US20150328254A1 - Fucoidan nanogels and methods of their use and manufacture - Google Patents

Fucoidan nanogels and methods of their use and manufacture Download PDF

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Publication number
US20150328254A1
US20150328254A1 US14/689,683 US201514689683A US2015328254A1 US 20150328254 A1 US20150328254 A1 US 20150328254A1 US 201514689683 A US201514689683 A US 201514689683A US 2015328254 A1 US2015328254 A1 US 2015328254A1
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Prior art keywords
nanogel
selectin
fucoidan
drug
nanoparticles
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US14/689,683
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Inventor
Daniel A. Heller
Yosef SHAMAY
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Memorial Sloan Kettering Cancer Center
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Memorial Sloan Kettering Cancer Center
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Priority to US14/689,683 priority Critical patent/US20150328254A1/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: SLOAN-KETTERING INST CAN RESEARCH
Assigned to MEMORIAL SLOAN KETTERING CANCER CENTER reassignment MEMORIAL SLOAN KETTERING CANCER CENTER ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HELLER, DANIEL, SHAMAY, Yosef
Publication of US20150328254A1 publication Critical patent/US20150328254A1/en
Priority to US15/069,311 priority patent/US9737614B2/en
Priority to US16/241,954 priority patent/US10478506B2/en
Abandoned legal-status Critical Current

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    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates generally to nanogels and methods of their manufacture and therapeutic use.
  • the invention relates to polymeric fucoidan-based nanogel vehicles for the treatment of cancer and other diseases associated with P-selectin.
  • Nanogels porous nanoscale hydrogel networks—are a class of nanomaterials with tunable chemical properties that facilitate targeting and delivery to specific tissues. They are intrinsically porous and can be loaded with small drugs or macromolecules by physical entrapment, covalent conjugation or controlled self-assembly. The porosity of nanogels protect the drugs they carry from degradation and environmental hazards; hence, nanogels can be used as drug delivery agents and contrast agents for medical imaging.
  • Fucoidans are a class of sulfated, fucose-rich polymers that can be found, for example, in brown macroalgae. Fucoidans have been reported to have anticoagulant, antiviral, anti-inflammatory, and anticancer activities, as well as high affinity to P-selectin. P-selectin is an inflammatory cell adhesion molecule responsible for leukocyte recruitment and platelet binding. It is expressed constitutively in endothelial cells where it is stored in intracellular granules (Weibel-Palade bodies).
  • P-selectin Upon endothelial activation with endogenous cytokines or exogenous stimuli such as ionizing radiation, P-selectin translocates to the cell membrane and into the lumen of blood vessels. P-selectin expression has been found to increase significantly in the vasculature of human lung, breast, and kidney cancers. P-selectin has been shown to facilitate the process of metastasis by coordinating the interaction between cancer cells, activated platelets and activated endothelial cells.
  • P-selectin is expressed in stroma and cancer cells in may human tumors, as well as in vasculature. Only one previous report describes P-selectin expression in cancer cells—a metastatic pancreatic tumor cell line.
  • endothelial-specific adhesion molecules such as ICAM-1, VCAM-1, CD31/PECAM-1 and VE-cadherin has been applied to various types of cancer cells and associated with increased metastasis and poor patient prognosis.
  • Nanoparticle drug carriers targeting the neovasculature are currently under clinical development, however, targeted delivery of therapeutic agents to micro-metastases or tumors lacking neovasculature remains an enduring challenge.
  • a nanogel containing fucoidan has been produced by chemical acetylation of the hydroxyl groups of fucoidan, rendering it amphipilic and able to form nanoparticles loaded with doxorubicin (Lee et al., Carbohydrate Polymers 95 (2013) 606-614).
  • doxorubicin Lee et al., Carbohydrate Polymers 95 (2013) 606-614.
  • specific affinity of the drug-containing nanogel to P-selectin is eliminated, thereby adversely affecting the ability of the nanogel to target cancer and other diseases associated with P-selectin.
  • nanogels that are capable of targeting to P-selectin and, therefore, are useful in the treatment of cancer and other diseases and conditions associated with P-selectin.
  • specific affinity to P-selectin requires both free hydroxyls and a proximate negative charge.
  • nanogels presented herein offer a drug release mechanism based on acidic pH in the microenvironment of a tumor, thereby providing improved treatment targeting capability and allowing use of lower drug doses, thereby reducing toxicity.
  • P-selectin is a new target for drug delivery in various cancers and contributes both at the tissue level and the cellular level. Since P-selectin is highly involved in inflammatory processes, it is useful for inflammatory diseases such as arthritis and atherosclerosis, which also involve P-selectin on endothelial cells. P-selectin is a cell adhesion molecule known to facilitate metastasis which is expressed in the vasculature of many human tumors. A delivery nanoparticle platform was developed using an algae-derived polysaccharide with intrinsic nanomolar affinity to P-selectin.
  • the nanoparticles target primary and metastatic tumors to impart a significant anti-tumor activity compared to untargeted nanoparticles encapsulating chemotherapies.
  • Single-dose administration of an encapsulated reversible MEK inhibitor results in prolonged inhibition of ERK phosphorylation and increased apoptosis at the tumor site.
  • ionizing radiation-induced P-selectin expression guides the targeted nanoparticles to the tumor site, demonstrating a potential strategy to target disparate drug classes to almost any tumor.
  • P-selectin was identified as a useful target for drug delivery and was used in a set of in vivo and in vitro models to explore its anti-tumor effectiveness, with multiple applications such as targeting aggressive primary and metastatic tumors using irreversible chemotherapies and reversible kinase inhibitor.
  • the nanogels described herein present fucoidan on their surface, specifically targeting P-selectin on activated platelets and activated endothelium.
  • the fucoidan on the surface of the nanoparticles making up the nanogel have free hydroxyl moieties and free sulfate moieties.
  • the nanoparticles release the drug moieties they contain in the acidic tumor microenvironment and lysosomes.
  • the fucoidan also appears to act as an immunomodulator, likely inducing an immune response against the tumor.
  • a fucoidan-based nanogel that delivers doxorubicin and releases it via pH-sensitive degradation of a hydrazone bond.
  • the doxorubicin is chemically conjugated to polyethylene glycol (PEG), but is only electrostatically bound to the anionic polymer fucoidan.
  • PEG polyethylene glycol
  • other cationic drugs may be used, for example, vincristine.
  • the particle size and charge can be modified according to the intended use.
  • nanogels are synthesized by non-covalent assembly of fucoidan with a hydrophobic drug.
  • Nanoparticle-drug assemblies synthesized using this method include, for example, particles encapsulating one or more of paclitaxel, MEK162, and ispinesib.
  • the invention encompasses methods of treatment of disease associated with P-selectin using the compositions described herein.
  • the compositions may be used in the treatment of malignant neoplasms including carcinomas, sarcomas, lymphomas, and leukemia.
  • the compositions may be used in other P-selectin-associated diseases such as sickle cell disease, arterial thrombosis, rheumatoid arthritis, ischemia, and reperfusion. Combination therapies are contemplated herein.
  • the use of compositions described herein with radiotherapy for improved P-selectin targeting and activity is contemplated.
  • the invention is directed to a polymeric nanogel with affinity to P-selectin
  • the nanogel comprises: (i) a sulfated polymer species comprising free hydroxyl moieties and sulfate moieties capable of targeting to P-selectin; and (ii) a drug.
  • the sulfated polymer species is a sulfated polysaccharide and/or protein.
  • the drug is a cationic drug.
  • the sulfated polymer species is a fucoidan.
  • the fucoidan is a sulfated polysaccharide comprising sulfated ester moieties of fucose.
  • the nanogel comprises nanoparticles that have a core comprising albumin and a surface comprising fucoidan.
  • the nanogel comprises polyethylene glycol (PEG), wherein the drug is conjugated to the polyethylene glycol via hydrozone linkages.
