WO2017095924A1 - Compositions de promédicaments ciblant le foie et leurs méthodes d'utilisation - Google Patents

Compositions de promédicaments ciblant le foie et leurs méthodes d'utilisation Download PDF

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Publication number
WO2017095924A1
WO2017095924A1 PCT/US2016/064216 US2016064216W WO2017095924A1 WO 2017095924 A1 WO2017095924 A1 WO 2017095924A1 US 2016064216 W US2016064216 W US 2016064216W WO 2017095924 A1 WO2017095924 A1 WO 2017095924A1
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prodrug
drug
group
liver
moiety
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PCT/US2016/064216
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English (en)
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Venkata M. Yenugonda
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Georgetown University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the disclosed invention is generally in the field of drug delivery and disease treatment, and specifically in the area of drug delivery for and treatment of liver disease, such as hepatocellular carcinoma (HCC).
  • liver disease such as hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • HCC hepatocellular carcinoma
  • HCC liver transplantation
  • compositions delivered into cells via asialoglycoprotein receptors It is also an object of the present invention to provide compositions delivered into cells via asialoglycoprotein receptors.
  • compositions and methods of delivering a drug to a liver cell or liver tissue in a subject are a prodrug of a drug where the drug, a hydrophilic linker, and a liver-targeted glycol ligand are conjugated together.
  • the hydrophilic linker contains or is coupled to the drug via a cleavable bond such that the cleavable bond is cleaved and the drug released after delivery into a target cell.
  • prodrugs comprising a drug moiety and a transport moiety covalently coupled to the drug moiety.
  • the transport moiety comprises a hydrophilic spacer covalently coupled to the drug moiety, and at least one liver-targeted glycol ligand covalently coupled to the hydrophilic spacer.
  • the hydrophilic spacer comprises a cleavable bond, where cleavage of the cleavable bond separates the drug moiety from the transport moiety.
  • the liver-targeted glycol ligand can be one or more ⁇ -D-galactose (Gal) moieties, N-acetylgalactoseamine (GalNAc) moieties, or combinations thereof.
  • the hydrophilic spacer can be selected from the group consisting of: a substituted branched or unbranched saturated or unsaturated alkyl chain, a substituted or unsubstituted branched or unbranched saturated or unsaturated alkoxy chain, a substituted or unsubstituted branched or unbranched saturated or unsaturated alkylamino chain, and a substituted or unsubstituted branched or unbranched saturated or unsaturated alkylthio chain.
  • the hydrophilic spacer can comprise ethylene glycol.
  • the hydrophilic spacer has of a length of 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or 3 atoms.
  • the drug moiety is covalently coupled to the hydrophilic spacer of the transport moiety via the cleavable bond.
  • the cleavable bond is a bond selected from the group consisting of: an ester, an amide, and a carbonate.
  • the cleavable bond is an internal bond in the hydrophilic spacer.
  • the cleavable bond is hydrolyzable.
  • the drug moiety is a cancer therapeutic.
  • the cancer therapeutic is sorafenib.
  • the drug moiety is selected from the group consisting of temozolomide, sorafenib, erlotinib, gefitinib, imatinib, pazopanib, rapamycin, raloxifene, lasofoxifene, basedoxifene, resveratrol, curcumin, etoposide, camptothecin, CPT-11, topotecan, irinotecan, exatecan, lurtecan, DB67, BNP1350, ST1481, CKD602, paclitaxel, docetaxel, vincristine, vinblastine, fingolimod, raltegravir, elvitegravir, MK-2408, lersivirine, daunorubicin, doxorubicin, epirubicin, and idarubic
  • the prodrug is taken into the cell or tissue by an asialo-glycoprotein receptor (ASGP-R).
  • ASGP-R asialo-glycoprotein receptor
  • the subject suffers from hepatocellular carcinoma (HCC).
  • Figures 1 A and IB are diagrams of an example of a liver-targeted prodrug of sorafenib showing the prodrug design strategy (A) and ASGP-R mediated drug uptake (B).
  • A Design strategy for liver specific prodrug sorafenib analogs.
  • B Schematic of ASGP-R mediated drug uptake: (1)
  • Figure 2 is a graph showing in vivo liver specific targeting of a reporter gene by synthetic cationic glycolipids 3 & 6.
  • Synthetic-glycolipids (3 & 6) were prepared by covalently linked single galactose (both cyclic-and open) with varying spacer units to quartemized nitrogen. Mice were injected intravenously with glycolipid: DNA complex at 4: 1 charge ratio and luciferase activities were estimated 8 h post-injection using the methods described in Mukthavaram et al, Biomaterials 30:2369-2383 (2009).
  • Figures 3A, 3B, and 3C are diagrams showing examples of prodrug design strategy.
  • A Chemical structure of sorafenib.
  • B Interaction of sorafenib with targeted protein B Raf.
  • C Chemical structures of gly co- conjugated sorafenib analogs (1-6).
  • Figure 4 is a diagram showing Scheme 1 : Synthesis of Prodrug Sorafenib analogs 1 & 2.
  • Figure 5 is a diagram showing Scheme lb: Synthesis of building block 10.
  • FIG. 7 is a diagram showing Scheme 2b: Synthesis of building block 14.
  • FIG 8 is a diagram showing Scheme 3: Synthesis of
  • Figure 9 is a diagram of sorafenib release mechanism of an example of an activatable prodrug from conjugates via a pH sensitive cleavable bond.
  • Figure 10 is a diagram of sorafenib release mechanism of an example of an activatable prodrug from conjugates via a disulfide cleavable bond.
  • Figure 11 is a diagram of an example of an ASGP-R drug uptake study. DETAILED DESCRIPTION OF THE INVENTION
  • compositions and methods of delivering a drug to a liver cell or liver tissue in a subj ect are a prodrug of a drug where the drug, a hydrophilic linker, and a liver-targeted glycol ligand are conjugated together.
