (DPP-IV) inhibitors (sitagliptin), saxagliptin (saxagliptin). These agents are collectively referred to as "antidiabetics".
These compositions can be used to treat inflammation of the pancreas (pancreatitis), liver (hepatitis), or colon (IBD). In contrast to biological agents or small molecule drugs (1-10 nm), PBA nanoparticles encapsulating therapeutic and/or imaging agents can pass through fenestrated vasculature of inflamed tissue and remain in inflamed tissue for a longer period of time due to their size. They are also efficiently internalized by antigen presenting cells (such as macrophages and dendritic cells), making PBA nanoparticles suitable for delivering agents to cells of the inflamed tissue and immune system.
Both forms of pancreatitis, acute and chronic pancreatitis, can be treated by oral administration of a PBA composition.
Acute pancreatitis is a sudden inflammation of short duration. It can range from slight discomfort to severe life threatening. In severe cases, acute pancreatitis can lead to gland bleeding, severe tissue damage, infection, and cyst formation. Severe pancreatitis also damages other vital organs such as the heart, lungs and kidneys.
Chronic pancreatitis is a long-term inflammation of the pancreas. It most often occurs after the onset of acute pancreatitis. High volume drinking is another major cause. Damage to the pancreas from high volume drinking may not cause symptoms for many years, but the subject may then suddenly develop severe pancreatitis symptoms. Patients with acute pancreatitis receive IV fluid and analgesic treatment at hospitals. Chronic pancreatitis can be difficult to treat. It is directed to pain relief and nutrition improvement. The subject is typically administered pancreatin or insulin.
Liver inflammation (hepatitis) is characterized by the presence of inflammatory cells in the tissues of organs. Hepatitis may present with limited or no symptoms, but often results in jaundice (yellowing of skin, mucous membranes and conjunctiva), loss of appetite and discomfort. Hepatitis is acute when it lasts less than six months and chronic when it lasts for a long period of time.
Acute hepatitis may be self-limiting (self-healing), may progress to chronic hepatitis, or, in rare cases, may cause acute liver failure. Chronic hepatitis may be asymptomatic or may develop over time into fibrosis (scarring of the liver) and cirrhosis (chronic liver failure). Cirrhosis of the liver increases the risk of hepatocellular carcinoma.
Viral hepatitis is the most common cause of liver inflammation. Other causes include autoimmune diseases and ingestion of toxic substances, in particular alcohol, certain drugs such as paracetamol, some industrial organic solvents and plants. Antiretroviral drugs such as tenofovir (tenofovir) and entecavir (entecoavir) are used to treat chronic hepatitis b.
5. Inflammatory bowel disease:
inflammatory Bowel Disease (IBD) is a broad term describing a condition with a chronic or recurrent immune response and inflammation of the gastrointestinal tract. The two most common inflammatory bowel diseases are ulcerative colitis and Crohn's disease. In crohn's disease, inflammation affects the entire digestive tract, and in ulcerative colitis, inflammation affects only the large intestine. Both diseases are characterized by an abnormal response to the body's immune system.
Crohn's disease is treated with drugs designed to suppress the abnormal inflammatory response of the immune system causing symptoms. Inhibiting inflammation can alleviate common symptoms such as fever, diarrhea and pain, and is helpful for healing intestinal tissues. The combination therapy may comprise adding a biologic to the immunomodulator. As with all therapies, combination therapies are both at risk and beneficial. Combining drugs with immunomodulatory therapies may increase the effectiveness of IBD treatment.
Examples of agents for treating symptoms of IBD include, but are not limited to, sulfasalazine (sulfasalazine), mesalamine (mesalamine), olsalazine (olsalazine), and balsalazide (balsalazide) containing 5-aminosalicylic acid (5-ASA), corticosteroids, immunomodulators, antibiotics, and biotherapy.
6. Delivery of antigen and induction of tolerance
Methods of inducing tolerance are provided. The method is generally based on the principle that immunosuppressive drugs and/or antigens can be targeted to the liver using the disclosed particles and will be taken up by hepatic Dendritic Cells (DCs) and/or hepatic Endothelial Cells (ECs). The liver is the organ of interest targeted to drugs for inducing tolerance to these drugs. It is believed that a composition loaded with an antigen of interest and/or in combination with an immunosuppressant will promote peripheral tolerance against the antigen of interest. Targeting may be passive (i.e., remain in the liver) or active (i.e., target specific cells in the liver). Thus, the liver targeting moiety is optional.
The particles carrying the antigen and/or immunosuppressive drug are preferably spatially localized to the same hepatic dendritic cells or hepatic endothelial cells to initiate tolerance. Thus, while different particles are contemplated that carry antigen in one group and immunosuppressant in another group and injected together, nanoparticles that carry both agents and target hepatic dendritic cells or endothelial cells are preferred.
The preferred strategy generally comprises administering particles comprising antigen and immunosuppressant, which remain in the liver and are taken up by liver antigen presenting cells or endothelial cells. Tolerogenic dendritic cells then circulate throughout the body to induce tolerance to the encapsulated antigen (peripheral tolerance). Exemplary cells that can be used as hepatic antigen presenting cells include hepatic Dendritic Cells (DCs), hepatic endothelial cells, kupffer cells, hepatic stellate cells, hepatocytes, and other cells that present antigens to the liver.
Hepatic DC or EC drains to regional lymph nodes (peritoneal cavity). They acquire tolerogenic programs that induce the expansion of antigen-specific regulatory T cells (tregs). APCs can also present antigens to T cells in the sinusoids without migrating out. Furthermore, antigens may be processed by DCs when they are in the liver or lymph nodes, or even migrate between them. In general, intracellular accumulation, transport or residence of the vector in hepatocytes is important for tolerance induction.
Antigen presenting cells also express anti-inflammatory markers or markers that mark the onset of the tolerogenic phenotype. Tregs migrate from the lymph nodes into the circulation and induce systemic-wide tolerance.
The preferred strategy can be summarized in five steps:
1) Homing to the liver;
2) Uptake of dendritic cells and/or APCs in the liver;
3) Drainage to local lymphatic vessels;
4) Expansion of regulatory T cells;
5) Migrate into the blood stream and initiate peripheral tolerance.
The methods disclosed herein generally comprise administering to a subject in need thereof an effective amount of the disclosed particles, most typically in a pharmaceutical composition, to induce or increase tolerance to an antigen of interest. In particular embodiments, the composition increases the number or activity of regulatory T cells. Accordingly, provided are pharmaceutical compositions comprising particles comprising tolerogenic antigens and/or immunosuppressants present in the composition in an amount effective to induce hepatic dendritic cells and/or hepatic endothelial cells to acquire a tolerogenic phenotype, induce the expansion of antigen specific regulatory T cells (tregs), or a combination thereof, and methods of use thereof.
Robust tolerability can be achieved by inducing antigen specific tregs, polyclonal tregs, tr1 cells, other CD4 cells expressing PD-L1 or CTLA-4, CD8 cell loss/anergy, and even Breg. Thus, in some embodiments, the composition is administered in an effective amount to achieve a tolerogenic procedure that reduces or prevents immunogenicity against a desired antigen (e.g., an antigen delivered by a particle).
Administration is not limited to the treatment of existing conditions and diseases, but may also be used to prevent or reduce the risk of individuals developing such diseases (i.e., for prophylactic use). These compositions may be used in prophylactic or therapeutic vaccines or therapies, which may be used to elicit or enhance immune tolerance in a subject to a pre-existing antigen or neoantigen.
The expected outcome of a prophylactic, therapeutic or desensitizing immune response may vary depending on the disease, according to principles well known in the art. Similarly, immune tolerance may treat a disease entirely, may alleviate symptoms, or may be an aspect of overall therapeutic intervention for a disease.
Potential candidates for prophylactic vaccination include individuals at high risk of developing autoimmunity against certain autoantigens, as well as patients receiving recombinant protein therapy (FVIII or FIX).
C. Imaging system
In other embodiments, the method of using the pharmaceutical composition may comprise a method of non-invasively imaging the target organ as a whole or a different microenvironment within the target organ, such as an inflammatory pocket, leaky vasculature, or tumor. In these embodiments, the method comprises administering to a subject in need thereof oral dosage units of pharmaceutical compositions containing non-targeted PBA nanoparticles encapsulating an effective amount of an imaging agent; delivering the effective amount of imaging agent to a target tissue, such as the pancreas, liver, or colon; optionally releasing an effective amount of an imaging agent from the nanoparticle at the target tissue; this allows enhanced detection of the target tissue or unique microenvironment within the target tissue by non-invasive imaging.
Imaging modalities suitable for detecting PBA nanoparticles and/or agents therein include Positron Emission Tomography (PET), computed Tomography (CT), magnetic Resonance Imaging (MRI), ultrasound imaging (US), and optical imaging. Suitable imaging agents (tracers) include radionuclide-labeled small molecules such as F-18 fluorodeoxyglucose, superparamagnetic iron oxide (SPIO), gadolinium, europium, diethylenetriamine pentaacetic acid (DTPA), 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (DOTA) and derivatives thereof, gases and fluorescent tracers. Such suitable modes with corresponding tracers are known in the art (Baum et al, theranostics, 2 (5) 437-447 (2012)).
D. Combination therapy and diagnosis
In other embodiments, methods of preventing, inhibiting, or treating a disease or condition are combined with methods of non-invasively imaging a target organ or tissue. In this example, these pharmaceutical compositions contain non-targeted PBA nanoparticles encapsulating both therapeutic and diagnostic/imaging agents. The method may comprise administering to a subject in need of prevention, inhibition or treatment of a disease and imaging of a target tissue an oral dosage unit containing a pharmaceutical composition of non-targeted PBA nanoparticles encapsulating an effective amount of one or more active agents and an effective amount of an imaging agent; delivering PBA nanoparticles to a target tissue, such as pancreas, liver or colon; an effective amount of one or more agents, and optionally an effective amount of an imaging agent, are released from the PBA nanoparticles at the target tissue, such that the disease is prevented, inhibited or treated by non-invasive imaging and detection of the target tissue or a unique microenvironment within the target tissue is enhanced.
The invention will be further understood by reference to the following non-limiting examples.
These examples demonstrate that pUDCA functions through parallel mechanisms involving protective transport, recognition enhancement, metabolism and anti-inflammatory immune signaling. Formulation of pUDCA NPs begins with monomeric UDCA, which is well known for its established medical benefits, followed by polymerization, and then formulation into NPs. As demonstrated in subsequent mechanism studies, the polymerization and formulation steps expand the benefits beyond those achieved by the use of monomers alone or even monomers on the surface of the particles. The efficacy of pUDCA is due to a variety of mechanisms. The first is protective transport, facilitating improved pharmacokinetic and biodistribution of the encapsulated agent.
The invention will be further understood by reference to the following non-limiting examples.
Examples
Example 1: polymeric BA not only facilitates formulation of orally ingestible therapeutic nanoparticles, but also provides a broad spectrum of biological activity
Nanoparticles provide broad spectrum activity for two reasons:
1) They are protective in nature and increase intestinal penetration and thus increase the systemic bioavailability of the relevant agent; and
2) They have signaling functions, can regulate glucose metabolism and immunity by binding to BA receptors, and thus act as an effector therapeutic system.
The basic principle for polymerization is based on: 1) Polymerization facilitates strategies for encapsulation and release of multiple therapeutic agents of interest including insulin. In other words, a solid, stable, biodegradable polymeric carrier contrasts with an inherently unstable monomeric BA micelle. 2) The manufacture of such polymeric NPs is capable of sustained release of encapsulated agents if the polymer is degradable in an aqueous environment. 3) The polymeric BA system acts as a robust carrier, exhibiting a different BA (very close and higher density) than BA monomers hybridized on the surface of another type of polymeric NP. Furthermore, if BA monomer has an inherent therapeutic effect, this effector function is amplified with polymerization and its bioavailability is longer than that of BA monomer on particles which can be easily released from the surface after oral ingestion. Furthermore, sustained availability of BA during drug release may be a desirable element of combined activity rather than additive activity. 4) The pH-stimulated response of BA provides gastric protection due to ionization potential and protonation of BA at low pH, while enhancing the multivalent nature of BA binding to its receptor. This multivalent response not only amplifies the extent of ionization, but also kinetically amplifies the low pH protection and higher pH deprotection response times as the particles are transferred from the stomach to the intestinal environment. 5) The polymer multivalent results in a high binding affinity to the BA receptor, which results in the conversion of the weak BA agonist to a stronger form upon polymerization. Stronger agonists are able to achieve greater receptor activation and therapeutic signaling functions at lower doses.