  • the drug is not chemically conjugated to the sulfated polymer species, but is electrostatically bound to the sulfated polymer species.
  • the sulfated polymer species is a fucoidan.
  • the drug is doxorubicin (DOX) ⁇ (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione ⁇ (trade name Adriamycin).
  • DOX doxorubicin
  • the drug is vincristine ⁇ (3aR,3a1R,4R,5S,5aR,10bR)-methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate ⁇ .
  • the cationic drug comprises one or more members selected from the group consisting of: DOX, vincristine, paclitaxel ⁇ (2 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ ,10 ⁇ ,13 ⁇ )-4,10-bis(acetyloxy)-13- ⁇ [(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy ⁇ -1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate ⁇ , MEK162 ⁇ 6-(4-bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide ⁇ , ispinesib ⁇ N-(3-aminopropyl)-N-[(1R)-1-(3-benzyl-7-chloro-4-oxoquinazolin-2-yl)-2-methylpropyl]-4
  • the nanogel comprises fucoidan and DOX-PEG-DOX constructs. In certain embodiments, the nanogel comprises fucoidan on the surface of nanoparticles of the nanogel. In certain embodiments, the nanogel comprises particles having an average particle diameter of from about 20 nm to about 400 nm (e.g., from about 100 nm to about 200 nm, or from about 150 nm to about 170 nm).
  • the nanogel further comprises a fluorophore.
  • the fluorophore is a near infra-red dye.
  • the near infra-red dye is IR783 ⁇ 2-[2-[2-Chloro-3-[2-[1,3-dihydro-3,3-dimethyl-1-(4-sulfobutyl)-2H-indol-2-ylidene]-ethylidene]-1-cyclohexen-1-yl]-ethenyl]-3,3-dimethyl-1-(4-sulfobutyl)-3H-indolium hydroxide, inner salt sodium salt ⁇ .
  • the nanogel is a pharmaceutical composition. In certain embodiments, the nanogel is pharmaceutically acceptable.
  • the invention is directed to a method of treating a P-selectin associated disease, the method comprising a step of administering to a subject in need of treatment a formulation comprising a polymeric nanogel with affinity to P-selectin, the nanogel comprising: (i) a sulfated polymer species comprising free hydroxyl moieties and sulfate moieties capable of targeting to P-selectin; and (ii) a drug; wherein the nanogel binds to P-selectin and translocates an active endothelial barrier.
  • the sulfated polymer species is a sulfated polysaccharide and/or protein.
  • the drug is a cationic drug.
  • the subject is human.
  • the formulation is a therapeutic agent.
  • the P-selectin associated disease is a member selected from the group consisting of carcinoma, sarcoma, lymphoma, leukemia, sickle cell disease, arterial thrombosis, rheumatoid arthritis, ischemia, and reperfusion.
  • the method comprises administering a radiotherapeutic, wherein the nanogel provides improved P-selectin targeting and activity.
  • the step of administering the nanogel results in targeted delivery of the drug to P-selectin.
  • a local environment having an acidic pH causes release of the drug from the nanogel.
  • the nanogel comprises PEG and the local acidic pH environment results in breakage of hydrozone linkages between the PEG and the drug.
  • the invention is directed to a method for manufacturing a nanogel comprising contacting fucoidan and a drug-PEG construct in the presence of a salt to form hydrogel aggregates, and agitating the hydrogel aggregates to form nanoparticles.
  • the drug-PEG construct is DOX-PEG-DOX.
  • the salt is a phosphonobile salt (PBS).
  • the agitating includes sonicating the hydrogel aggregates.
  • the invention is directed to a method for manufacturing a nanogel comprising contacting albumin, fucoidan, and sorafenib in an aqueous salt solution to form hydrogel aggregates, and agitating the hydrogel aggregates to form nanoparticles.
  • the albumin is Human Serum Albumin.
  • the salt solution is a phosphonobile salt (PBS).
  • agitating includes sonicating the hydrogel aggregates.
  • the invention is directed to a method for manufacturing a nanogel comprising contacting fucoidan and paclitaxel in an aqueous solution to form hydrogel aggregates, and agitating the hydrogel aggregates to form nanoparticles.
  • agitating includes sonicating the hydrogel aggregates.
  • the invention is directed to a polymeric fucoidan-based nanogel with affinity to P-selectin, the nanogel comprising a non-covalent assembly of fucoidan and a hydrophobic drug.
  • the hydrophobic drug comprises one or more members selected from the group consisting of paclitaxel ⁇ (2 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ ,10 ⁇ ,13 ⁇ )-4,10-bis(acetyloxy)-13- ⁇ [(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy ⁇ -1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate ⁇ , docetaxel ⁇ 1,7 ⁇ ,10 ⁇ -trihydroxy-9-oxo-5 ⁇ ,20-epoxytax-11-ene-2 ⁇ ,4,13 ⁇ -triyl 4-acetate 2-benzoate 13- ⁇ (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate ⁇ , Camptothecin ⁇ (S)-4-ethyl-4-hydroxy-1H-pyrano[3′,4′:6,7]
  • the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • administering refers to introducing a substance into a subject.
  • any route of administration may be utilized including, for example, parenteral (e.g., intravenous), oral, topical, subcutaneous, peritoneal, intraarterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments.
  • administration is oral. Additionally or alternatively, in some embodiments, administration is parenteral. In some embodiments, administration is intravenous.
  • amino acid refers to any compound and/or substance that can be incorporated into a polypeptide chain.
  • an amino acid has the general structure H2N—C(H)(R)—COOH.
  • an amino acid is a naturally occurring amino acid.
  • an amino acid is a synthetic amino acid; in some embodiments, an amino acid is ad-amino acid; in some embodiments, an amino acid is an 1-amino acid.
  • Standard amino acid refers to any of the twenty standard 1-amino acids commonly found in naturally occurring peptides.
  • Nonstandard amino acid refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source.
  • synthetic amino acid encompasses chemically modified amino acids, including but not limited to salts, amino acid derivatives (such as amides), and/or substitutions.
  • Amino acids, including carboxy- and/or amino-terminal amino acids in peptides, can be modified by methylation, amidation, acetylation, protecting groups, and/or substitution with other chemical groups that can change the peptide's circulating half-life without adversely affecting their activity. Amino acids may participate in a disulfide bond.
  • Amino acids may comprise one or posttranslational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.).
  • chemical entities e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.
  • amino acid is used interchangeably with “amino acid residue,” and may refer to a free amino acid and/or to an amino acid residue of a peptide. It will be apparent from the context in which the term is used whether it refers to a free amino acid or a residue of a
  • antibody polypeptide As used herein, the terms “antibody polypeptide” or “antibody”, or “antigen-binding fragment thereof’, which may be used interchangeably, refer to polypeptide(s) capable of binding to an epitope. In some embodiments, an antibody polypeptide is a full-length antibody, and in some embodiments, is less than full length but includes at least one binding site (comprising at least one, and preferably at least two sequences with structure of antibody “variable regions”). In some embodiments, the term “antibody polypeptide” encompasses any protein having a binding domain which is homologous or largely homologous to an immunoglobulin-binding domain.
  • antibody polypeptides encompasses polypeptides having a binding domain that shows at least 99% identity with an immunoglobulin binding domain.
  • antibody polypeptide is any protein having a binding domain that shows at least 70%, 80%, 85%, 90%, or 95% identity with an immunoglobulin binding domain, for example a reference immunoglobulin binding domain.
  • An included “antibody polypeptide” may have an amino acid sequence identical to that of an antibody that is found in a natural source.
  • Antibody polypeptides in accordance with the present invention may be prepared by any available means including, for example, isolation from a natural source or antibody library, recombinant production in or with a host system, chemical synthesis, etc., or combinations thereof.
  • an antibody polypeptide may be monoclonal or polyclonal.
  • An antibody polypeptide may be a member of any immunoglobulin class, including any of the human classes: IgG, IgM, IgA, IgD, and IgE.
  • an antibody may be a member of the IgG immunoglobulin class.
  • the terms “antibody polypeptide” or “characteristic portion of an antibody” are used interchangeably and refer to any derivative of an antibody that possesses the ability to bind to an epitope of interest.
  • the “antibody polypeptide” is an antibody fragment that retains at least a significant portion of the full-length antibody's specific binding ability.
  • antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, scFv, Fv, dsFv diabody, and Fd fragments.
  • an antibody fragment may comprise multiple chains that are linked together, for example, by disulfide linkages.
  • an antibody polypeptide may be a human antibody. In some embodiments, the antibody polypeptides may be a humanized.
  • Humanized antibody polypeptides include may be chimeric immunoglobulins, immunoglobulin chains or antibody polypeptides (such as Fv, Fab, Fab′, F(ab′)2 or other antigen binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity.
  • CDR complementary-determining region
  • an antigen is a molecule or entity to which an antibody binds.
  • an antigen is or comprises a polypeptide or portion thereof.
  • an antigen is a portion of an infectious agent that is recognized by antibodies.
  • an antigen is an agent that elicits an immune response; and/or (ii) an agent that is bound by a T cell receptor (e.g., when presented by an MHC molecule) or to an antibody (e.g., produced by a B cell) when exposed or administered to an organism.
  • an antigen elicits a humoral response (e.g., including production of antigen-specific antibodies) in an organism; alternatively or additionally, in some embodiments, an antigen elicits a cellular response (e.g., involving T -cells whose receptors specifically interact with the antigen) in an organism.
  • a particular antigen may elicit an immune response in one or several members of a target organism (e.g., mice, rabbits, primates, humans), but not in all members of the target organism species.
  • an antigen elicits an immune response in at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the members of a target organism species.
  • an antigen binds to an antibody and/or T cell receptor, and may or may not induce a particular physiological response in an organism.
  • an antigen may bind to an antibody and/or to a T cell receptor in vitro, whether or not such an interaction occurs in vivo.
  • an antigen may be or include any chemical entity such as, for example, a small molecule, a nucleic acid, a polypeptide, a carbohydrate, a lipid, a polymer [in some embodiments other than a biologic polymer (e.g., other than a nucleic acid or amino acid polymer)] etc.
  • an antigen is or comprises a polypeptide.
  • an antigen is or comprises a glycan.
  • an antigen may be provided in isolated or pure form, or alternatively may be provided in crude form (e.g., together with other materials, for example in an extract such as a cellular extract or other relatively crude preparation of an antigen-containing source).
  • antigens utilized in accordance with the present invention are provided in a crude form.
  • an antigen is or comprises a recombinant antigen.
  • associated typically refers to two or more entities in physical proximity with one another, either directly or indirectly (e.g., via one or more additional entities that serve as a linking agent), to form a structure that is sufficiently stable so that the entities remain in physical proximity under relevant conditions, e.g., physiological conditions.
  • associated moieties are covalently linked to one another.
  • associated entities are non-covalently linked.
  • associated entities are linked to one another by specific non-covalent interactions (i.e., by interactions between interacting ligands that discriminate between their interaction partner and other entities present in the context of use, such as, for example, streptavidin/avidin interactions, antibody/antigen interactions, etc.).
  • a sufficient number of weaker non-covalent interactions can provide sufficient stability for moieties to remain associated.
  • exemplary non-covalent interactions include, but are not limited to, electrostatic interactions, hydrogen bonding, affinity, metal coordination, physical adsorption, host-guest interactions, hydrophobic interactions, pi stacking interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, dipole-dipole interactions, etc.
  • ligand encompasses moieties that are associated with another entity, such as a nanogel polymer, for example.
  • a ligand of a nanogel polymer can be chemically bound to, physically attached to, or physically entrapped within, the nanogel polymer, for example.
  • Biocompatible The term “biocompatible”, as used herein is intended to describe materials that do not elicit a substantial detrimental response in vivo. In certain embodiments, the materials are “biocompatible” if they are not toxic to cells. In certain embodiments, materials are “biocompatible” if their addition to cells in vitro results in less than or equal to 20% cell death, and/or their administration in vivo does not induce inflammation or other such adverse effects. In certain embodiments, materials are biodegradable.
  • Biodegradable As used herein, “biodegradable” materials are those that, when introduced into cells, are broken down by cellular machinery (e.g., enzymatic degradation) or by hydrolysis into components that cells can either reuse or dispose of without significant toxic effects on the cells. In certain embodiments, components generated by breakdown of a biodegradable material do not induce inflammation and/or other adverse effects in vivo. In some embodiments, biodegradable materials are enzymatically broken down. Alternatively or additionally, in some embodiments, biodegradable materials are broken down by hydrolysis. In some embodiments, biodegradable polymeric materials break down into their component polymers.
  • breakdown of biodegradable materials includes hydrolysis of ester bonds. In some embodiments, breakdown of materials (including, for example, biodegradable polymeric materials) includes cleavage of urethane linkages.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • the composition described herein is a carrier.
  • “Combination Therapy” refers to those situations in which two or more different pharmaceutical agents for the treatment of disease are administered in overlapping regimens so that the subject is simultaneously exposed to at least two agents.
  • the different agents are administered simultaneously.
  • the administration of one agent overlaps the administration of at least one other agent.
  • the different agents are administered sequentially such that the agents have simultaneous biologically activity with in a subject.
  • Hydrolytically degradable materials are those that degrade by hydrolytic cleavage. In some embodiments, hydrolytically degradable materials degrade in water. In some embodiments, hydrolytically degradable materials degrade in water in the absence of any other agents or materials. In some embodiments, hydrolytically degradable materials degrade completely by hydrolytic cleavage, e.g., in water.
  • non-hydrolytically degradable typically refers to materials that do not fully degrade by hydrolytic cleavage and/or in the presence of water (e.g., in the sole presence of water).
  • “Pharmaceutically acceptable” refers to substances that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
  • Protein refers to a polypeptide (i.e., a string of at least 3-5 amino acids linked to one another by peptide bonds). Proteins may include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and/or may be otherwise processed or modified. In some embodiments “protein” can be a complete polypeptide as produced by and/or active in a cell (with or without a signal sequence); in some embodiments, a “protein” is or comprises a characteristic portion such as a polypeptide as produced by and/or active in a cell. In some embodiments, a protein includes more than one polypeptide chain.
  • proteins or polypeptide chains may be linked by one or more disulfide bonds or associated by other means.
  • proteins or polypeptides as described herein may contain Lamino acids, D-amino acids, or both, and/or may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, methylation, etc.
  • proteins or polypeptides may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and/or combinations thereof.
  • proteins are or comprise antibodies, antibody polypeptides, antibody fragments, biologically active portions thereof, and/or characteristic portions thereof.
  • physiological conditions The phrase “physiological conditions”, as used herein, relates to the range of chemical (e.g., pH, ionic strength) and biochemical (e.g., enzyme concentrations) conditions likely to be encountered in the intracellular and extracellular fluids of tissues.
  • chemical e.g., pH, ionic strength
  • biochemical e.g., enzyme concentrations
  • Polypeptide refers to a string of at least three amino acids linked together by peptide bonds.
  • a polypeptide comprises naturally-occurring amino acids; alternatively or additionally, in some embodiments, a polypeptide comprises one or more non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain; see, for example, http://www.cco.caltech.edu/ ⁇ dadgrp/Unnatstruct.gif, which displays structures of non-natural amino acids that have been successfully incorporated into functional ion channels) and/or amino acid analogs as are known in the art may alternatively be employed).