UDCA has a use record in type 2 diabetes (T2D) for reducing the establishment of insulin resistance, however, this use is dose intensive (mice are typically 40-450mg/kg and are orally administered for 2-20 weeks). UDCA is rarely tested in T1D because it affects mainly insulin sensitivity. The functional impact of pUDCA is not only to improve the transport of encapsulated agents (e.g., insulin) but also to amplify their effector functions beyond that which can be achieved by the monomer itself. UDCA, if stably bound to an extracellular wuta G protein coupled receptor (TGR 5), can trigger protein kinase cascade cell activation, regulate glucose and energy homeostasis, and can regulate nuclear factor kb (NF-kb) and signal kinases such as protein kinase B (Akt). TGR5 activation also results in an increase in anti-inflammatory immunity, anti-fibrotic activity, induction and secretion of enteroendocrine L-cell GLP-1, and adipose tissue energy expenditure. pUDCA can not only significantly reduce the dose, but also expand the range of action of UDCA, since its monomeric counterpart UDCA is an intrinsically weaker TGR5 agonist.
From the standpoint of improving insulin transport, biodistribution and pharmacokinetics, BA is a natural emulsifier. Thus, the biodegradable polymer BA is even better at dissolving lipids and fats in vivo. Generally, BA plays a digestive role by self-assembling into micelles with lipids; so that the orally ingested fatty substances have better molecular biological distribution and blood circulation. Bile and pancreatic digestive juices are known to be secreted into the duodenum, in particular, bile is returned from the ileum to the liver via the portal venous circulation and then back again into the intestine for further digestion of ingested fatty foods. The circulatory action of BA from the intestines to the bile duct and back is called "intestinal hepatic circulation". The biodistribution is affected and the cycle life is longer due to the enhanced binding of the polymeric BA NP.
Methods and materials
The methods used in the examples are as follows.
Reagents and antibodies: all bile acids, p-toluenesulfonic acid, 4-Dimethylaminopyridine (DMAP), polyvinyl alcohol (PVA), tween 20, pepsin, triamterene, lipopolysaccharide (LPS) and Ovalbumin (OVA) were obtained from Sigma and Sigma-Aldrich. Cyclophosphamide (CY), anhydrous dichloromethane, anhydrous pyridine, diisopropylcarbodiimide and anhydrous methanol were purchased from ACROS. Poly (lactic-co-glycolic acid) (PLGA, intrinsic viscosity 0.55-0.75dL/g, carboxyl terminal) from Durect corporation was used as a control polymer. Rapamycin (RAPA, LC laboratories), mouse insulin (INS, R)&D systems), 1 '-dioctadecyl-3, 3' -tetramethyl indole tricarbocyanine iodine (DIR, biocompare), and coumarin 6 (ACROS) are encapsulated in NP.FS 30D was obtained from Evonik, inc., and CpG was purchased from InvivoGen, inc. Antibodies to CD8 (APC), CD44 (PE), CD4 (APC), CD25 (Alexa Fluor-700), CD11c (PE-Cy 7), F4/80 (Alexa Fluor-647), F4/80 (Alexa Fluor-700) and CD206 (FITC) were obtained from the hundred-in biological company (BioLegend). Foxp3 (PE) and CD86 were purchased from England corporation (Invitrogen) and e biosciences corporation (eBioscience), respectively. Recombinant human GPCR TGR5 protein, atto565 conjugated TGR5 antibody and blocking buffer were obtained from Ai Bokang company (Abcam) and used for competitive binding studies.
And (3) cells: human colon adenocarcinoma Caco-2 cells were purchased from ATCC. Cells were cultured in Du's modified It's medium (DMEM, life technologies Co., ltd. (Life Technologies)) containing 4.5g/L glucose, 10% fetal bovine serum (FBS, atlantic Bio Inc. (Atlanta Biologicals)), antibiotics (100 units/mL penicillin and 100pg/mL streptomycin, ji Boke Co., gibco)) and 1% non-essential amino acids (NEAA, ji Boke Co.). Mice from cervical dislocationLong bones and spleens were harvested in (C57 BL/6 or Rag 2/OTII). Bone marrow was eluted from long bones and spleens were immersed using los velopak souvenir institute (Roswell Park Memorial Institute, RPMI) -1640 (life technologies) medium supplemented with 10% fbs. Red Blood Cells (RBCs) in the sample were lysed using ammonium-potassium chloride (ACK) lysis buffer (Lonza). Bone marrow derived macrophages (BMM) were cultured in Rockwell Pack souvenir institute (RPMI, life technologies Co.) medium with macrophage colony stimulating factor (MCSF, 10ng/mL, sigma-Aldrich). Bone marrow derived dendritic cells (BMDC) were generated using conventional expansion protocols, wherein 5X 10 5 Individual cells/mL were plated in RPMI supplemented with 20ng/mL GM-CSF (Sigma-Aldrich Co.) and cultured for 5 days. On day 5, non-adherent cells were collected and cultured in GM-CSF medium for an additional 2 days. Using EasySep TM The mouse CD4+ T cell isolation kit (Stem cell technologies Co. (STEMCELL Technologies)) purified CD4+ T cells from the spleen cell population of C57 BL/6. All cells were at 37℃and 5% CO 2 Is cultured in a humidified atmosphere.
To test insulin production by pancreatic beta cells promoted by activation of TGR5 receptor, mouse pancreatic beta cell line (MIN 6, ATCC) cells were incubated in Hank's balanced salt solution, HBSS, life technologies company, containing 3mM glucose for 2 hours and then in HBSS containing 25mM glucose and UDCA, PLGA or pucca NP (40 μg/mL) for 30 minutes. Insulin concentration was measured using ultrasensitive insulin ELISA kit (ALPCO). The same experiment was performed in the presence of the TGR5 antagonist triamcinolone acetonide (50 μg/mL) as a control to distinguish intrinsic insulin production from cells that did not activate TGR5 and used to normalize the results. The biological activity of insulin released from pUDCA was measured using Chinese hamster ovary cells transfected with a gene expressing the insulin receptor (CHO INSR cells, ATCC). Insulin released from pUDCA at 3 or 24 hours was incubated with CHO INSR cells for 1 hour and phosphoprotein kinase B (pAkt) levels were measured by ELISA (Ai Bokang). pAkt yield of CHO cells incubated with fresh or denatured insulin was compared to calculate percent bioactivity.
Animals: c57BL/6 mice (B6, 6-8 week old, female) NOD mice (NOD/ShiLtJ, 8 week old, female) and nude mice (athymic nude, nu/nu,7 week old, female) obtained from Ha Lan spell labs (Harlan Sprague Dawley inc.) were supplied by jackson laboratory (Jackson Laboratory). Mice were housed in autoclaved mini-cages placed in positive pressure containment shelves. Ossabaw pigs derived from Ossabaw barrier islands (17 months old, 42 kg) were used. All experiments and maintenance were performed according to the protocol approved by the institutional animal care and use committee (Yale University Institutional Animal Care and Use Committee) of the university of yards.
Polymer synthesis and Nanoparticle (NP) formulation: poly-bile acids (pBA) were synthesized by esterification of the carbon 24 groups of bile acid monomers (fig. 2A-2E), as shown in fig. 1A-1E for chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA), respectively. BA (5.4 mmol), para-toluene sulfonic acid (0.652 mmol) and DMAP (0.652 mmol) were added to 60mL of a 5:1 anhydrous dichloromethane to anhydrous pyridine solvent mixture and stirred at 40℃to give a clear solution. 6.92mmol of diisopropylcarbodiimide was added to the reaction mixture, and the reaction was allowed to proceed under nitrogen atmosphere for 2 hours. The polyester product pBA was precipitated into 400mL of cold anhydrous methanol, collected by centrifugation (centrifuge 5810R, ai Bende (Eppendorf)) and dried to retain a white powder. Polymerization was confirmed by Nuclear Magnetic Resonance (NMR) and Gel Permeation Chromatography (GPC). UDCA and poly (ursodeoxycholic acid) (pUDCA) 1 H and 2D- (COSY, DQF-COSY, HSQC and HMBC) NMR spectra data were recorded on an Agilent NMR spectrometer (Agilent) with a 3mm cold probe at 600MHz or 400MHz, and 13 the C NMR data were measured at a magnetic field of 100 MHz. Chloroform-d 1 (99.96%, sisal isotope laboratories, inc. (Cambridge Isotope Laboratories, inc.)) was used as deuterated NMR solvent and solvent reference signal (delta) for all NMR experiments H 7.25,δ C 76.98). The Molecular Weight (MW) of pBA (10 mg/mL in chloroform) was evaluated by GPC using a Waters HPLC system equipped with an isocratic pump of the 1515 type, a 717plus autosampler and a Waters Styragel column HT6E in series with2414 Refractive Index (RI) detector of HT 2. Chloroform was used as the mobile phase, with a flow rate of 1 ml/min, and both the column and RI detector maintained at 40 ℃. MW characteristics were determined relative to a calibration curve generated from a narrow polydispersity polystyrene standard (Aldrich Chemical). The Empower II GPC software was used to run the GPC instrument and subsequent chromatographic analysis. The pBA or PLGA or encapsulated dye (DIR or coumarin 6), drug (RAPA or INS) or iron oxide mixtures (50/50, W/W) NPs were formulated using water-in-oil-in-water (W/O/W) double emulsification techniques (FIGS. 2C-2E). The polymer or mixture (100 mg) was dissolved in 2mL of chloroform containing DIR (1 mg), coumarin 6 (10 mg), RAPA (10 mg) or iron oxide (1 mg). Phosphate buffered saline (PBS, 100. Mu.L) or INS-containing PBS (10. Mu.g) was added dropwise to the chloroform polymer solution while vortexing and homogenizing using the IKA T25 digital Ultra-Turrax (IKA). This dispersant phase was then added drop wise to the continuous phase of 5% pva and homogenized. The mixture was then added drop wise to 200ml of 0.2% pva and allowed to stir for 2 hours to evaporate the solvent. NPs were collected by centrifugation at 12,000rpm for 20 minutes at 4℃and then washed 3 times with deionized water. The particles were lyophilized and stored at-20 ℃. The hydrodynamic diameter and surface charge of the nanoparticles were measured by Malvern Zetasizer. The dispersion of NPs was filtered through a 0.45pm microporous filter into a cuvette prior to measurement. Dynamic light scattering was measured by backscattering at a detection angle of 173 ° at a wavelength of 532nm and the hydrodynamic radius was calculated using Stokes-einstein equation (Stokes-Einstein equation). The morphology of NPs was observed by Hitachi S-4800 high resolution scanning electron microscopy (SEM, norcross). A dispersion of NP in ethanol (2 μl) was placed on a wafer substrate and dried at room temperature. The sample was mounted on an aluminum sample holder and then gold sputtered. NP was observed at a working distance of 4mm with an acceleration voltage of 15 kV. DIR and insulin release were measured in gastric simulated media. NPs were dispersed in medium (citrate buffer, pH 2.0) at 37℃in the presence of pepsin (10 mg/mL). At each time point, NPs were centrifuged and the supernatant was collected for use with a plate reader (λ ex 750nm,λ em 790nm,SpectraMax M5, mei Gum instruments Co., ltd (Molecular Devices)) measures the amount of DIR released from the particles. Insulin release was quantified by BCA assay. By dispersing PLGA in 5wt%Preparing +.>Coated PLGA->
Permeability of NP through the epithelial cell layer of human intestine:
caco-2 cells were grown at 7X 10 4 Individual cells/cm 2 The cells were inoculated onto a trans-pore filter (corning) with a pore size of 0.4 pm. Cells were grown to confluence and incubated at 37℃and 5% CO 2 Maturing for about 30 days. Prior to the permeability study, an epithelial voltmeter (EVOM TM Epithelial voltmeters/ohm meters, world precision instruments (World Precision Instruments, inc.) measure transepithelial resistance (TEER). TEER values greater than 300 Ω cm 2 For permeability and cytotoxicity studies. A1 mg/mL dispersion of DIR-loaded NPs or a solution containing an equivalent concentration of soluble DIR was prepared in a phenol-free HBSS (life technologies) containing 25mM glucose and added to the top chamber of a trans-pore filter. HBSS in the substrate outside chamber was sampled and replaced with fresh medium at each time point. The rate of transport of the accumulated DIR to the substrate outside chamber gives the flux dQ/dt. Apparent permeability (P) app ) Calculated by (1).
Wherein C is 0 Is the initial concentration of total DIR in the top chamber, and a is the area of the trans-pore filter.