  • non-natural amino acids i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain; see, for example, http://www.cco.caltech.edu/ ⁇ dadgrp/Unnatstruct.gif, which displays structures of non-natural amino acids that have been successfully incorporated into functional ion channels
  • one or more of the amino acids in a protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc.
  • a chemical entity such as a carbohydrate group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc.
  • Polysaccharide refers to a polymer of sugars. Typically, a polysaccharide comprises at least three sugars.
  • a polypeptide comprises natural sugars (e.g., glucose, fructose, galactose, mannose, arabinose, ribose, and xylose); alternatively or additionally, in some embodiments, a polypeptide comprises one or more non-natural amino acids (e.g, modified sugars such as 2′-fluororibose, 2′-deoxyribose, and hexose).
  • substantially refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • Subject includes humans and mammals (e.g., mice, rats, pigs, cats, dogs, and horses). In many embodiments, subjects are be mammals, particularly primates, especially humans. In some embodiments, subjects are livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats. In some embodiments (e.g., particularly in research contexts) subject mammals will be , for example, rodents (e.g., mice, rats, hamsters), rabbits, primates, or swine such as inbred pigs and the like.
  • rodents e.g., mice, rats, hamsters
  • rabbits, primates, or swine such as inbred pigs and the like.
  • Therapeutic agent refers to any agent that has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect, when administered to a subject.
  • Treatment refers to any administration of a substance that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
  • FIG. 1 is a schematic diagram illustrating the preparation of pH-sensitive fucoidan nanogels for the delivery of doxorubicin (FiDOX), according to an illustrative embodiment of the invention.
  • FIG. 2A shows vials containing fucoidan-paclitaxel nanoparticles (FiPXL), according to an illustrative embodiment of the invention.
  • FIG. 2B shows the chemical structure of paclitaxel (PX) and fucoidan (Fi) in the fucoidan-paclitaxel nanoparticles, according to an illustrative embodiment of the invention.
  • FIG. 3A are plots of dynamic light scattering measurements of FiDOX nanogels, according to an illustrative embodiment of the invention.
  • FIG. 3B are transmission electron microscope images of nanogels, according to an illustrative embodiment of the invention.
  • FIG. 4 is a graph showing rate of release of doxorubicin from FiDOX nanogels over time, as a function of pH, according to an illustrative embodiment of the invention.
  • FIG. 5A shows a plot of fluorescence intensity demonstrating in vitro activity of FiDOX nanogels, according to an illustrative embodiment of the invention.
  • FIG. 5B shows a plot of an MTT cell viability assay, according to an illustrative embodiment of the invention.
  • FIG. 6 shows bioluminescence images demonstrating anti-tumor efficacy of FiDOX nanogels, according to an illustrative embodiment of the invention.
  • FIG. 7 is a plot of bioluminescence showing anti-tumor efficacy of FiDOX nanogels, according to an illustrative embodiment of the invention.
  • FIG. 8 is a plot showing laboratory mouse survival curve data following injection of FiDOX nanogel, according to an illustrative embodiment of the invention.
  • FIG. 9 is a schematic showing fucoidan-ispinesib nanogels (Fi-ISP) and analogous nanoparticles, according to an illustrative embodiment of the invention.
  • FIGS. 10A and 10B are electron micrographs of fucoidan-ispenesib nanoparticles (Fi-ISP) and PGA-ispinesib nanoparticles, according to an illustrative embodiment of the invention.
  • Fi-ISP fucoidan-ispenesib nanoparticles
  • PGA-ispinesib nanoparticles according to an illustrative embodiment of the invention.
  • FIG. 11 is an electron micrograph of fucoidan-MEK162 nanoparticles, according to an illustrative embodiment of the invention.
  • FIGS. 12A-12C illustrate P-selectin expression in human cancers.
  • FIG. 12A illustrates human tissue microarrays (TMA) stained with P-selectin antibody
  • Lymphoma normal tissue is from the spleen; Lymphoma 1: non-Hodgkin B cell lymphoma (Lymph node); 2: peripheral T cell lymphoma (Lymph node); 3: brain metastases of non-Hodgkin B cell lymphoma; Lung cancer 1: lung squamous cell carcinoma; 2: small cell undifferentiated carcinoma; 3: metastatic lung adenocarcinoma; Breast cancer 1: Infiltrating ductal carcinoma; 2: advanced infiltrating ductal carcinoma; 3: lymph node metastases of infiltrating ductal carcinoma.)
  • FIG. 12B illustrates a percentage of positively stained samples from the TMAs calculated with imaging software.
  • FIG. 12C illustrates data from The Cancer Genome Atlas showing P-selectin gene alterations in various cancers
  • FIGS. 12D-12E illustrate a preparation scheme of P-selectin targeted nanoparticles.
  • FIG. 12D illustrates preparation schemes for fucoidan-encapsulated paclitaxel nanoparticles (FiPAX) via nanoprecipitation (top) and doxorubicin-encapsulated fucoidan nanoparticles (FiDOX) (bottom) via layer-by-layer assembly, and SEM images of FiPAX and FiDOX nanoparticles (right).
  • FiPAX fucoidan-encapsulated paclitaxel nanoparticles
  • FiDOX doxorubicin-encapsulated fucoidan nanoparticles
  • FIG. 12E illustrates binding of IR783 dye loaded FiPAX to immobilized human recombinant P-selectin after 15 min of incubation. Fluorescence was measured with a fluorescent plate reader.
  • FIGS. 13A-13E illustrate anti-tumor efficacy of FiPAX vs. DexPAX with and without radiation.
  • FIGS. 14A-14E illustrate selective endothelial/tumor penetration assessments in vitro.
  • FIG. 14A illustrates assay to test penetration of nanoparticles into an activated endothelial monlayer barrier and infiltration into spheroids composed of tumor cells from a small cell lung cancer patient upon activation with TNF- ⁇ .
  • FIG. 14B illustrates fluorescence of FiPAX or DexPAX nanoparticles in the upper and lower chambers was measured with a fluorescence plate reader at 780 nm (excitation) and 815 nm (emission) after 1 h of incubation.
  • FIG. 14C illustrates the endothelial monolayer component of the chamber was visualized to estimate nanoparticle internalization using a fluorescent microscope equipped with a NIR sensitive XM10 Olympus CCD camera, binding/internalization of FiPAX or control DexPAX nanoparticles to a bEnd.3 endothelial cell monolayer (CellMask Green membrane stain) upon activation with TNF- ⁇ .
  • FIG. 14D illustrates fluorescence images of nanoparticle penetration into tumor spheres upon endothelial activation.
  • FIG. 14E illustrates quantification of tumor sphere uptake from 6 images per condition using ImageJ.
  • FIGS. 15A-15F illustrate targeting P-selectin positive and negative tumors in-vivo.
  • FIG. 15C illustrates radiation induced expression of P-selectin in mice with bilateral 3LL tumors treated with 6Gy gamma radiation on the right flank tumor only.
  • FIG. 15D illustrates a percentage of P-selectin positive blood vessels from entire CD31 stained blood vessels. Data is presented as the mean of 4 images per timepoint at 10 ⁇ .
  • FIG. 15E illustrates fluorescence efficiency from IR783 loaded FiPAX and DexPAX injected to 3LL tumor bearing mice with or without treatment of 6Gy gamma radiation on the right flank tumor only.
  • FIG. 15F illustrates tumor growth inhibition via single administration of nanoparticles after radiation treatment. The data is presented as mean ⁇ standard error.
  • FIGS. 16A-16D illustrate FiDOX efficacy in lung metastasis, P-selectin expression, and Bio distribution of FiDOX.
  • FIGS. 17A-17E illustrate the efficacy of P-selectin targeted nanoparticles in metastases.
  • FIG. 17A illustrates representative images of P-selectin and vasculature (CD31) staining in a B16F10 melanoma experimental lung metastasis model 14 days after inoculation.
  • FIG. 17B illustrates survival data from two experiments using the B16F10 metastasis model treated with a single injection on day 7 after inoculation.
  • FIG. 17C illustrates survival data from two experiments using the B16F10 metastasis model treated with a single injection on day 7 after inoculation.
  • FIG. 17D illustrates bioluminescence images acquired 7 days after a single administration of treatment with FiDOX, free doxorubicin (DOX), fucoidan vehicle (Fi), or PBS control.
  • FIG. 17E illustrates median photon count of the 6 treatment groups measured by IVIS and quantified by LivingImage software.
  • FIGS. 18A-18E illustrate FiMEK improved pERK inhibition and efficacy.
  • FIGS. 19A-19D illustrate inhibition of MEK improved anti-tumor efficacy and induced apoptosis by P-selectin targeted nanoparticles in vitro and in vivo.
  • FIG. 19A illustrates proliferation of and A549 cell lines measured after 4 days of treatment with MEK162 or FI-MEK as indicated (top), and biochemical analysis of A375 and A549 cell lines treated for 4 hours with MEK163 or FI-MEK (bottom).
  • FIG. 19C illustrates biochemical (western blot) quantification of pERK and Cleavage PARP on xenografts A375 tumors treated for 2 and 16 hours with MEK163 or FI-MEK.
  • FIG. 19D illustrates immunohistochemistry of Clevage PARP on xenograft HCT116 tumors treated with MEK162 or MEK-IR.
  • FIG. 20A shows the size distribution of FiDOX, DexDOX, FiPAX, and DexPAX nanoparticles.
  • FIG. 20B shows the zeta potential of FiDOX, DexDOX, FiPAX, and DexPAX nanoparticles.
  • FIG. 20C shows SEM images of FiPAX and FiDOX nanoparticles. Scale bar is 100 nm.
  • FIG. 20D shows that the sizes of FiDOX and FiPAX stays constant over a 5 day period.
  • FIG. 20E shows the release of DOX over time for pH 7.4 and pH 5.5.
  • FIG. 20F shows release of PXL over time for pH 7.4 and pH 5.5.
  • FIG. 21 shows proliferation of cell lines was measured after 4 days of treatment with MEK162 or FI-MEK as indicated. Open circle-MEK162, Open Square-FiMEK.
  • FIG. 22 shows the drug release profile MEK162 drug from nanoparticles over time at different pH.
  • FIG. 23A shows IHC staining of P-selectin expression in MEK162 sensitive HCT116 and SW620 xenografts.
  • FIG. 23B shows whole body imaging of FiMEK nanoparticles in A375 and SW620 xenografts 24 h post administration.
  • FIG. 23C shows percentage % of tumor size change as calculated from day 0.
  • FIG. 23D shows growth inhibition of different regiments.
  • FIG. 23E shows evaluation of apoptosis after single administration of MEK162 or FiMEK.
  • compositions are described as having, including, or comprising specific components, or where methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • Fucoidan is a sulfated polysaccharide that is found in various species of brown algae and brown seaweed. It can be obtained and purified from natural sources, or it may be synthesized. In general, fucoidan has an average molecular weight of from about 10,000 to about 30,000 (e.g., about 20,000), but other molecular weights may be found as well.
  • Naturally-occurring fucoidan includes F-fucoidan, which has a high content of sulfated esters of fucose (e.g., no less than 95 wt. %), and U-fucoidan, which contains sulfates esters of fucose but is about 20% glucuronic acid.
  • the fucoidan used in various embodiments described herein contains no less than 50 wt. %, no less than 60 wt. %, no less than 70 wt. %, no less than 80 wt. %, no less than 90 wt. %, or no less than 95 wt. % sulfate esters of fucose.
  • FIG. 1 is a schematic diagram 100 illustrating the preparation of pH-sensitive fucoidan nanogels for the delivery of doxorubicin (FiDOX).
  • the pH sensitivity is conferred by hydrozone linkages between doxorubicin and polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the fucoidan and DOX-PEG-DOX constructs are assembled via a layer-by-layer approach. Fucoidan (Fi) at 102 is contacted with the DOX-PEG-DOX construct (DPD) at 104 in the presence of a phosphonobile salt (PBS), thereby forming hydrogel aggregates at 106 .
  • PBS phosphonobile salt
  • the resulting aggregates are sonicated to form FiDOX nanoparticles.
  • the particles had average diameter of from about 150 nm to about 170 nm, with a zeta potential of ⁇ 55 mV.
  • the average particle diameter of FiDOX, or other drug-containing fucoidan nanogel is from about 20 nm to about 400 nm, or from about 100 nm to about 200 nm, or from about 150 nm to about 170 nm.
  • the average particle diameter may be measured, for example, via dynamic light scattering (DLS) of a nanogel dispersed in a solvent, or can be measured via transmission electron micrograph (TEM).
  • DLS dynamic light scattering
  • TEM transmission electron micrograph
  • the nanogel has a substantially monodisperse particle size (e.g., has polydispersity index, Mw/Mn of less than 20, more preferably less than 10, and still more preferably less than 5, less than 2, or less than 1.5, e.g., has polydispersity index in the range from 0 to 1, e.g., from 0.05 to 0.3).
  • Nanoparticles similar to FiDOX can be synthesized to encapsulate the drug vincristine, or other cationic drugs, by replacing the DOX-PEG-DOX construct with another drug construct containing the desired drug.
  • FIG. 2A shows vials containing fucoidan-paclitaxel nanoparticles (FiPXL). These were prepared using a self-assembly approach, without chemical conjugation. This can be performed to encapsulate other drugs as well, such as ispinesib, MEK162, and sorafenib, for example.
  • FIG. 2B shows the chemical structure of paclitaxel (PX) and fucoidan (Fi) in the fucoidan-paclitaxel nanoparticles.
  • FIG. 3A shows plots of dynamic light scattering measurements of FiDOX nanogels, showing the particle diameter characterization is stable over at least seven days.
  • FIG. 3B shows transmission electron microscope images of the FiDOX nanogels at different concentrations and magnification.
  • FIG. 4 is a graph showing the percentage of released doxorubicin from FiDOX nanogels over time, as a function of pH. Low pH allows faster release due to the breakage of hydrazone bonds.
  • FIG. 5A shows a plot of fluorescence intensity demonstrating in vitro activity of FiDOX nanogels.
  • the binding of FiDOX to immobilized P-selectin was estimated by measuring fluorescence intensity of bound particles. Soluble fucoidan was able to inhibit binding. A recombinant human P-selectin protein was immobilized on an ELISA plate. FiDOX particles were added to the wells for 15 min and then washed. The bound particles were detected with a fluorescence plate reader. Free fucoidan was used to inhibit the binding of the particles to the immobilized P-selectin on the surface. The particles did not bind to immobilized albumin (BSA).
  • BSA immobilized albumin
  • FIG. 5B shows a plot of an MTT cell viability assay. The plot shows that FiDOX was more cytotoxic to B16F10 cells compared to polyglutamic acid-based nanogels.
  • FIG. 6 shows bioluminescence images at day 21 of testing, demonstrating anti-tumor efficacy of FiDOX nanogels.
  • a luciferase-expressing B16F10 melanoma lung metastasis model was used. The cells were injected into the tail vein at day 0. The FiDOX particles and controls were injected at day 7. The progression of metastasis was monitored with bioluminescence imaging after injection of luciferin.
  • the bioluminescence images show the luciferase-expressing B16F10 cancer cells after injection of D-luciferin, 21 days after inoculation and 14 days after a single treatment.
  • FiDOX nanoparticles at 30 mg/kg and above clearly show more effective treatment than the untreated specimens, as well as specimens administered free DOX drug (not in nanoparticle form), or fucoidan nanoparticles without the DOX drug (Fi NPs).