TGR5 binding study: pUDCA, UDCA and PLGA NPs and Atto 565-affix were performedCompetitive binding of synthetic TGR5 antibody saturated macrophages. Cells in 96-well plates (10) 5 Individual cells/well) were incubated with a useable amount (4 μg/mL) of fluorescently labeled TGR5 antibody at 4 ℃ for 2 hours and then exposed to different concentrations of NP. After 2 hours of incubation, the cells were washed three times with PBS and the amount of Atto565-TGR5 antibody bound to the cells was measured using a plate reader. Specific and non-specific k d Site saturation total binding equation y=b by nonlinear fitting max ×X/(k d +X) +NS X calculation, wherein B max Is the maximum specific binding, k d Is the equilibrium dissociation constant and NS is the slope of non-specific binding. To study pancreatic beta cells (10 6 Individual cells/pores) and TGR 5-bound valency dependent NPs, biotinylating the UDCA monomer and conjugating it to the surface of the avidinated PLGA NP. PLGA (100 mg) in 2mL of chloroform was added dropwise to a mixture of avidin-palmitate (10 mg/2 mL) and 2mL of 5% PVA in PBS and homogenized. The UDCA was conjugated to biotin (1:1 molar ratio) using EDC/NHS chemistry prior to immobilization of biotinylated UDCA (0, 50, 250 and 1000 ng/mL) to the avidin-coated PLGA NP (5 mg/mL). To prepare plated TGR5, recombinant TGR5 receptor (5 μg/mL) was coated on the plate overnight and the non-specific binding sites were blocked using a protein blocking buffer. The TGR5 receptor on the plate was incubated with a useable amount (4 μg/mL) of fluorescent labelled TGR5 antibody for 2 hours at 4 ℃ and subsequently exposed to different concentrations of NP. After 2 hours of incubation, the plates were washed three times with PBS and the amount of Atto565-TGR5 antibody bound to the receptor was measured using a plate reader.
The data were in accordance with the following competitive inhibition equation (using Graphpad Prism) which gives the estimated value of pucca (EC) at which 50% of the labeled antibody was completely removed 50 ) And affinity constant (K) i ):
Wherein the method comprises the steps of
F = fluorescence change upon competition with the labeled TGR5 antibody;
concentration of [ pucca ] =pucca;
F initial initiation Upper plateau of =fluorescence or initial fluorescence;
F final result Lower plateau of =fluorescence or final fluorescence;
EC 50 concentration of pucca which reduces total fluorescence by 50%;
K i =pudca affinity constant;
CA nti concentration of the =labeled anti-TGR 5 antibody;
K d, resistance to Estimated affinity constant of labeled anti-TGR 5 antibodies to TGR5 receptor in nanomolar range.
It is estimated that a shell having a thickness corresponding to the diameter of the UDCA molecule can bind about 2000 UDCA monomers on a 350nm diameter pUDCA particle.
Quantification of endocytosis and exocytosis rates for NP:
BMM was seeded in 96-well plates (10 5 Cells/well) and DIR loaded pUDCA, PLGA and PLGA/pUDCA blend NP (100 pg/mL) were added to the medium. Cells were incubated at 37 ℃ for 1, 3 and 6 hours, and endocytosis of NPs was measured using a plate reader. After washing the cells and replacing with fresh medium, exocytosis of the NPs was monitored at 37 ℃ or 4 ℃ by measuring DIR-labeled NPs released from BMMs to the medium over time.
The balanced endocytic-exocytosis reaction can be reduced to:
wherein [ P ] = concentration of particles in medium (particle count/mL)
[C] Concentration of cells in culture medium (number of cells/mL)
[ PC ] = concentration of cell-associated pellet (pellet-cell number/mL)
k exo Exocytosis rate (t) -1 )
Then k exo =endocytic rate (([ P)]·t) -1 ),
According to the signals reporting endocytic and exocytosis processes, it is a fluorescent signal associated with each process [ S ].
This differential equation has a solution between the two limits that no uptake has reached maximum uptake:
S 0 at any start time t 0 Signal at the time
Analysis and fitting of kendo and kexo was done using two graphs.
Exocytosis period
Where St is the signal at any time (t)
S0 is an arbitrary time (t 0 ) Signal at the time
Association period
The association phase was analyzed according to two graphs:
dS/dt gives S
At slope = - (kendo [ P ]]+kexo), intercept=kendo [ P]Smax,Equation 9 and as described above, ln (dS/dt) gives t
At slope = - (kendo [ P ]]+kexo), intercept=ln (kendo [ P ]]Smax)),Equation 10.
Assume that: this analysis did not take into account the reuptake of the particles after exocytosis.
Flow cytometry and ELISA: cd4+cd8+ cells and cd4+cd25+foxp3+ tregs were obtained 3 days and 5 days after CY treatment for CY-induced mice. For spontaneous T1D animal models, T cells were collected on day 1 after the last NP dosing. In both cases, pancreatic lymph nodes were collected and processed with a 40pm cell filter. Cell surface markers were determined by incubation at 4℃for 30 min with fluorescent antibodies against CD8 (APC), CD44 (PE), CD4 (APC) and CD25 (Alexa Fluor-700). Cells were then fixed, permeabilized and Foxp3 (PE) stained using Foxp3 staining kit (e biosciences). Immediately after the last wash, the samples were run on an LSR-II polychromatic flow cytometer (BD Biosciences) and analyzed using FlowJo software (Tree Star). To study antigen-specific T cell responses, OVA-specific cd4+ cells were used in OTII co-culture assays. BMDC (2.5X10) 4 Individual cells/well, 96-well plates) were pretreated with pUDCA NP for 24 hours, washed, and then stimulated with LPS (10 ng/mL) and OVA (20. Mu.g/mL) for 24 hours, followed by OTII CD4+ T cells (5X 10) 4 Individual cells/well, 96-well plate) were co-cultured for 3 days. Cell proliferation and cytokine production were then quantified.
BMM(10 5 Individual cells/well, 96-well plates) were incubated with pUDCA NP (50. Mu.g/mL), UDCA monomer (50. Mu.g/mL), PLGA (50. Mu.g/mL) or PBS for 4 hours, and CpG (100 ng/mL) was added. After 20 hours, IL-6, IL-10 and CCL1 readings were collected from the culture supernatant. Cells were stained for F4/80 (Alexa Fluor-647), CD86 (PE) and CD206 (FITC). After washing 3 times with buffer (2% fbs in PBS), the samples were fixed in 2% paraformaldehyde and run on an Attune NxT polychromatic flow cytometer (life technologies). CD11c-F4/80+NP+ was used for NP tracking of macrophages with dye-loaded particles. NP+ designation refers toThe particles are read out by fluorescence of the loaded dye. Mice were fasted for 4 hours and treated with labeled pUDCA NP by oral gavage (500 mg/kg, 250. Mu.L). After one day, pancreas, liver, lung and spleen were harvested, gently processed with a homogenizer, and cells were isolated from the debris using a 40 μm cell filter and piston. Cell surface markers were stained with fluorescent antibodies against F4/80 (Alexa Fluor-700) and CD11c (PE-Cy 7) and measured by Attune NxT polychromatic flow cytometry. All antibodies were diluted 1:500 for flow cytometry and cytokines (IL-6, IL-10 and IFNγ) were measured by ELISA (BD biosciences).
Biodistribution and histology: b6 mice, NOD mice or nude mice were fasted for 4 hours and treated with DIR-or coumarin 6-encapsulated NPs by oral gavage (50, 100 or 500mg/kg, 250. Mu.L). Free DIR or coumarin 6 (dissolved with 1% tween 20) was used as control. Mice were sacrificed at time points 4, 8, 12 or 24 hours post-gavage and isolated organs were scanned using a Bruker molecular imaging instrument (ruke medical company (Carestream Health, inc.)) to measure fluorescence intensity. The fluorescence data conforms to a single component exponential decay model: y=y f +(Y o -e -kt ). DIR-loaded NPs formulated from pUDCA, PLGA or mixtures (50:50, w/w) were also administered Intravenously (IV) to mice by tail infusion (100 mg/kg, 50. Mu.L) to compare their biodistribution with free dye. Macrophage depletion reagent kitEncapula nanoscience (Encapsula NanoSciences), 100mg/kg, intraperitoneal (IP) injection) was used to deplete macrophages in B6 mice. For histology, pancreas from mice orally receiving iron oxide loaded pucca NP was fixed in 10% neutral buffered formalin for the passage of hematoxylin and eosin (H&E) Histological analysis was performed with Prussian blue staining. Stained sections were prepared by the university of jerusalem pathology histology service center (Yale University Pathology Histology Service). Tissues were imaged on a Nikon TE-2000U microscope with a Nikon DS Fil color camera and NIS element AR software (version 2.30).
Diabetes animal model experiment: NOD mice were intraperitoneally injected with CY (200 mg/kg) to induce acute type I diabetes (T1D) (fig. 8A). After 24 hours, mice were orally gavaged with empty NP, RAPA-loaded NP (50, 100 and 500mg NP/kg = 40mg RAPA/kg), soluble RAPA (40 mg/kg dissolved with 1% tween 20) and saline. pUDCA (pUDCA) RAPA Orally administered on day 1 (dose I) or orally administered twice on days 1 and 2 (dose II). Using blood sugar monitorMeter, home Diagnostics (inc.) monitors blood glucose levels. Two readings above 200mg/dL (1 day apart) are considered to be indicative of the onset of T1D. pUDCA was also used for this model RAPA Comparison was made with insulin administered as "gold standard" insulin, subcutaneously (SQ) or Intraperitoneally (IP). pUDCA was given in 7 consecutive injections of insulin or orally given bolus doses of insulin INS Thereafter, blood glucose was measured over the course of 25 days. Using the operative receptor depletion model y=basal+ (action max Basic)/(1 + operation) fitting data, where operation= (((10) logkA )+(10 X ))/(10 (logtau+X) )) n Action max is the largest possible systemic response, the basis is the response in the absence of agonist, kA is the agonist-receptor dissociation constant, and tau is the kinetics of reduction to half-maximal response.
For the spontaneous T1D model, NOD mice were housed for approximately 2 months to allow for natural development of T1D. For the spontaneous T1D model, NOD mice of the same age (8 weeks of age) were selected for study only when they became diabetic at the same week (16 weeks of age, after 2 random tail vein blood glucose measurements of 200.+ -.15 mg/dL). Mice were orally treated 7 times with empty NPs, INS loaded NPs (100 or 500mg NP/kg and 285mIU INS/kg) or free INS (285 mIU/kg) for 1 week to monitor diabetes and body weight. GLP-1 concentration was measured from plasma using ELISA kit (Injetty Corp.). Fasted pigs>12 hours, with water, and IV administration of tetraoxapyrimidine (250 mL,150 mg/kg). Animals (n=3) were given 7 times daily oral gavage of pucca 10 days after tetraoxapyrimidine treatment INS (6.4mg/kg, equivalent to 100mg/kg of mice) and glucose readings were monitored using the continuous glucose monitoring system DexCom 6 (Dexcom. Inc.). The whole blood sample was calibrated by ear-stick using a Relion Prime BG glucometer (Relion), and further vein calibration by antai diagnosis (Antech Diagnostics).
Calculation of the selected INS dose in spontaneous T1D study: it is known that an INS of 1 International Unit (IU) is required to lower the blood glucose level of 50mg/dL in humans. In order to reduce the hyperglycemia level (> 400 mg/dL) below the hyperglycemia threshold (200 mg/dL), at least 4IU of INS is required. The INS of the mice was 0.02IU according to the following equation (9).
Where HED = human equivalent dose (mg/kg), animals NOAEL = no observed adverse effect level (mg/kg) of animals, 1IU INS = 0.036mg based on world health organization conversion factor.
The INS loading in pUDCA NP was about 20ng/mg Np and 5.6X10 4 IU/mg NP. For feeding 0.02IU INS, 35mg pUDCA should be treated for a single mouse INS NP. Thus, diabetic mice were treated with 3 doses of 10mg NP and mice were continued to be treated with another 4 doses to maintain low glucose levels (0.04 IU INS and 70mg NP total).
Toxicology of pUDCA and UDCA: acute toxicity studies were performed on female B6 mice of 10 weeks of age. pUDCA (100 and 500 mg/kg) and UDCA (100 mg/kg) were orally administered to mice on day 0. The serum concentration of alkaline phosphatase, alanine transferase concentration, total bilirubin concentration and blood urea nitrogen concentration were analyzed on days 3, 5 and 7 using a kit from eastern diagnostic company (Teco diagnostic). EDTA anticoagulated blood was analyzed with a Hemavet blood counter (Drew Scientific).
And (3) statistics: all statistical analyses were performed using GraphPad Prism software (version 7.01). ANOVA analysis using Ponfluo post hoc test or double tail Style Chardonner t test Groups were compared experimentally. Log rank test and χ on survival data 2 And (5) carrying out statistical analysis. A P value of 0.05 or less is considered statistically significant.
Results
Preparation of bile Polymer solid biodegradable NPs: to generate the BA vector, biodegradable pBA was first synthesized and then the polymer was formulated into NPs. This approach is for four reasons, as opposed to using BA monomer alone: 1) The stability of the BA drug combination (if present) during digestive transport is increased compared to micelle vesicles formed above BA micelle concentration. 2) A carrier is formulated that can deliver the encapsulated drug (if present) in a sustained manner. 3) Ensuring a constant ratio of BA to encapsulated drug (if present) during the delivery and release process. 4) Increasing the valence of BA to potentially increase affinity for BA receptor binding.