  • FIG. 7 is a plot of bioluminescence from the same test, showing anti-tumor efficacy of FiDOX nanogels.
  • the median number of photons/sec/cm 2 /steradian was measured at given time points to demonstrate decreased tumor burden in FiDOX treated mice.
  • FIG. 8 is a plot showing laboratory mouse survival curve data in the B16F10 melanoma lung metastasis model treated with a single injection of FiDOX nanoparticles, injected on day 7. The results compared favorably to an injection of free doxorubicin (DOX), fucoidan alone (Fi), and the untreated control.
  • DOX free doxorubicin
  • Fi fucoidan alone
  • FIG. 9 is a schematic showing fucoidan-ispinesib nanogels (Fi-ISP) and analogous nanoparticles made by combining ispinesib with fucoidan or Poly Glutamic Acid (PGA) or PGA-PEG. Nanoparticles were formed by non-covalent assembly. Dynamic light scattering (DLS) plots are shown at 906 , 910 , and 914 .
  • FIGS. 10A and 10B are electron micrographs of the fucoidan-ispenesib nanoparticles (Fi-ISP) and PGA-ispinesib nanoparticles.
  • FIG. 11 is an electron micrograph of fucoidan-MEK162 nanoparticles.
  • Fucoidan from Fucus vesiculosus SIGMA and DPD were both dissolved in double distilled water and were mixed together at a weight ratio of 1:1 and formed immediate gel aggregates.
  • the aggregates were collected with centrifugation (15,000 g 10 min) and re-suspended in PBS containing excess of ⁇ 5 Fucoidan.
  • the mixture was sonicated with a probe sonicator 40% intensity (sonics vibra-cell) for 10 sec until a clear dark red solution appeared containing nanoparticles.
  • the particles were collected with centrifugation (30,000 g 30 min), re-suspended in PBS, and sonicated in a bath sonicator for 10 min.
  • FIGS. 20A-B The particles were characterized with DLS, TEM, and zeta potential measurement, and 150 nm particles were obtained with ⁇ 55 mV surface zeta potential measurements ( FIGS. 20A-B ).
  • FIG. 20C shows SEM images of FiDOX nanoparticles. Scale bar is 100 nm.
  • FIG. 20D shows that the sizes of FiDOX stay constant over a 5 day period.
  • FIG. 20E shows the release of DOX over time for pH 7.4 and pH 5.5.
  • FIG. 20E shows release of PXL over time for pH 7.4 and pH 5.5.
  • Paclitaxel-encapsulated fucoidan/dextran sulfate nanoparticles were synthesized using a nano-precipitation method.
  • 0.1 ml of paclitaxel dissolved in DMSO (10 mg/ml) was added drop-wise (20 ⁇ L per 15 sec) to a 0.6 ml aqueous polysaccharide solution (15 mg/ml) containing IR783 (1 mg/ml) and 0.05 mM sodium bicarbonate.
  • the solution was centrifuged twice (20,000 G 30 min) and re-suspended in 1 ml of sterile PBS.
  • the suspension of nanoparticles was sonicated for 10 sec with a probe sonicator at 40% intensity (Sonics).
  • the resulted nanoparticles had zeta potential of ⁇ 52 mV and a size of 95 nm with a PDI of 0.12 ( FIGS. 20A-B ).
  • PXL Paclitaxel
  • the nanoparticles were lyophilized with a saline/sucrose 5% solution and reconstituted in water at this concentration.
  • FIG. 20C shows SEM images of FiPAX nanoparticles.
  • FIG. 20D shows that the sizes of FiPAX stay constant over a 5 day period.
  • FIG. 20E shows the release of DOX over time for pH 7.4 and pH 5.5.
  • FIG. 20E shows release of PXL over time for pH 7.4 and pH 5.5.
  • 150 ⁇ l of BSA (20 mg/ml) was mixed with 150 ⁇ l of Fucoidan solution (80 mg/ml), then 150 ⁇ l of 0.1 M sodium bicarbonate buffer, pH 8.0, was added.
  • the mixture was frozen at ⁇ 80° C., freeze-dried, and heated at 60° C. for 5 hr. After heating, samples were dissolved in 1 ml of water, and purified with Sephadex G25 PD10 column to remove salts and unbound sugar, then freeze dried.
  • the Fucoidan BSA conjugate (Fi-BSA, 15 mg) was dissolved in 0.5 ml of water. 0.1 mg of IR783 (Sigma) in water was added to the solution. 1 mg of Paclitaxel in 0.1 ml of ethanol was added dropwise and the mixture was sonicated with a probe sonicator for 1 min. The mixture was centrifuged at 20,00 g for 20 min and the pellet was re-suspended in 1 ml PBS. 110 nm particles were obtained with ⁇ 45 mV surface zeta potential.
  • Human recombinant P- and E-selectin 50 ng in 50 ⁇ l was added to high hydrophobicity 96 well elisa plate and incubated at 4° C. overnight. The wells were washed with PBS, incubated with BSA (3% 0.2 ml), and incubated with FiPAX or DexPAX in Hank's balanced salt solution (HBSS) for 15 min. The wells were gently washed three times with HBSS and the binding of nanoparticles was evaluated using scanning fluorescence intensity performed by TECAN T2000 (‘multiple reads per well’ mode, ex 780 nm, em 820 nm).
  • Green—Cell membrane (ex 488 nm, em 525 nm), Blue—Nucleus (ex 350 nm, em 460 nm), Red—IR783 dye in particles (ex 780 nm, em 820 nm).
  • a modified Transwell assay was used to test penetration of particles through a monolayer of endothelial cells expressing P-selectin.
  • bEnd3 cells (5 ⁇ 10 4 in 0.5 ml) were grown on Transwell inserts in 24 wells plate for 7 days. The medium was replaced every other day. The confluence of the monolayer was validated with imaging of membrane cell staining to validate the lack of gaps between cell junctions. Following activation by TNF- ⁇ as described above, the cells were incubated with 20 ⁇ g/ml of nanoparticles for 1 h and then samples from the upper chamber (50 ⁇ l) and fluorescent intensity was measured with a fluorescence plate reader (TECAN T2000) at ex 780 nm, em 820 nm. To visualize the particles in the endothelial cells on the insert component of the chamber, the cells were washed twice with PBS and then incubated in HBSS. Images were acquired and processed as described above.
  • bEnd3 cells (5 ⁇ 10 4 ) were seeded in a 96-well plate. Nanoparticles were added to cells that were pre-activated by TNF- ⁇ for 30 min, at equivalent drug concentration, and were incubated for 1 h at 37° C. Cells not activated with TNF- ⁇ were treated similarly. The drug solution was then removed and replaced with fresh medium, followed by 72 h of incubation at 37° C. Cell survival was assayed by discarding the medium and adding 100 ⁇ l of fresh medium and 25 ⁇ l of 5 mg/ml MTT solution in PBS to each well. After 90 minutes, the solution was removed and 200 ⁇ l of DMSO were 10 added. Cell viability was evaluated by measuring the absorbance of each well at 570 nm relative to control wells.
  • Murine Lewis lung carcinoma LLC were maintained in Dulbecco's Modified Eagle Medium (DMEM) cell culture medium supplemented with 10% fetal bovine serum, 1 mM Na pyruvate, and 50 ug/ml penicillin and streptomycin.
  • DMEM Dulbecco's Modified Eagle Medium
  • Tumor cells were subcutaneously implanted (1 ⁇ 10 6 cells per injection) in both hind limbs of eightweek old hairless SKH-1 mice. The tumor models were used for biodistribution and tumor growth studies when the tumor size reached 0.5 cm in diameter.
  • Irradiation of the tumors was conducted at 6gy doses using X-ray irradiator.
  • NIR near infrared
  • mice were inoculated intravenously (i.v.) with 1 ⁇ 10 5 B16-F10 cells on day 0 and the tumor was allowed to establish until day 7.