BA polymerization and formulation into NP: for screening purposes, a panel of BAs comprising Cholic Acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) was tested (fig. 1A-1E). BA was polymerized under mild conditions at 40 ℃ and atmospheric pressure for 2 hours (see methods). The use of Diisopropylcarbodiimide (DIC) and 1:1 salt of dimethylaminopyridine with p-toluenesulfonic acid (DMAP/PTSA) resulted in selective activation and esterification of the carbon-24 position of BA, yielding BA polymers (fig. 1F-1J). Polymerization begins at the end of the negatively charged monomer. The degree of polymerization and the molecular weight were determined by Nuclear Magnetic Resonance (NMR) and Gel Permeation Chromatography (GPC), respectively. Polymerization and crosslinking were verified by two-dimensional (2D) Heteronuclear Single Quantum Coherence (HSQC) spectroscopy and 2D double quantum filter correlation spectroscopy (DQF-COSY) analysis. Typically, the number average molecular weight (Mn) ranges from 1360 to 2230g/mol and the weight average molecular weight (Mw) ranges from 1600 to 3210g/mol. The polymer dispersibility was evaluated with a polydispersity index (PDI) and did not exceed 1.5 (table 1). The linearity of the polymer was assessed by 2D NMR, where it was shown that the two hydroxy substituents at C-3 and C-7 esterified during the polymerization process in a molar ratio of 2.5:1.
A double emulsification method using water-in-oil-in-water (W/O/W) for the nanoparticle formulation (fig. 1H-1J). The polyester PLGA is used herein as a comparator for drug delivery. Blends of pBA and PLGA were prepared to demonstrate the relative effect of pBA on PLGA function. Encapsulation of the agent is achieved by first dissolving the polymer initially in chloroform, then adding the agent during emulsion formulation. The agents used in this study included: infrared fluorescent dye (1, 1 '-dioctadecyl-3, 3' -tetramethyl indole tricarbocyanine iodine (DIR)), green fluorescent dye (coumarin 6), drug Rapamycin (RAPA), 10-20nm iron oxide particles for histological staining with iron sensitive Prussian blue, and saline buffered mouse insulin (see methods). The loading efficiencies of DIR, coumarin 6, RAPA, iron oxide and insulin were 6.7, 84.3, 80.1, 9.0 and 0.02pg/mg particles, respectively. The spherical morphology of the NPs was verified by Scanning Electron Microscopy (SEM), which showed uniform spherical particles with an average diameter of 344.3 ±4.7nm quantified using dynamic light scattering (DLS, zetasizer, malvern instruments (Malvern Instruments)). The electrostatic charge of pBA NP was negative, with a zeta potential of-24.9.+ -. 4.4mV. All formulations were engineered to have similar size, charge, morphology and encapsulation efficiency to ensure that any observed biodistribution or functional differences were only a function of intrinsic material properties, not biophysical changes (table 1).
Table 1. Particle properties and loading efficiency.
a number average molar mass (GPC)
b weight average molar mass (GPC)
Polymer polydispersity index (GPC)
d particle polydispersity index (DLS)
e (weight of encapsulated dye/weight of NP) x 100
f (weight of encapsulated dye/weight of dye for encapsulation) x 100
g polymer blend nanoparticles (pucca: plga=50:50, w/w).
Improved GI transit, gastric protection and enhanced intestinal penetration.
BA ionization under acidic conditions affects its water solubility, limiting water penetration into individual particles, while promoting hydrophobic interactions between particles under acidic conditions. This protection mechanism limits the exposure of most particles to the gastric environment, and reverses as the pH conditions in the intestinal lumen increase.
The PLGA particles began to degrade at 2 and 4 hours after incubation, releasing up to 8% of the encapsulated dye. In contrast, pUDCA retained the dye for more than 4 hours in a manner similar to Eudragit modified PLGA. The PLGA blend with pUDCA gave Eudragit considerable stability, which further validated the pH responsive properties of pUDCA. The spherical particle morphology of pUDCA was also retained, while that of PLGA showed significant swelling over time under acidic conditions. Blending PLGA with pUDCA has a short stabilizing effect. These observations demonstrate the protective properties of pBA, which confer stability to encapsulated insulin during GI transport. In contrast to UDCA micelles, pucca showed minimal leakage of encapsulated insulin. Furthermore, after low pH exposure, the insulin encapsulated in pUDCA functions as fresh insulin, which is produced from pUDCA INS The ability of the released insulin to bind to insulin receptors on pAkt-producing CHO cells was demonstrated (fig. 3G).
After gastric digestion, NPs encounter a higher pH microenvironment and become more permeable to water. The penetration of BA particles through the intestinal lumen may be by passive translocation of intestinal epithelial cells or by active translocation of colonic receptors. pUDCA appears to be transported passively through the intestinal lumen because dye loaded pUDCA NPs have significantly higher permeability through model epithelial cell lines (Caco-2 human cells) than PLGA, PLGA blended with pUDCA, or other pBA NPs (FIG. 3H). In fact, pUDCA has a permeability coefficient of about 50X 10-6 cm/s, which means that it will be fully absorbed in the intestinal lumen of the human body 63.
Blood pool access of BA may be mediated by the intestinal hepatic circulation or blood cells such as monocytes or macrophages in the intestinal lumen. To elucidate the mechanism of the cycle of pUDCA NP, NP was injected Intravenously (IV) and pUDCA NP was found to show a high pancreatic uptake profile 2 hours after IV administration. Thus, pancreatic accumulation is also involved in cellular transport in the blood and is not entirely driven by the hepatointestinal circulation. Given that intestinal macrophages are one of the largest cell pools in the body, and the immediate vicinity of the lamina propria in healthy colon, the use of depleting agents such as chlorophosphonate liposomes to reduce the number of cells in such pool should affect pancreatic biodistribution. The effect on biodistribution is shown in figure 31, supporting the partial role of macrophages in the biological transport of particles into the pancreas. Complete elimination of pancreatic distribution by this mechanism would negate the effect of the intestinal hepatic circulation, but figure 3J shows that only 16% of macrophages are associated with pucca NP. The overlapping mechanisms that contribute to NP cycling are summarized below. Here, the NP is passed through the intestinal epithelium into the duodenum and through the common bile duct into the pancreatic duct. Particles may also be taken up by resident and circulating monocytes and macrophages for transport to the pancreas, or self-filtered through capillaries and lymphatic vessels 66 in the absence of a cellular host. Another potential mechanism not studied here is the binding to serum albumin, which has affinity for different bile acids.
pUDCA NP binds to extracellular bile acid receptor (TGR 5) with high affinity and promotes glucagon-like peptide and endogenous insulin secretion.
BA is involved in the active transport of fatty foods by top membrane transporters such as CD36, pit proteins and Fatty Acid Transporter (FAT), so high affinity binding can enhance endocytosis and BA-mediated signal transduction cascades. Furthermore, monomer UDCA is a weak TGR5 receptor agonist, so understanding the change in binding affinity will help elucidate the amplification response of polymer BA compared to monomer. FIG. 3K and Table 2 show competitive binding of pUDCA to macrophages saturated with anti-TGR 5 antibodies. Table 2 dissociation constants for pUDCA, UDCA and PLGA.
Specific k d | Unspecified k d | |
pUDCA | 1.25 | -0.0061 |
UDCA | 29.97 | -0.0055 |
PLGA | N/A | About 0 |
FIG. 3F is a graph showing insulin production (ng/ml) induced from pancreatic beta cells by pUDCA and UDCA.
FIG. 3G is a graph showing IFN-y production by CD4+ T cells treated directly with pUDCA (50 and 5 micrograms/ml) and stimulated with anti-CD 3 and anti-CD 28.
pUDCA has approximately 30 times higher affinity than UDCA, with minimal non-specific binding. PLGA NPs used as negative controls showed no affinity. The rate of intracellular NP transport is also affected by the higher binding affinity. Quantitative assessment of the pUDCA NP rate of endocytosis and exocytosis of macrophages at 37℃showed that internalization (kendo) was 3.6 times that of the non-binding control (PLGA) and exocytosis rate (kexo) was 2.3 times that of the non-binding control. The assay effectiveness of the quantitative rate determination was performed at 4 ℃ when minimal or no active internalization or exocytosis was demonstrated (fig. 3L). Interestingly, the increase in internalization magnitude or faster exocytosis was dependent on the amount of pucca in the formulation. By blending with PLGA, the pUDCA concentration was reduced by 50% resulting in an internalization rate or exocytosis rate greater or faster than PLGA itself, respectively. Thus, an increase in pUDCA binding affinity results in an increase in the rate of receptor-mediated intracellular transport (endocytosis and exocytosis). In fact, high affinity binding was not limited to macrophages, but was also observed in pancreatic β cells, where TGR5 binding resulted in an enhancement of endogenous GLP-1 secretion (fig. 6J) and insulin production (fig. 6K), thereby facilitating effective control of blood glucose levels. In addition to metabolic control, the increase in binding avidity also enables inherently effective anti-inflammatory immune response control through the involvement of a variety of immune regulatory mechanisms, e.g., by the slope of the macrophage phenotype from Ml to M2 (fig. 6O), the decrease in ifnγ secretion (fig. 3D), the decrease in pro-inflammatory IL-6 (fig. 3E), the increase in anti-inflammatory activity with the production of IL-10 and CCL1 (fig. 6N), and the induction of tolerance by proliferation of regulatory T cell responses (cd4+foxp3+cd25) while inhibiting the activated cd8+ (cd4+cd8+) T cell responses (fig. 4F-4I, 6L and 6M). This multivariable innate and adaptive immune modulation by the carrier material itself provides significant therapeutic control of pancreatic inflammation, while providing synergistic agents for neutralizing the pro-inflammatory response associated with hyperglycemia.
The pUDCA effect is mediated through enhancement of valence and proximity of multivalent display
The anti-inflammatory effects of UDCA have been widely studied and used medically to dissolve gallstones and prevent chronic graft versus host disease in the liver. In chinese, "Urso" is the meaning of "bear", and ursodeoxycholic acid is a billion dollar industry in chinese traditional medicine because it has anti-inflammatory properties and is generally beneficial to healthy and ill people. Furthermore, clinical trials are ongoing, with emphasis on the role of UDCA in the treatment of diabetes. pUDCA is a multivalent form of UDCA, and its enhanced effect is due to high affinity binding to TGR5 receptor, in addition to acting as a vector.
To demonstrate that increased multivalent is the mechanism behind the observed effect, the effect of pucca on insulin secretion by pancreatic beta cells in vitro was tested. The carrier PLGA, which had no intrinsic effect on insulin secretion by pancreatic cells, was modified with different concentrations of monomeric UDCA (fig. 6K) until the surface was completely saturated, i.e. about 2000 UDCA molecules per PLGA particle. Although an increase in UDCA concentration on the surface enhanced the binding of non-pucca vector (i.e., PLGA) to target pancreatic cells, pucca was still better than PLGA particles saturated with monomeric UDCA (up to 2000 UDCA molecules per PLGA particle). Therefore, the enhancement effect cannot be fully reproduced by merely increasing the monomer valence on the nanoparticle. Additional geometric or biophysical factors are required and may include the proximity of molecules on the multivalent platform to the mobility or relative persistence of ligands on the activated surface. Consistent with the concept that increasing affinity alone is generally insufficient to achieve optimal response, the spacing between proteins needs to be considered in designing multivalent targeting systems. Polymeric ligands can inherently span the length of the targeted BA receptor because the composition is a distribution of randomly spaced ligands that spans a wider range of lengths than monomers conjugated or adsorbed to the surface of a solid support or nanoparticle. In addition, the pUDCA encapsulant allows for a fixed ratio between bile acid and drug released over a period of time, which is required to add two parts to improve the response. The surface of the particles modified with the monomer will degrade with kinetics different from the release kinetics of the encapsulant. If the therapy requires the combined delivery of a pair of pluripotent drugs, the temporal stability of the combination plays a key role. Time stability is a prerequisite for potential synergistic activity and is preferably achieved by a system that provides the active agent at a fixed rate over a period of time. This can be easily achieved if the carrier is one of two effect drugs (bile acid and encapsulating agent).
The multivariable nature of this vector is summarized below. After oral ingestion (pH about 7-7.5), the particles are anionic and dispersible. Protonation in the stomach (pH 2-3) limits water penetration. The small intestine pH (6-6.5) reduces hydrophobic interactions and allows water to penetrate into the particles and be transported through the intestinal lumen, followed by intestinal macrophage binding and internalization. In summary, particles circulate throughout the body by a variety of mechanisms, involving cell-mediated transport or individual transport of particles from the duodenum to the common bile duct, facilitating entry into the exocrine pancreas. These particles show protective and local transport through the GI tract, as well as metabolic and immune control of the response. Together, these properties constitute a means of enhancing the therapeutic effect of encapsulated anti-inflammatory or metabolic therapy.
Excipient mediated drug delivery has encountered a number of different innovative designs for oral delivery and enhanced function. Examples include: protective excipients, macromolecular transporters, nanoparticles, polymeric scaffolds, and millimeter microneedle-like pills for direct delivery of insulin through the stomach wall. However, for these innovations, there is no way to address the metabolic management aspects of drug delivery in parallel with strategies to treat potential pathologies (e.g., pancreatic metabolism and dysfunction of local pro-inflammatory immunity in type 1 diabetes). Thus, such lack of development requires lifetime dependent insulin administration.
Examples show that polymer BA not only facilitates formulation of orally ingestible therapeutic nanoparticles, but also provides a broad spectrum of biological activity for two reasons:
1) They may be protective in nature and increase intestinal penetration and thus increase the systemic bioavailability of the relevant agent; and
2) They have signaling functions, can regulate glucose metabolism and immunity by binding to BA receptors, and thus act as an effector therapeutic system.
The basic principle for aggregation is based on the following concept: 1) Polymerization facilitates strategies for encapsulation and release of multiple therapeutic agents of interest including insulin. In other words, a solid, stable, biodegradable polymeric carrier contrasts with an inherently unstable monomeric BA micelle. 2) The manufacture of such polymeric NPs is capable of sustained release of encapsulated agents if the polymer is degradable in an aqueous environment. 3) The polymeric BA system acts as a robust carrier, exhibiting a different BA (very close and higher density) than BA monomers hybridized on the surface of another type of polymeric NP. Furthermore, if BA monomer has an inherent therapeutic effect, this effector function is amplified with polymerization and its bioavailability is longer than that of BA monomer on particles which can be easily released from the surface after oral ingestion. Furthermore, sustained availability of BA during drug release may be a desirable element of the synergistic activity of the combined activities. 4) The pH-stimulated response of BA provides gastric protection due to ionization potential and protonation of BA at low pH, while enhancing the multivalent nature of BA binding to its receptor. This multivalent response not only amplifies the extent of ionization, but also kinetically amplifies the low pH protection and higher pH deprotection response times as the particles are transferred from the stomach to the intestinal environment. 5) The polymer multivalent results in a high binding affinity to the BA receptor, which results in the conversion of the weak BA agonist to a stronger form upon polymerization. Stronger agonists are able to achieve greater receptor activation and therapeutic signaling functions at lower doses.
For the above reasons, the use of polymers formed from the BA monomer ursodeoxycholic acid (UDCA) is described. UDCA has a use record in type 2 diabetes (T2D) for reducing the establishment of insulin resistance, however, this use is dose intensive (mice are typically 40-450mg/kg and are orally administered for 2-20 weeks). UDCA is rarely tested in T1D because it affects mainly insulin sensitivity. The functional impact of pUDCA is not only to improve the transport of encapsulated agents (e.g., insulin) but also to amplify their effector functions beyond that which can be achieved by the monomer itself. UDCA, if stably bound to an extracellular wuta G protein coupled receptor (TGR 5), can trigger protein kinase cascade cell activation, regulate glucose and energy homeostasis, and can regulate nuclear factor kb (NF-kb) and signal kinases such as protein kinase B (Akt). TGR5 activation also results in an increase in anti-inflammatory immunity, anti-fibrotic activity, induction and secretion of enteroendocrine L-cell GLP-1, and adipose tissue energy expenditure. pUDCA can not only significantly reduce the dose, but also expand the range of action of UDCA, since its monomeric counterpart UDCA is an intrinsically weaker TGR5 agonist.
From the standpoint of improving insulin transport, biodistribution and pharmacokinetics, BA is a natural emulsifier. Thus, the biodegradable polymer BA is even better at dissolving lipids and fats in vivo. Generally, BA plays a digestive role by self-assembling into micelles with lipids; so that the orally ingested fatty substances have better molecular biological distribution and blood circulation. Bile and pancreatic digestive juices are known to be secreted into the duodenum, in particular, bile is returned from the ileum to the liver via the portal venous circulation and then back again into the intestine for further digestion of ingested fatty foods. The circulatory action of BA from the intestines to the bile duct and back is called "intestinal hepatic circulation". The biodistribution is affected and the cycle life is longer due to the enhanced binding of the polymeric BA NP. While previous work on covalent or non-covalent attachment of drugs to BA has utilized this cyclic process to enhance intestinal permeation and pharmacokinetics, there has been no report to explore or record the multi-modal therapeutic aspects of polymeric BA, particularly pucca, in combination with insulin loading for T1D management, prevention and treatment.
Method
The methods used in the examples are as follows.
Reagents and antibodies: all bile acids, p-toluenesulfonic acid, 4-Dimethylaminopyridine (DMAP), polyvinyl alcohol (PVA), tween 20, pepsin, triamterene, lipopolysaccharide (LPS) and Ovalbumin (OVA) were obtained from sigma and sigma-Aldrich. Cyclophosphamide (CY), anhydrous dichloromethane, anhydrous pyridine, diisopropylcarbodiimide and anhydrous methanol were purchased from ACROS. Poly (lactic-co-glycolic acid) (PLGA, intrinsic viscosity 0.55-0.75dL/g, carboxyl terminal) from Durect corporation was used as a control polymer. Rapamycin (RAPA, LC laboratories), mouse insulin (INS, R & D systems), 1 '-dioctadecyl-3, 3' -tetramethylindole tricarbocyanine iodine (DIR, bayer biotechnology limited) and coumarin 6 (ACROS) are encapsulated in NP. Eudragit FS 30D was obtained from the winning company and CpG was purchased from InvivoGen company. Antibodies to CD8 (APC), CD44 (PE), CD4 (APC), CD25 (Alexa Fluor-700), CD11c (PE-Cy 7), F4/80 (Alexa Fluor-647), F4/80 (Alexa Fluor-700) and CD206 (FITC) were obtained from the hundred-in biological company (BioLegend). Foxp3 (PE) and CD86 were purchased from invitrogen and e biosciences, respectively. Recombinant human GPCR TGR5 protein, atto565 conjugated TGR5 antibody, and blocking buffer were obtained from Ai Bokang company and used for competitive binding studies.
And (3) cells: human colon adenocarcinoma Caco-2 cells were purchased from ATCC. The cells contained 4.5g/LGlucose, 10% fetal bovine serum (FBS, alkala Biotechnology Co.), antibiotics (100 units/mL penicillin and 100. Mu.g/mL streptomycin, ji Boke Co.) and 1% nonessential amino acids (NEAA, ji Boke Co.) were cultured in Du's modified It's medium (DMEM, life technologies Co.). Long bones and spleens were harvested from mice (C57 BL/6 or Rag 2/OTII) after cervical dislocation. Bone marrow was eluted from long bones and spleens were immersed using los velopak souvenir institute (RPMI) -1640 (life technologies) medium supplemented with 10% fbs. Red Blood Cells (RBCs) in the sample were lysed using ammonium-potassium chloride (ACK) lysis buffer (longsha). Bone marrow derived macrophages (BMM) were cultured in Rockwell Pack souvenir institute (RPMI, life technologies Co.) medium with macrophage colony stimulating factor (MCSF, 10ng/mL, sigma-Aldrich). Bone marrow derived dendritic cells (BMDC) were generated using conventional expansion protocols, wherein 5X 10 5 Individual cells/mL were plated in RPMI supplemented with 20ng/mL GM-CSF (Sigma-Aldrich Co.) and cultured for 5 days. On day 5, non-adherent cells were collected and cultured in GM-CSF medium for an additional 2 days. Using EasySep TM The mouse CD4+ T cell isolation kit (Stem cell technology Co.) purified CD4+ T cells from the spleen cell population of C57 BL/6. All cells were at 37℃and 5% CO 2 Is cultured in a humidified atmosphere.
To test insulin production by pancreatic beta cells promoted by activation of TGR5 receptor, mouse pancreatic beta cell line (MIN 6, ATCC) cells were incubated in hank's balanced salt solution (HBSS, life technologies) containing 3mM glucose for 2 hours and then in HBSS containing 25mM glucose and UDCA, PLGA or pucca NP (40 pg/mL) for 30 minutes. Insulin concentration was measured using ultrasensitive insulin ELISA kit (ALPCO). The same experiment was performed in the presence of the TGR5 antagonist triamcinolone acetonide (50 pg/mL) as a control to distinguish intrinsic insulin production from cells that did not activate TGR5 and used to normalize the results. The biological activity of insulin released from pUDCA was measured using Chinese hamster ovary cells transfected with a gene expressing the insulin receptor (CHO INSR cells, ATCC). Insulin released from pUDCA at 3 or 24 hours was incubated with CHO INSR cells for 1 hour and phosphoprotein kinase B (pAkt) levels were measured by ELISA (Abeam). pAkt yield of CHO cells incubated with fresh or denatured insulin was compared to calculate% bioactivity.
Animals: c57BL/6 mice (B6, 6-8 week old, female) were obtained from Ha Lan Sprague. NOD mice (NOD/ShiLtJ, 8 week old, females) and nude mice (athymic nude mice, nu/nu,7 week old, females) were supplied by jackson laboratories. Mice were housed in autoclaved mini-cages placed in positive pressure containment shelves.
Ossabaw pigs derived from Ossabaw barrier islands (17 months old, 42 kg) were used. All experiments and maintenance were performed according to protocols approved by the institutional animal care and use committee of the university of yards.
Polymer synthesis and Nanoparticle (NP) formulation: poly bile acids (pBA) were synthesized by esterification of carbon 24 groups (fig. 1F-1G). BA (5.4 mmol), para-toluene sulfonic acid (0.652 mmol) and DMAP (0.652 mmol) were added to 60mL of a 5:1 anhydrous dichloromethane to anhydrous pyridine solvent mixture and stirred at 40℃to give a clear solution. 6.92mmol of diisopropylcarbodiimide was added to the reaction mixture, and the reaction was allowed to proceed under nitrogen atmosphere for 2 hours. The polyester product pBA was precipitated into 400mL of cold anhydrous methanol, collected by centrifugation (centrifuge 5810R, ai Bende) and dried to retain a white powder. Polymerization was confirmed by Nuclear Magnetic Resonance (NMR) and Gel Permeation Chromatography (GPC). UDCA and poly (ursodeoxycholic acid) (pUDCA) 1 H and 2D- (COSY, DQF-COSY, HSQC and HMBC) NMR spectra data were recorded on an Agilent NMR spectrometer (Agilent) with a 3mm cold probe at 600MHz or 400MHz, and 13 the C NMR data were measured at a magnetic field of 100 MHz. Chloroform-d 1 (99.96%, cambridge isotope laboratories Co., ltd.) was used as deuterated NMR solvent and solvent reference signal (delta) for all NMR experiments H 7.25,δ C 76.98). The Molecular Weight (MW) of pBA (10 mg/mL in chloroform) was assessed by GPC using a Waters HPLC system equipped with an isocratic pump of model 1515, a 717plus autosampler, and a 2414 Refractive Index (RI) detector in series with Waters Styragel columns HT6E and HT 2. Chloroform was used as the mobile phase, wherein the flow rate was1 ml/min, and both the column and RI detector were maintained at 40 ℃. MW characteristics were determined relative to a calibration curve generated from a narrow polydispersity polystyrene standard (Aldrich chemistry). The Empower II GPC software was used to run the GPC instrument and subsequent chromatographic analysis. The pBA or PLGA or encapsulated dye (DIR or coumarin 6), drug (RAPA or INS) or iron oxide mixtures (50/50, W/W) NPs were formulated using water-in-oil-in-water (W/O/W) double emulsification techniques (FIGS. 1H-1J). The polymer or mixture (100 mg) was dissolved in 2mL of chloroform containing DIR (1 mg), coumarin 6 (10 mg), RAPA (10 mg) or iron oxide (1 mg). Phosphate buffered saline (PBS, 100. Mu.L) or INS-containing PBS (10. Mu.g) was added dropwise to the chloroform polymer solution while vortexing and homogenizing using the IKA T25 digital Ultra-Turrax (IKA). This dispersant phase was then added drop wise to the continuous phase of 5% pva and homogenized. The mixture was then added drop wise to 200ml of 0.2% pva and allowed to stir for 2 hours to evaporate the solvent. NPs were collected by centrifugation at 12,000rpm for 20 minutes at 4℃and then washed 3 times with deionized water. The particles were lyophilized and stored at-20 ℃. The hydrodynamic diameter and surface charge of the nanoparticles were measured by Malvern Zetasizer. The dispersion of NPs was filtered through a 0.45 μm microporous filter into a cuvette prior to measurement. Dynamic light scattering was measured by backscattering at a detection angle of 173 ° at a wavelength of 532nm and the hydrodynamic radius was calculated using stokes-einstein equation. The morphology of NPs was observed by Hitachi S-4800 high resolution scanning electron microscopy (SEM, noocross). A dispersion of NP in ethanol (2 μl) was placed on a wafer substrate and dried at room temperature. The sample was mounted on an aluminum sample holder and then gold sputtered. NP was observed at a working distance of 4mm with an acceleration voltage of 15 kV. DIR and insulin release were measured in gastric simulated media. NPs were dispersed in medium (citrate buffer, pH 2.0) at 37℃in the presence of pepsin (10 mg/mL). At each time point, NPs were centrifuged and the supernatant was collected for use with a plate reader (λ ex 750nm,λ em 790nm,SpectraMax M5, mei Valley instruments) measures the amount of DIR released from the particles. Quantification of insulin release by BCA assay. Eudragit coated PLGA (PLGA@Eudragit) was prepared by dispersing PLGA in 5wt% Eudragit solution and centrifuging.