  • mice were divided randomly into 5 groups and injected i.v. with FiDOX, Fi, DexDOX.
  • mice were monitored up to 8 or 17 weeks, depending on the treatment received. At the end of the experiments, mice were sacrificed, their lungs were collected, and the number of surface-visible tumors was examined. The Kaplan-Meier method was used to evaluate survival.
  • mice Six-week-old female athymic NU/NU nude mice were injected subcutaneously with 5 ⁇ 10 5 of A375, SW620, LOVO, and HCT116 in 100 ml culture media/Matrigel at a 1:5 ratio.
  • Animals were orally treated daily with MEK162 (10 mg/kg or 30 mg/kg in 0.5% carboxymethylcel-lulose sodium salt [CMC]; Sigma).
  • Xenografts were measured with digital caliper, and tumor volumes were determined with the formula: (length ⁇ width) ⁇ ( ⁇ /6).
  • mice were euthanized using CO 2 inhalation. Tumor volumes are plotted as means ⁇ SEM. Mice were housed in air-filtered laminar flow cabinets with a 12-hr light/dark cycle and food and water ad libitum.
  • tissue sections were deparaffinized with EZPrep buffer, antigen retrieval was performed with CC1 buffer, and sections were blocked for 30 minutes with Background Buster solution (Innovex).
  • Human P-Selectin/CD62P Monoclonal Antibody (Catalog #BBA30) at 5-15 ⁇ g/mL overnight at 4° C.
  • human tumors e.g., lymphomas
  • P-selectin primarily on cancer cells and to a lesser extent in the vasculature. Because of the augmented expression on certain tumor cells and vasculature, P-selectin was tested on targeted nanoparticles in a murine model that express P-selectin in both cancer and endothelial cells, models that only express endothelial P-selectin, and models that do not express P-selectin but it can be induced by radiation. For each of the models, appropriate drugs were chosen to achieve high response to a single injection, which demonstrated the platform capabilities of Fi-based nanoparticles.
  • a reversible MEK inhibitor encapsulated in fucoidan nanoparticles allowed evaluation of kinase inhibition in cancer cells and correlation with drug delivery to cancer cells. Comparison of a clinically relevant regimen of daily administration of MEK162 to a single or weekly dose of the nanoparticle formulation was performed. A single or a weekly administration of a reversible inhibitor such as MEK162 encapsulated in a nanoparticle was similar to or more effective as a daily administration. This demonstrates the effectiveness of the delivery system to reach not just endothelial cells but also cancer cells. The reduction of a chronic and systemic inhibition of the pathway and the increase in local tumor concentrations for prolonged periods of time using Fi nanoparticles will be more efficacious and better tolerated.
  • P-selectin was investigated as a target for localized drug delivery to tumor sites, including metastases. It was found that many human tumors surprisingly express P-selectin spontaneously within their stroma, tumor cells, and tumor vasculature.
  • a nanoparticle carrier was synthesized for chemotherapeutic and targeted therapies using the algae-derived polysaccharide, fucoidan, which exhibits nanomolar affinity for P-selectin. It was found that the targeting of activated endothelium improved the penetration of fucoidan-based nanoparticles through endothelial barriers, leading to a therapeutic advantage in P-selectin-expressing tumors and metastases.
  • SELP is amplified in many cancers including breast (27.5%), liver (15%), bladder urothelial carcinoma (13.4%), and lung adenocarcinoma (12.2%). Moreover, the expression of SELP is associated with poor prognosis in squamous cell carcinoma of the lung and renal cell carcinoma. ( FIG. 12C ). The abundant expression of P-selectin in cancer prompted the development a P-selectin-targeted vehicle for selective drug delivery.
  • fucoidan (Fi)-based nanoparticles were prepared to encapsulate three different drug classes with dose-limiting toxicities.
  • Fucoidan-encapsulated paclitaxel (PAX) nanoparticles (FiPAX) were synthesized by co-encapsulating paclitaxel, and a near infra-red dye (IR783) to facilitate imaging, via nano-precipitation as described above in Preparation of FiPAX and DexPAX nanoparticles ( FIG. 12D ).
  • a reversible MEK inhibitor, MEK162 was encapsulated in fucodian nanoparticles (FiMEK) in the same manner that FiPAX was prepared.
  • Fucoidan-encapsulated doxorubicin (DOX) nanoparticles were synthesized via layer-by-layer assembly of a cationic doxorubicin-polymer conjugate via pH sensitive hydrazone bond (DOX-PEG-DOX, DPD) and the anionic fucoidan ( FIG. 12E ).
  • the DPD conjugate was synthesized via pH-cleavable hydrazine linkages to promote release of the drug in the acidic tumor microenvironment or lysosomes.
  • the FiDOX, FiPAX and FiMEK nanoparticles measured 150 ⁇ 8.1 , 105 ⁇ 4.2 and 85 ⁇ 3.6 nm in diameter respectively, and exhibited approximately ⁇ 55 mV surface charge (zeta potential). Microscopy showed relatively uniform spherical morphology. As shown in Table 1 below and in FIGS. 13A-E , the particles exhibited good serum stability and reconstituted after lyophilization.
  • Dextran sulfate-encapsulated paclitaxel (DexPAX) nanoparticles were assembled with the same methods as used above.
  • the binding of FiPAX and DexPAX was compared to immobilized human recombinant P-selectin, E-selectin, and BSA, thereby confirming the selective binding to P-selectin in a dose dependent manner ( FIG. 12E : P ⁇ 0.05).
  • mice were randomized into 4 arms: PBS, FiPAX, DexPAX and paclitaxel (PAX). Upon 24 h and 72 h after injection of nanoparticles, the mice were imaged to compare particle localization.
  • PDX patient-derived xenograft
  • the average fluorescence intensity was 2.5 times higher than that of DexPAX after 24 h, and the signal difference increased to 4.1 times at 72 h ( FIG. 15A , FIG. 16B ).
  • FiPAX nanoparticles significantly inhibited tumor progression as compared to free paclitaxel or untargeted DexPAX nanoparticles ( FIG. 15B ).
  • nude mice were inoculated in both flanks with Lewis lung carcinoma (3LL) cells.
  • the resulting tumor did not endogenously express P-selectin, as observed by tissue staining ( FIG. 15C ).
  • the right flank tumor of each mouse was irradiated with 6 Gy, while the left tumors were left un-irradiated. It was observed that the expression of P-selectin in the irradiated tumor was apparent by 4 hours and increased substantially by 24 hours ( FIG. 15C ).
  • P-selectin expression was found in the non-irradiated tumors of the irradiated mice after a 24 hour delay ( FIG. 15C ), as well as an increase in soluble P-selectin (sP-selectin) in the blood of the irradiated mice ( FIGS. 16A-16D ).
  • the anti-tumor efficacy of P-selectin-targeted drug carrier nanoparticles was assessed against an aggressive experimental metastasis model.
  • the i.v. injection of 10 5 B16F10 melanoma cells results in lung metastases which exhibit P-selectin expression in the associated vasculature ( FIG. 17A-B ).
  • Three different doses of FiDOX (fucoidan-encapsulated doxorubicin) nanoparticles were then administered to identify a therapeutic window.
  • mice were divided into 6 groups of 5 mice and treated with a single dose of either free doxorubicin at 6 mg/kg or 8 mg/kg, close to the maximum tolerated dose, fucoidan (30 mg/kg), as a vehicle control, and three concentrations of FiDOX (1 mg/kg, 5 mg/kg and 30 mg/kg).
  • the treatment with FiDOX nanoparticles at all three concentrations resulted in decreased tumor burden and prolonged survival upon a single injection, whereas an equivalent amount of free doxorubicin at its maximum tolerated dose, did not have a significant effect ( FIG. 17C ). Fucoidan alone also showed no survival benefit.