Permeability of NP through the epithelial cell layer of human intestine: caco-2 cells were grown at 7X 10 4 Individual cells/cm 2 The cells were inoculated onto a 0.4 μm Kong Fanshi filter (Corning Co.). Cells were grown to confluence and incubated at 37℃and 5% CO 2 Maturing for about 30 days. Prior to the permeability study, an epithelial voltmeter (EVOM TM Epithelial voltmeters/ohm meters, world precision instruments, inc.) measure transepithelial resistance (TEER). TEER values greater than 300 Ω cm 2 For permeability and cytotoxicity studies. A1 mg/mL dispersion of DIR-loaded NPs or a solution containing an equivalent concentration of soluble DIR was prepared in a phenol-free HBSS (life technologies) containing 25mM glucose and added to the top chamber of a trans-pore filter. HBSS in the substrate outside chamber was sampled and replaced with fresh medium at each time point. The rate of transport of the accumulated DIR to the substrate outside chamber gives the flux dQ/dt. Apparent permeability (P) app ) Calculated by (1).
Wherein C is 0 Is the initial concentration of total DIR in the top chamber, and a is the area of the trans-pore filter.
TGR5 binding study: competitive binding of pUDCA, UDCA and PLGA NPs to TGR5 antibody saturated macrophages conjugated with Atto565 was performed. Cells in 96-well plates (10) 5 Individual cells/well) were incubated with a useable amount (4 μg/mL) of fluorescently labeled TGR5 antibody at 4 ℃ for 2 hours and then exposed to different concentrations of NP. After 2 hours of incubation, the cells were washed three times with PBS and the amount of Atto565-TGR5 antibody bound to the cells was measured using a plate reader. Specific and non-specific k d Site saturation total binding equation y=b by nonlinear fitting max ×X/(k d +X) +NS X calculation, wherein B max Is the maximum specific binding, k d Is equilibrium dissociation constant, and NS is non-specifically boundSlope. To study pancreatic beta cells (10 6 Individual cells/pores) and TGR 5-bound valency dependent NPs, biotinylating the UDCA monomer and conjugating it to the surface of the avidinated PLGA NP. PLGA (100 mg) in 2mL of chloroform was added dropwise to a mixture of avidin-palmitate (10 mg/2 mL) and 2mL of 5% PVA in PBS and homogenized. The UDCA was conjugated to biotin (1:1 molar ratio) using EDC/NHS chemistry prior to immobilization of biotinylated UDCA (0, 50, 250 and 1000 ng/mL) to the avidin-coated PLGA NP (5 mg/mL). To prepare plated TGR5, recombinant TGR5 receptor (5 μg/mL) was coated on the plate overnight and the non-specific binding sites were blocked using a protein blocking buffer. The TGR5 receptor on the plate was incubated with a useable amount (4 μg/mL) of fluorescent labelled TGR5 antibody for 2 hours at 4 ℃ and subsequently exposed to different concentrations of NP. After 2 hours of incubation, the plates were washed three times with PBS and the amount of Atto565-TGR5 antibody bound to the receptor was measured using a plate reader.
The data were in accordance with the following competitive inhibition equation (using Graphpad Prism) which gives the estimated value of pucca (EC) at which 50% of the labeled antibody was completely removed 50 ) And affinity constant (K) i ):
Wherein the method comprises the steps of
F = fluorescence change upon competition with the labeled TGR5 antibody;
concentration of [ pucca ] =pucca;
F initial initiation Upper plateau of =fluorescence or initial fluorescence;
F final result Lower plateau of =fluorescence or final fluorescence;
EC 50 concentration of pucca which reduces total fluorescence by 50%;
K i =pudca affinity constant;
C anti-cancer agent Concentration of the =labeled anti-TGR 5 antibody;
K d, resistance to Estimated affinity constant of labeled anti-TGR 5 antibodies to TGR5 receptor in nanomolar range.
It is estimated that a shell having a thickness corresponding to the diameter of the UDCA molecule can bind about 2000 UDCA monomers on a 350nm diameter pUDCA particle.
Quantification of endocytosis and exocytosis rates for NP: BMM was seeded in 96-well plates (10 5 Cells/well) and DIR loaded pUDCA, PLGA and PLGA/pUDCA blend NP (100 μg/mL) were added to the medium. Cells were incubated at 37 ℃ for 1, 3 and 6 hours, and endocytosis of NPs was measured using a plate reader. After washing the cells and replacing with fresh medium, exocytosis of the NPs was monitored at 37 ℃ or 4 ℃ by measuring DIR-labeled NPs released from BMMs to the medium over time. The following method is the first application of such an assay to determine the rate of endocytosis and exocytosis. A separate manuscript is being prepared and this method is discussed in more detail, but briefly as follows: the balanced endocytic-exocytosis reaction can be reduced to:
Wherein [ P ] = concentration of particles in medium (particle count/mL)
[C] Concentration of cells in culture medium (number of cells/mL)
[ PC ] = concentration of cell-associated pellet (pellet-cell number/mL)
k ex o=exocytosis rate (t -1 )
k ex o = endocytic rate (([ P)]·t) -1 )
Then, the process is carried out,
according to the signals reporting endocytic and exocytosis processes, it is a fluorescent signal associated with each process [ S ].
This differential equation has a solution between the two limits that no uptake has reached maximum uptake:
S 0 at any start time t 0 Signal at the time
Analysis and fitting of kendo and kexo was done using two graphs.
Exocytosis period
Where St is the signal at any time (t)
S0 is an arbitrary time (t 0 ) Signal at the time
Association period
The association phase was analyzed according to two graphs:
dS/dt gives S
At slope = - (k) endo [P]+k exo ) When intercept=k endo [P]S max ,
Equation 9
And Ln (dS/dt) gives t
At slope = - (k) endo [P]+k exo ) When intercept=1, n (k endo [P]S max )),
Equation 10.
Assume that: this analysis did not take into account the reuptake of the particles after exocytosis.
Flow cytometry and ELISA: cd4+cd8+ cells and cd4+cd25+foxp3+ tregs were obtained 3 days and 5 days after CY treatment for CY-induced mice. For spontaneous T1D animal models, T cells were collected on day 1 after the last NP dosing. In both cases, pancreatic lymph nodes were collected and processed with a 40pm cell filter. Cell surface markers were determined by incubation at 4℃for 30 min with fluorescent antibodies against CD8 (APC), CD44 (PE), CD4 (APC) and CD25 (Alexa Fluor-700). Cells were then fixed, permeabilized and Foxp3 (PE) stained using Foxp3 staining kit (e biosciences). Immediately after the last wash, the samples were run on an LSR-II polychromatic flow cytometer (BD Biosciences) and analyzed using FlowJo software (Tree Star). To study antigen-specific T cell responses, OVA-specific cd4+ cells were used in OTII co-culture assays. BMDC (2.5X10) 4 Individual cells/well, 96-well plates) were pretreated with pUDCA NP for 24 hours, washed, and then stimulated with LPS (10 ng/mL) and OVA (20. Mu.g/mL) for 24 hours, followed by OTII CD4+ T cells (5X 10) 4 Individual cells/well, 96-well plate) were co-cultured for 3 days. Cell proliferation and cytokine production were then quantified.
BMM(10 5 Individual cells/well, 96-well plates) were incubated with pUDCA NP (50. Mu.g/mL), UDCA monomer (50. Mu.g/mL), PLGA (50. Mu.g/mL) or PBS for 4 hours, and CpG (100 ng/mL) was added. After 20 hours, IL-6, IL-10 and CCL1 readings were collected from the culture supernatant. Cells were stained for F4/80 (Alexa Fluor-647), CD86 (PE) and CD206 (FITC). After washing 3 times with buffer (2% fbs in PBS), the samples were fixed in 2% paraformaldehyde and run on an Attune NxT polychromatic flow cytometer (life technologies). CD11c-F4/80+NP+ was used for NP tracking of macrophages with dye-loaded particles. Np+ designation refers to reading particles by dye-loaded fluorescence. Mice were fasted for 4 hours and treated with labeled pUDCA NP by oral gavage (500 mg/kg, 250. Mu.L). After one day, pancreas, liver, lung and spleen were harvested, gently processed with a homogenizer, and cells were isolated from the debris using a 40pm cell filter and piston. With a reagent directed against F4/80 (Alexa Fluor) -700) and CD11c (PE-Cy 7) and was stained for cell surface markers and measured by Attune NxT polychromatic flow cytometry. All antibodies were diluted 1:500 for flow cytometry and cytokines (IL-6, IL-10 and IFNγ) were measured by ELISA (BD biosciences).
Biodistribution and histology:
b6 mice, NOD mice or nude mice were fasted for 4 hours and treated with DIR-or coumarin 6-encapsulated NPs by oral gavage (50, 100 or 500mg/kg, 250. Mu.L). Free DIR or coumarin 6 (dissolved with 1% tween 20) was used as control. Mice were sacrificed at time points of 4, 8, 12 or 24 hours after gavage and isolated organs were scanned using a Bruker molecular imaging instrument (ruke medical company) to measure fluorescence intensity. The fluorescence data conforms to a single component exponential decay model: y=y f +(Y o -e -kt ). DIR-loaded NPs formulated from pUDCA, PLGA or mixtures (50:50, w/w) were also administered Intravenously (IV) to mice by tail infusion (100 mg/kg, 50. Mu.L) to compare their biodistribution with free dye. Macrophage depletion reagent kitEncapula nanoscience, 100mg/kg, intraperitoneal (IP) injection) was used to deplete macrophages in B6 mice. For histology, pancreas from mice orally receiving iron oxide loaded pucca NP was fixed in 10% neutral buffered formalin for the passage of hematoxylin and eosin (H &E) Histological analysis was performed with Prussian blue staining. Stained sections were prepared by the university of jerusalem histology service center. Tissues were imaged on a Nikon TE-2000U microscope with a Nikon DS Fil color camera and NIS element AR software (version 2.30).
Diabetes animal model experiment: NOD mice were intraperitoneally injected with CY (200 mg/kg) to induce acute type I diabetes (T1D) (fig. 4A-4I). After 24 hours, mice were orally gavaged with empty NP, RAPA-loaded NP (50, 100 and 500mg NP/kg = 40mg RAPA/kg), soluble RAPA (40 mg/kg dissolved with 1% tween 20) and saline. pUDCA (pUDCA) RAPA Orally administered on day 1 (dose I) or on days 1 and 2Two administrations (dose II). Using blood sugar monitorMeter, home diagnostic company) monitors blood glucose levels. Two readings above 200mg/dL (1 day apart) are considered to be indicative of the onset of T1D. pUDCA was prepared using this model RAPA Comparison was made with insulin administered as "gold standard" insulin, subcutaneously (SQ) or Intraperitoneally (IP). pUDCA was given in 7 consecutive injections of insulin or orally given bolus doses of insulin INS Thereafter, blood glucose was measured over the course of 25 days. Using the operative receptor depletion model y=basal+ (action max Basic)/(1 + operation) fitting data, where operation= (((10) logkA )±(10 X ))/(10 (logtau+X) )) n Action max is the largest possible systemic response, the basis is the response in the absence of agonist, kA is the agonist-receptor dissociation constant, and tau is the kinetics of reduction to half-maximal response.
For the spontaneous T1D model, NOD mice were housed for approximately 2 months to allow for natural development of T1D. For the spontaneous T1D model, NOD mice of the same age (8 weeks of age) were selected for study only when they became diabetic at the same week (16 weeks of age, after 2 random tail vein blood glucose measurements of 200.+ -.15 mg/dL). Mice were orally treated 7 times with empty NPs, INS loaded NPs (100 or 500mg NP/kg and 285mIU INS/kg) or free INS (285 mIU/kg) for 1 week to monitor diabetes and body weight. GLP-1 concentration was measured from plasma using ELISA kit (Injetty Corp.). Fasted pigs>12 hours, with water, and IV administration of tetraoxapyrimidine (250 mL,150 mg/kg). Animals (n=3) were given 7 times daily oral gavage of pucca 10 days after tetraoxapyrimidine treatment INS (6.4 mg/kg, equivalent to 100mg/kg in mice) and glucose readings were monitored using the continuous glucose monitoring system DexCom 6 (Dekang).
The whole blood sample was calibrated by ear-stick using a Relion Prime BG glucometer (rayleigh inc.) and further vein-calibrated by antai diagnosis.
Calculation of the selected INS dose in spontaneous T1D study: it is known that an INS of 1 International Unit (IU) is required to lower the blood glucose level of 50mg/dL in humans. In order to reduce the hyperglycemia level (> 400 mg/dL) below the hyperglycemia threshold (200 mg/dL), at least 4IU of INS is required. The INS of the mice was 0.02IU according to the following equation (9).
Where HED = human equivalent dose (mg/kg), animals NOAEL = no observed adverse effect level (mg/kg) of animals, 1IU INS = 0.036mg based on world health organization conversion factor.
The INS loading in pUDCA NP was about 20ng/mg Np and 5.6X10 4 IU/mg NP. For feeding 0.02IU INS, 35mg pUDCA should be treated for a single mouse INS NP. Thus, diabetic mice were treated with 3 doses of 10mg NP and mice were continued to be treated with another 4 doses to maintain low glucose levels (0.04 IU INS and 70mg NP total).
Toxicology of pUDCA and UDCA: acute toxicity studies were performed on female B6 mice of 10 weeks of age. pUDCA (100 and 500 mg/kg) and UDCA (100 mg/kg) were orally administered to mice on day 0. The serum concentration of alkaline phosphatase, alanine transferase concentration, total bilirubin concentration and blood urea nitrogen concentration were analyzed on days 3, 5 and 7 using a kit from eastern diagnostic company (Teco diagnostic). EDTA anticoagulated blood was analyzed with a Hemavet blood counter (Deruujie Corp.).
And (3) statistics: all statistical analyses were performed using GraphPad Prism software (version 7.01). Experimental comparisons were made for multiple groups using ANOVA analysis of post-partum bonfield test or double tailed schwann t-test. Log rank test and χ on survival data 2 And (5) carrying out statistical analysis. A P value of 0.05 or less is considered statistically significant.
Example 2: pUDCA is a vector and not just an additive metabolism/immune modulator.
Materials and methods
Materials and methods are described above.
To test insulin production by pancreatic beta cells promoted by activation of TGR5 receptor, mouse pancreatic beta cell line (MIN 6, ATCC) cells were incubated in hank's balanced salt solution (HBSS, life technologies) containing 3mM glucose for 2 hours and then in HBSS containing 25mM glucose and UDCA, PLGA or pucca NP (40 μg/mL) for 30 minutes. Insulin concentration was measured using ultrasensitive insulin ELISA kit (ALPCO).
The same experiment was performed in the presence of the TGR5 antagonist triamcinolone acetonide (50 μg/mL) as a control to distinguish intrinsic insulin production from cells that did not activate TGR5 and used to normalize the results.
To test insulin production by pancreatic beta cells promoted by activation of TGR5 receptor, mouse pancreatic beta cell line (MIN 6, ATCC) cells were incubated in hank's balanced salt solution (HBSS, life technologies) containing 3mM glucose for 2 hours and then in HBSS containing 25mM glucose and UDCA, PLGA or pucca NP (40 μg/mL) for 30 minutes. Insulin concentration was measured using ultrasensitive insulin ELISA kit (ALPCO). The same experiment was performed in the presence of the TGR5 antagonist triamcinolone acetonide (50 μg/mL) as a control to distinguish intrinsic insulin production from cells that did not activate TGR5 and used to normalize the results.
Plated anti-CD 28. Mu.g/mL soluble and anti-CD 3. Mu.g/mL are used to stimulate OTII CD4+ T cells (5X 10) 4 Individual cells/well, 96-well plate) for 3 days. Ifnγ was determined by ELISA (BD biosciences).
Results
pUDCA serves as a drug carrier, but is also therapeutic in nature. Thus, for pUDCA INS Glycemic control is the convolution of inherent therapeutic benefits resulting from the strong attachment of the BA receptor, directly to the blood pool providing insulin. Figures 6H and 6I show the bioavailability of insulin in materials in both the pancreas and blood pool. First, consistent with early studies of the biodistribution of orally ingested dye-loaded pUDCA, insulin provided by pUDCA first appeared higher in the pancreas and then flowed naturally to the bloodThe pool underscores the concept that pUDCA-mediated insulin delivery occurs in a physiologically relevant manner, where insulin originates from the pancreas and is then available in the blood. pUDCA was fed orally with force INS At the last 4, 8, 24 hours, an increase in pancreatic and blood insulin from pucca compared to soluble insulin delivered or injected by PLGA was observed.
Second, the inherent therapeutic properties of pUDCA are emphasized by the fact that: without encapsulated insulin, it increased secretion of endogenous glucagon-like peptide (GLP-1) and production of insulin (fig. 6J and 6K). GLP-1 is an incretin, has insulinotropic activity, and can reduce blood glucose levels by promoting endogenous insulin secretion. The fact that GLP-1 secretion by enteroendocrine L cells is lost after blocking TGR5 receptor in vivo after pucca uptake underscores the role of pucca in binding TGR5 and inducing therapeutic effects beyond insulin delivery alone. Indeed, in addition to metabolic control of insulin, binding to TGR5 resulted in T cell frequency immunomodulation, decreased cd44+cd8+ T cell frequency in pancreatic lymph nodes of animals treated with pucca, increased Treg (fig. 6L and 6M), consistent with the T1D prevention study (fig. 4F-4I).
Both UDCA and pucca were able to induce more insulin secretion from pancreatic beta cells than PLGA particles (fig. 3M).
A decrease in interferon gamma (ifnγ) was also observed when T cells were exposed to pucca and subsequently bound to antigen presenting dendritic cells (fig. 3D), or when cd4+ T cells were treated directly with pucca and stimulated with anti-CD 3 and anti-CD 28 (fig. 3N) and macrophages were phenotypically sloped from Ml to M2 (fig. 6N and 6O, fig. 3E). Thus, the anti-inflammatory function of pucca spans a variety of immune mechanisms from innate immunity to adaptive immunity, and is consistent with previous reports that exemplify various therapeutic and immunomodulatory aspects of monomeric UDCA in different disease states. However, pUDCA is a very efficient form of UDCA, and thus introduces mechanisms and functional modes that UDCA alone cannot achieve, as shown in FIGS. 6A-6O.
Prevention of t1 d: verification of pUDCA loaded with RAPA.
Given the biodistribution properties of pucca and the potential role of binding TGR5 with high affinity, leading to therapeutic agonism in inducing anti-inflammatory responses, the role of pucca in preventing T1D was studied. Two T1D animal models were utilized: chemically induced pancreatic inflammation using Cyclophosphamide (CY) was used for prophylaxis studies (fig. 4A-4I) and for treatment of spontaneous murine non-obese diabetic (NOD) mouse models of T1D (fig. 6A-6O). Initial control of disease pathophysiology is achieved using a chemically inducible model, and thus the optimal time for preventive intervention is chosen.
Materials and methods
Materials and methods are described above.
This study compared pUDCA with the monomers UDCA, polylithocholic acid (pLCA) and polydeoxycholic acid (pDCA). Although LCA and DCA are known pro-inflammatory and carcinogenic agents, they are strong natural agonists of TGR5 and were used for comparison with pucca and its monomer UDCA in preventing T1D (fig. 4A). CY (200 mg/kg) was injected Intraperitoneally (IP) to induce diabetic animals, and animals were administered at two doses of 500mg/kg on days 1 and 2. Blood glucose levels were then monitored for 30 days.
RAPA is a macrolide mTOR inhibitor with immunosuppressive effects, involving reduced sensitivity of T and B cells to interleukin-2 (IL-2) 51. One time after induction (dose I) or two times on days 1 and 2 (dose II) of RAPA-encapsulated pUDCA (pUDCA) RAPA 0.08mg/mg NP) (FIG. 4A).
Results
Remarkably, oral intake of pucca resulted in the lowest blood glucose levels compared to pLCA, pDCA and even UDCA, and the frequency of conversion to diabetic state was the lowest without any loading of drug (fig. 4B and 4C). Although LCA and DCA are the two strongest TGR5 agonists, the benefit of pucca is greater than that of pLCA and pDCA. This may be mediated by differences in hydrophobicity and lower bioavailability compared to pUDCA, or because LCA and DCA are pro-inflammatory. The high initial affinity reduced avidity of LCA and DCA may also be a multivalent result; a ubiquitous biophysical phenomenon reduces intrinsic affinity with higher valency due to competition for limited BA receptor sites. Typically, pUDCA amplifies the therapeutic effects of UDCA and explores the mechanism of this amplified response and the potential for synergy with encapsulated drugs.
Although 60% of drug-induced mice showed high blood glucose levels by PLGA treatment 10 days after induction>200 mg/dL), but glucose levels were attenuated by the RAPA-loaded pucca NP in a dose-dependent manner for 30 days (fig. 4D and 4e,5a and 5B). PLGA alone RAPA And RAPA were unable to attenuate blood glucose to the same level, and 60% of animals developed T1D (fig. 4D and 4E). Analysis of cd4+ and cd8+ T cell responses in pancreatic draining lymph nodes of surviving animals (fig. 4F-4I) showed that pUDCA compared to saline RAPA The frequency of activated cd8+ T cells (cd44+) was reduced in treated mice (doses I and II were reduced by 63% and 88% on day 5, respectively). In addition, compared with saline, through pUDCA RAPA At the same time the frequency of regulatory (cd4+cd25+foxp3+) T cells (Treg) was increased (2.4 and 9.7 fold increase for doses I and II, respectively).
Example 4 multi-mode processing of t1 d: preclinical validation of orally administered insulin pucca.
Treatment of established diseases is a more challenging proposition due to the spontaneous nature of the pathology and the heterogeneity of disease manifestations over time. Since insulin is a "gold standard" systemic therapeutic, insulin loaded pucca (pucca was tested in NOD T1D animal models INS ) Ability to eradicate established diseases. This is a long-history model, which is a model of human equivalent diabetes in mice, with clear expectations in terms of therapeutic effects of soluble insulin.
Materials and methods
pUDCA was used at two different doses INS NOD mice with blood glucose levels of about 200mg/dL (100 or 500mg/kg, corresponding to 2 and 10mg NP per animal, respectively) were fed orally (fig. 6A). Due to the weak agonistic nature of monomeric UDCA, a comparison with pUDCA was made at a higher dose (500 mg/kg). Based onA rough estimate of the predicted amount of insulin required to restore blood glucose levels to normal (below 200 mg/dL) is used to determine the dose; the cumulative dose per mouse in each group was 40mIU, corresponding to 10mg of particles per mouse per day for seven consecutive days (fig. 6A-6E).
Results
Glucose levels decreased after 2 doses of pUDCA encapsulating a total of 0.011IU of insulin; blood glucose levels were reduced to or below the diabetes threshold of 200mg/dL (fig. 6A). pUDCA significantly more effectively reduced blood glucose levels over a seven day period compared to its monomeric counterpart. For humans, 1IU of insulin typically corresponds to a 50mg/dL reduction in blood glucose. This result demonstrates that renormalization of blood glucose levels can be achieved in a more efficient manner in the short term at doses nearly 100 times lower with pucca than UDCA.
Table 3: the time required to reduce 50% glucose.
Pathway | T | |
Brine | Oral administration | 9474.0 |
Oral administration | 4318.0 | |
Soluble INS | SC | 7.4 |
IP | 0.3 | |
pUDCA INS | Oral administration | About 0 |
Example 5 antigen specific tolerance of pUDCA to model antigen ovalbumin
Materials and methods
Materials and methods are described above.
The pUDCA NPs tested were empty and contained only the antigen OVA (ovalbumin), or a combination of OVA and RAPA.
Two groups of mice were used for this study: group a was used to test efficacy with OTii adoptive transfer, and group B was used to evaluate efficacy in OTii mice (no cell transfer). The experimental setup is shown in fig. 7A and 7B.
Results
The results are shown in fig. 7C.
The results are also summarized in table 4 below.
Table 4 percentage change of cd25+foxp3-and cd25+foxp3+ cells from group a and group B mice (n=2).
Prevention of t1 d: verification of pUDCA loaded with RAPA.
Given the biodistribution properties of pucca and the potential role of binding TGR5 with high affinity, leading to therapeutic agonism in inducing anti-inflammatory responses, the role of pucca in preventing T1D was studied.
Treatment of established diseases is a more challenging proposition due to the spontaneous nature of the pathology and the heterogeneity of disease manifestations over time. Since insulin is a "gold standard" systemic therapeutic, insulin loaded pucca (pucca was tested in NOD T1D animal models INS ) Ability to eradicate established diseases. This is a long-history model, which is a model of human equivalent diabetes in mice, with clear expectations in terms of therapeutic effects of soluble insulin.