  • tumor bioluminescence shows a clear reduction in median photon count in the medium and the high dose groups ( FIG.
  • the Ras-ERK pathway is frequently hyperactive in substantial types of cancers including melanoma, colorectal, and lung cancers, and therefores MEK/ERK reversible inhibitors have been tested in large number of clinical trials in RAS- and BRAF-mutated cancers. Blocking this pathway using systemic MEK/ERK inhibitors is, however, dose-limiting with only temporal target inhibition. At high dosage, these treatments cause toxicity in patients such as severe rash and chronic serous retinoscopy (CSR).
  • CSR chronic serous retinoscopy
  • P-selectin-targeted delivery improved the efficacy of reversible kinase inhibitors which are specific to cancer cells.
  • the delivery of MEK inhibitor to the tumor microenvironment using P-selectin targeted nanoparticles increased the concentration of drug in the tumor itself, therefore prolonging the duration of inhibition and reduce systemic toxicity.
  • MEK162 was co-encapsulated with IR783 within fucoidan-based nano-particles (FiMEK) in the same manner that FiPAX was prepared.
  • the release of the MEK162 by the nano-particle was sustained with maximum of 85% reached in 24 hours and accelerated by acidic pH ( FIG. 23A ).
  • FIG. 22 shows the drug release profile MEK162 from nanoparticles over time at different pH.

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9737614B2 (en) 2014-04-17 2017-08-22 Memorial Sloan Kettering Cancer Center Fucoidan nanogels and methods of their use and manufacture
US20180251574A1 (en) * 2018-05-02 2018-09-06 Arc Medical Devices Inc. Fucan-dendrimer based compounds and complexes
WO2020116831A1 (fr) * 2018-12-05 2020-06-11 주식회사 이노테라피 Microbilles pour chimioembolisation transartérielle et son procédé de fabrication
US11478493B2 (en) * 2019-03-08 2022-10-25 University Of South Carolina Fabrication and application of a hetero-targeted nano-cocktail with traceless linkers
WO2023006003A1 (fr) * 2021-07-27 2023-02-02 Mien-Chie Hung Composition pharmaceutique comprenant un polysaccharide

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2926888C (fr) * 2013-10-22 2020-03-24 Cell Receptor Gmbh Modulation de l'interaction physique entre les plaquettes et la surface des cellules affectant la proliferation des cellules
EP3470056B1 (fr) * 2017-10-16 2022-04-27 Medtronic Vascular Inc. Nanoparticules thérapeutiques pour le traitement de maladies vasculaires
US11879012B2 (en) * 2018-03-02 2024-01-23 Peter GILLIES Method of modulating cell proliferation
WO2019210414A1 (fr) * 2018-05-02 2019-11-07 Arc Medical Devices Inc. Composés et complexes à base de fucane
CN111529715B (zh) * 2020-04-22 2021-10-01 山东大学 一种右旋糖酐-二十二碳六烯酸偶联聚合物及其合成方法和应用
KR20220034504A (ko) 2020-09-11 2022-03-18 아주대학교산학협력단 셀루메티닙을 유효성분으로 포함하는 퇴행성 관절염 예방 또는 치료용 조성물
CN112461716B (zh) * 2020-10-29 2024-03-22 四川省肿瘤医院 大黄素联合索拉非尼的纳米制剂对HepG2增殖的抑制验证方法
CN113018461B (zh) * 2021-03-09 2022-07-26 南京邮电大学 一种可磁共振成像的岩藻多糖栓塞微球及其制备方法
EP4444346A1 (fr) * 2021-12-08 2024-10-16 ImmunityBio, Inc. Excipient d'administration de vaccin à néo-épitope et ses méthodes de fabrication

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110085974A1 (en) * 2008-06-13 2011-04-14 Cedars-Sinai Medical Center Small molecule ligand-drug conjugates for targeted cancer therapy

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4110854B2 (ja) * 2002-06-28 2008-07-02 マックス株式会社 電動ステープラ
WO2005072710A2 (fr) 2004-01-28 2005-08-11 Johns Hopkins University Medicaments et particules de transport de genes se deplaçant rapidement a travers les barrieres muqueuses
WO2007001448A2 (fr) 2004-11-04 2007-01-04 Massachusetts Institute Of Technology Particules polymeres revetues a diffusion regulee comme vecteurs efficaces d'administration par voie orale de produits biopharmaceutiques
WO2006091180A2 (fr) * 2005-02-25 2006-08-31 Ali Demir Sezer Systemes vecteurs du medicament multiparticulaire fucoidane
US20070238656A1 (en) 2006-04-10 2007-10-11 Eastman Kodak Company Functionalized poly(ethylene glycol)
US20140107062A1 (en) 2007-04-27 2014-04-17 Aravasc Inc. Compositions and methods for treating or preventing diseases of body passageways
JP5443976B2 (ja) 2007-05-01 2014-03-19 国立大学法人 東京医科歯科大学 化学架橋ヒアルロン酸誘導体を含むハイブリッドゲルおよびそれを用いた医薬組成物
WO2009129352A2 (fr) * 2008-04-15 2009-10-22 Windy Hill Medical Dispositif et procédé pour accéder aux canaux des glandes mammaires et les traiter
US20130030282A1 (en) 2011-07-18 2013-01-31 Bar Ilan University Synthesis and characterization of near ir fluorescent magnetic and non-magnetic albumin nanoparticles for biomedical applications
EP2736506B1 (fr) 2011-07-26 2018-09-05 University Of Southern California Inhibiteurs de monoamine oxydase et procédés pour le traitement et le diagnostic du cancer de la prostate
WO2013148158A1 (fr) * 2012-03-30 2013-10-03 President And Fellows Of Harvard College Nanoparticules thérapeutiques activées par laser
DE102012108345A1 (de) 2012-09-07 2014-05-15 Freie Universität Berlin Verfahren zur Herstellung eines Polyglycerin-Nanogels zur Verkapselung und Freisetzung biologisch aktiver Substanzen
US20140220346A1 (en) 2012-12-04 2014-08-07 Memorial Sloan-Kettering Cancer Center Modular polymer hydrogel nanoparticles and methods of their manufacture
US20150328254A1 (en) 2014-04-17 2015-11-19 Memorial Sloan Kettering Cancer Center Fucoidan nanogels and methods of their use and manufacture
US20180021259A1 (en) 2015-02-10 2018-01-25 Memorial Sloan Kettering Cancer Center Dye-stabilized nanoparticles and methods of their manufacture and therapeutic use
WO2016153920A1 (fr) 2015-03-20 2016-09-29 Memorial Sloan Kettering Cancer Center Nanoparticules à échelle moyenne permettant le ciblage sélectif de rein, et procédés pour leur utilisation thérapeutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110085974A1 (en) * 2008-06-13 2011-04-14 Cedars-Sinai Medical Center Small molecule ligand-drug conjugates for targeted cancer therapy

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9737614B2 (en) 2014-04-17 2017-08-22 Memorial Sloan Kettering Cancer Center Fucoidan nanogels and methods of their use and manufacture
US20180251574A1 (en) * 2018-05-02 2018-09-06 Arc Medical Devices Inc. Fucan-dendrimer based compounds and complexes
WO2020116831A1 (fr) * 2018-12-05 2020-06-11 주식회사 이노테라피 Microbilles pour chimioembolisation transartérielle et son procédé de fabrication
US11478493B2 (en) * 2019-03-08 2022-10-25 University Of South Carolina Fabrication and application of a hetero-targeted nano-cocktail with traceless linkers
WO2023006003A1 (fr) * 2021-07-27 2023-02-02 Mien-Chie Hung Composition pharmaceutique comprenant un polysaccharide

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US10478506B2 (en) 2019-11-19
US20160193349A1 (en) 2016-07-07
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US20190142960A1 (en) 2019-05-16

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