Materials and methods
Materials and methods are described above.
Two T1D animal models were utilized: chemically induced pancreatic inflammation using Cyclophosphamide (CY) was used for prophylaxis studies (fig. 9A-9B) and spontaneous murine non-obese diabetic (NOD) mouse models for treatment of T1D (fig. 11A-11O and table 6). Initial control of disease pathophysiology is achieved using a chemically inducible model, and thus the optimal time for preventive intervention is chosen.
This study compared pUDCA with the monomers UDCA, polylithocholic acid (pLCA) and polydeoxycholic acid (pDCA). Although LCA and DCA are known pro-inflammatory and carcinogenic agents, they are strong natural agonists of TGR5 and were used for comparison with pucca and its monomer UDCA in preventing T1D (fig. 9A).
CY (200 mg/kg) was injected Intraperitoneally (IP) to induce diabetic animals, and animals were administered at two doses of 500mg/kg on days 1 and 2. Blood glucose levels were then monitored for 30 days.
pUDCA was used at two different doses INS (100 or 500mg/kg, corresponding to 2 and 10mg NP per animal, respectively) NOD mice with blood glucose levels of about 200mg/dL were fed orally (FIG. 11A). Due to the weak agonistic nature of monomeric UDCA, a comparison with pUDCA was made at a higher dose (500 mg/kg). Determining a dose based on a rough estimate of a predicted amount of insulin required to restore blood glucose levels to normal (below 200mg/dL, see methods); the cumulative dose per mouse in each group was 40mIU, corresponding to 10mg of particles per mouse per day for seven consecutive days (fig. 11A-11E).
RAPA is a macrolide mTOR inhibitor with immunosuppressive effects, involving reduced sensitivity of T and B cells to interleukin-2 (IL-2) 51. One time after induction (dose I) or two times on days 1 and 2 (dose II) of RAPA-encapsulated pUDCA (pUDCA) RAPA 0.08mg/mg NP) (FIG. 9A).
Results
Remarkably, oral intake of pucca resulted in the lowest blood glucose levels compared to pLCA, pDCA and even UDCA, and the frequency of conversion to the diabetic state was the lowest without any drug loading (fig. 9B and 9C).
Table 5: the time required to reduce 50% glucose.
Pathway | T | |
Brine | Oral administration | 9474.0 |
Soluble INS | Oral administration | 4318.0 |
SC | 7.4 | |
IP | 0.3 | |
pUDCA ins | Oral administration | About 0 |
FIGS. 3A-3E are graphs showing distribution and uptake of polymeric bile acids (pBA) in vitro and in vivo. Although LCA and DCA are the two strongest TGR5 agonists, the benefit of pucca is greater than that of pLCA and pDCA. This may be mediated by its difference in hydrophobicity and lower bioavailability compared to pucca (fig. 3A), or because LCA and DCA are pro-inflammatory. The high initial affinity reduced avidity of LCA and DCA may also be a multivalent result; a ubiquitous biophysical phenomenon reduces intrinsic affinity with higher valency due to competition for limited BA receptor sites. Typically, pUDCA amplifies the therapeutic effects of UDCA and explores the mechanism of this amplified response and the potential for not only additive effects with encapsulated drugs.
Although 60% of drug-induced mice showed high blood glucose levels by PLGA treatment 10 days after induction>200 mg/dL), but glucose levels were attenuated by the RAPA-loaded pucca NP in a dose-dependent manner for 30 days (fig. 10A and 10B). PLGA alone RAPA Or RAPA cannot attenuate blood glucose to the same level and 60% of animals develop T1D. Analysis of cd4+ and cd8+ T cell responses in pancreatic draining lymph nodes of surviving animals showed PUDCA compared to saline RAPA The frequency of activated cd8+ T cells (cd44+) was reduced in treated mice (doses I and II were reduced by 63% and 88% on day 5, respectively).
In addition, compared with saline, through pUDCA RAPA At the same time the frequency of regulatory (cd4+cd25+foxp3+) T cells (Treg) was increased (2.4 and 9.7 fold increase for doses I and II, respectively).
When BDC and RAPA-pUDCA were administered (FIGS. 8B-8E), oral administration of pUDCA/insulin reversed hyperglycemia in the short term and induced long-lasting therapeutic immunomodulation in spontaneous T1D in NOD mice (FIG. 8A).
Glucose levels decreased after 2 doses of pUDCA encapsulating a total of 0.011IU of insulin; blood glucose levels were reduced to or below the diabetes threshold of 200 mg/dL. pUDCA significantly more effectively reduced blood glucose levels over a seven day period compared to its monomeric counterpart. For humans, 1IU of insulin typically corresponds to a 50mg/dL reduction in blood glucose. This result demonstrates that renormalization of blood glucose levels can be achieved in a more efficient manner in the short term at doses nearly 100 times lower with pucca than UDCA.
Example 7 insulin loaded pUDCA NP rapidly reversed tetraoxapyrimidine-induced diabetes in adult Ossabaw pigs.
Materials and methods
Materials and methods are described above.
In the tetraoxypyrimidine-induced diabetes, glucokinase is inhibited (short to medium term), and beta cell selective necrosis (long term) due to reactive oxygen species ROS formation is observed. Animals were "stable" after 10 days and had diabetes (fig. 9A and 9B).
The goal of this study was to test the therapeutic effect beyond the possible automatic recovery fluctuations of tetraoxadiazine (about 10% over a 10 day period). Three pigs were used for this study, pigs #2869, #2847 and #2832, with tetraoxapyrimidine-induced diabetes. Pigs received 7 days of pUDCA at a cumulative daily dose and 0.01% insulin at a dose of 6.4 mg/kg.
Results
The results in fig. 10A show that seven days of treatment of tetraoxapyrimidine-induced diabetic pigs with insulin-containing pucca produced significant changes in average blood glucose levels (fig. 10A and table 6). There was a significant change in blood glucose levels when treated with oral pucca-insulin when compared to treatment with subcutaneous insulin (fig. 10B and 10C). Fig. 10C shows that a single dose of pucca-insulin (ndp=200) is sufficient to eliminate the need for repeated SC insulin injections. FIG. 10E shows that pUDCA NP provides diabetes care and treatment from three aspects: oral delivery with good bioavailability for the treatment of late T1D and T2D, for the treatment of metabolic recovery of early T1D, and for the reduction of autoimmune reactivity of early T1D.
Table 6. Influence of pUDCA-insulin treatment on blood glucose levels (BG, in mg/dL) in tetrauracil-induced diabetic pigs.
Day 1 | Day 7 | Change% | |
Average BG | 199 | 102 | -49% |
Fasting BG | 144 | 81 | -44% |
Postprandial BG (0.5-4 hours) | 233 | 109 | -53% |
Example 8 antigen-specific tolerance in multiple sclerosis animal models
Materials and methods
Materials and methods are described above.
The experimental protocol is shown in fig. 11A. The immune and tolerogenic antigen is myelin oligodendrocyte glycoprotein 35-55 (MOG). Therapeutic administration, i.e., histological and physical evidence of disease. Traditional scores, 0 to 5 reflect tail weakness to hind/forelimb paralysis.
Results
Oral administration of PUDCA NP resulted in a significant decrease in disease scores. PUDCA-MOG is effective, but adding Rapa is most effective. MOG-containing soluble Rapa was ineffective, demonstrating the effects of PUDCA platform (delivery, cytoprotection and anti-inflammatory effects) (fig. 11B).
Example 9 antigen-specific tolerance in animal models of collagen-induced arthritis
Materials and methods
Materials and methods are described above.
The experimental protocol is shown in fig. 12A. The immune and tolerogenic antigen is Collagen (COL) used to model animals for rheumatoid arthritis. Semi-therapeutic dosing, i.e., histological evidence of disease, is used. Collagen-induced arthritis (CIA) disease scores were used with traditional scoring, 0 to 4 score per paw, up to 16 score per mouse.
On day 21, treatment was started after two doses of antigen challenge.
Results
Oral administration of PUDCA NP resulted in a decrease in disease scores. PUDCA-COL is effective, but adding Rapa is most effective. PUDCA-Rapa showed some efficacy, possibly reflecting synergistic anti-inflammatory activity. The model ended early due to severe disease. The results are shown in fig. 12B.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention belongs. The disclosures cited herein and the materials cited therein are specifically incorporated by reference.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
Claims (28)
1. A formulation for inducing antigen-specific tolerance or non-specific reduced inflammation in a subject, the formulation comprising an effective amount of nanoparticles comprising a bile acid esterified polymer having a molecular weight of between about 800 and 240,000 daltons (Da), an immune modulator that reduces an immune response to an antigen, reduces inflammation or increases regulatory T cells, and optionally an antigen associated with an undesired immune response.
2. The formulation of claim 1, wherein the bile acid esterified polymer has a molecular weight of between about 8000 and 20,000da, corresponding to a polymer of at least two bile acid monomers.
3. The formulation of claim 1, wherein the bile acid esterified polymer is selected from the group consisting of: polymeric ursodeoxycholic acid (pUDCA); lithocholic acid (pLCA); polymeric deoxycholic acid (pDCA); polymeric chenodeoxycholic acid (pCDCA); and polymeric cholic acid (pCA).
4. The formulation of claim 1, wherein the bile acid esterified polymer is pucca with a molecular weight between about 800 and 5000 da.
5. The formulation of claim 4, wherein the bile acid esterified polymer is pucca having the formula VII:
where n is a number between 2 and 20.
6. The formulation of claim 1, wherein the bile acid esterified polymer forms a surface on the nanoparticle comprising 100 to 5000 bile acid monomers and has an affinity for bile acid receptors that is at least 1.5 times greater than the affinity of the corresponding monomers forming the bile acid esterified polymer.
7. The formulation of claim 1, wherein the bile acid esterified polymer is a linear and/or branched polymer.
8. The formulation of claim 1, wherein the immunomodulator is selected from the group consisting of: rapamycin (sirolimus) and analogues of rapamycin.
9. The formulation of claim 1, wherein the immunomodulator is an immunosuppressant.
10. The formulation of claim 1, wherein the immunomodulator increases the number of regulatory T cells.
11. The formulation of claim 1, wherein the formulation comprises or is in a kit comprising: autoantigens, disease-specific antigens, species-specific antigens or expression vector-specific antigens.
12. The formulation of claim 1, comprising a diagnostic agent.
13. A method of inducing tolerance or reducing an immune response in a subject, the method comprising orally administering to the subject an effective amount of the formulation of claim 1.
14. The method of claim 13, wherein the nanoparticle preferentially distributes to an internal organ selected from the group consisting of: heart, kidney, spleen, lung, liver and pancreas.
15. The method of claim 13, wherein the subject has an autoimmune or allergic disease selected from the group consisting of: type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, food allergy, environmental allergy, and diseases with anti-drug or nucleic acid antibodies (ADA).
16. The method of claim 13, wherein the effective amount of the formulation comprises about 0.1mg nanoparticle/kg to 1000mg nanoparticle/kg body weight.
17. The method of claim 13, wherein the subject has type 1 diabetes, the method comprising orally administering to a subject in need thereof an effective amount of the formulation comprising an immunosuppressant or tolerance inducer to reduce blood glucose.
18. The method of claim 17, wherein the nanoparticle comprises rapamycin and insulin.
19. The method of claim 17, wherein the formulation is administered for a period of at least one week, at least two weeks, or at least three weeks.
20. The method of claim 17, wherein the formulation is administered once daily.
21. The method of claim 17, wherein the subject maintains healthy blood glucose for at least about three days, about five days, about one week, about two weeks, about one month, or more after discontinuing administration of the formulation of claim 1.
22. The method of claim 17, wherein the method increases the number of regulatory T cells in the subject.
23. The method of claim 17, wherein the method induces a tolerogenic phenotype in the subject.
24. The method of claim 13, wherein the subject has systemic lupus erythematosus, the method comprising orally administering to a subject in need thereof an effective amount of the formulation of claim 1 to reduce one or more symptoms of the disease.
25. The method of claim 13, wherein the subject has rheumatoid arthritis, the method comprising orally administering to a subject in need thereof an effective amount of the formulation of claim 1 to reduce pain.
26. The method of claim 13, wherein the subject has multiple sclerosis, the method comprising orally administering to a subject in need thereof an effective amount of the formulation of claim 1 to reduce one or more symptoms of the disease.
27. The method of claim 13, wherein the drug has or is at risk of developing an anti-drug antibody, the method comprising orally administering to a subject in need thereof an effective amount of the formulation of claim 1 to induce tolerance to the drug.
28. The method of claim 13, wherein the subject has an allergy, the method comprising orally administering to a subject in need thereof an effective amount of the formulation of claim 1 to reduce an allergic response.
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US5489680A (en) | 1992-10-13 | 1996-02-06 | American Home Products Corporation | Carbamates of rapamycin |
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