  • the hydrophilic linker contains or is coupled to the drug via a cleavable bond such that the cleavable bond is cleaved and the drug released after delivery into a target cell.
  • the disclosed compositions simplify production of deliverable prodrugs by minimizing the components used and the assembly and stability of the compositions.
  • the disclosed compositions use a single cell- or tissue-targeting glycol ligand, such as a single galactose moiety, which is sufficient for high cell- or tissue-specificity (liver specificity in the case of the galactose moiety).
  • the disclosed compositions provide improved pharmokinetics by use of a water soluble spacer or linker, such as an ethylene glycol spacer.
  • a liver-specific Gal/GalNAc additive prodrug with the hydrophilic spacer including a disulfide bond cleavable via GSH results in improved delivery of a drug.
  • a liver-specific Gal/GalNAc additive prodrug with the hydrophilic spacer including a disulfide bond cleavable via GSH results in improved delivery of a drug.
  • such an approach provides an improved version of glycoconjugated sorafenib analogs.
  • Benefits of such prodrug compositions can include (1) enhanced delivery to liver cancer cells through ASGP-R mediated endocytosis, (2) improved pharmacokinetics by modifying its water solubility and bioavailability, (3) reduced unwanted toxicities by liver specific receptors, or combinations thereof.
  • the disclosed compositions improve results over polymeric nanoscale-based technologies.
  • the single compound form that is, using a compound with each component of the prodrug covalent coupled together
  • the disclosed compositions improve specificity and reduce intracellular residence time of the delivery components, which can increase the therapeutic index and reduce dose- limiting systemic toxicity of the drug composition.
  • the use of a single form of cell- or tissue-targeting glycol ligand improves the kinetics of drug exposure at the target organ, tissue, or cells (in contrast to more complex glycol and carbohydrate moieties and compounds used for targeting in other compositions).
  • “Sugar additive prodrug approach” and similar phrases refer to adding or including one or more sugar moieties to a prodrug composition or compound to facilitate sugar-based binding (and uptake) of the prodrug composition or compound to a sugar receptor.
  • a Gal/GalNAc additive prodrug approach includes a Gal and/or GalNAc moiety to a prodrug composition or compound to facilitate Gal-based binding and uptake of the prodrug composition or compound via asialo-glycoprotein receptor (ASGP-R).
  • ASGP-R asialo-glycoprotein receptor
  • references to components as being “covalently coupled” means that the components are connected via covalent bonds (for example, that the drug moiety and the transport moiety are connected via covalent bonds). That is, there is a continuous chain of covalent bonds between, for example, the drug moiety and the transport moiety.
  • Components can be covalently coupled either directly or indirectly.
  • Direct covalent coupling refers to the presence of a covalent bond between atoms of each of the components.
  • Indirect covalent coupling refers to the absence of a covalent bond between atoms of each of the components. That is, some other atom or atoms not belonging to either of the coupled components intervenes between atoms of the components.
  • Both direct and indirect covalent coupling involve a continuous chain of covalent bonds.
  • "Separates the drug moiety form the transport moiety” refers to the drug moiety no longer being covalently coupled to the glycol ligand. Some part of the transport moiety can remain attached to the drug moiety, such as if the cleavable bond is an internal bond of the hydrophobic spacer.
  • Internal bond of a compound, group, moiety, or the like refers to a bond between two atoms that are both atoms belonging to the compound, group, moiety, or the like.
  • Hydrolysable bond refers to a bond that can be cleaved in a reaction involving the addition of water.
  • test compound refers to a chemical to be tested by one or more screening method(s) as a putative modulator.
  • a test compound can be any chemical, such as an inorganic chemical, an organic chemical, a protein, a peptide, a carbohydrate, a lipid, or a combination thereof.
  • various predetermined concentrations of test compounds are used for screening, such as 0.01 micromolar, 1 micromolar and 10 micromolar.
  • Test compound controls can include the measurement of a signal in the absence of the test compound or comparison to a compound known to modulate the target.
  • the terms “high,” “higher,” “increases,” “elevates,” or “elevation” refer to increases above basal levels, e.g., as compared to a control.
  • the terms “low,” “lower,” “reduces,” or “reduction” refer to decreases below basal levels, e.g., as compared to a control.
  • modulate refers to the ability of a compound to change an activity in some measurable way as compared to an appropriate control.
  • activities can increase or decrease as compared to controls in the absence of these compounds.
  • an increase in activity is at least 25%, more preferably at least 50%, most preferably at least 100% compared to the level of activity in the absence of the compound.
  • a decrease in activity is preferably at least 25%, more preferably at least 50%, most preferably at least 100% compared to the level of activity in the absence of the compound.
  • a compound that increases a known activity is an "agonist".
  • One that decreases, or prevents, a known activity is an "antagonist".
  • inhibitor means to reduce or decrease in activity or expression. This can be a complete inhibition or activity or expression, or a partial inhibition. Inhibition can be compared to a control or to a standard level. Inhibition can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,
  • monitoring refers to any method in the art by which an activity can be measured.
  • providing refers to any means of adding a compound or molecule to something known in the art. Examples of providing can include the use of pipettes, pipettemen, syringes, needles, tubing, guns, etc. This can be manual or automated. It can include transfection by any mean or any other means of providing nucleic acids to dishes, cells, tissue, cell-free systems and can be in vitro or in vivo.
  • preventing refers to administering a compound prior to the onset of clinical symptoms of a disease or conditions so as to prevent a physical manifestation of aberrations associated with the disease or condition.
  • in need of treatment refers to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, or individual in the case of humans; veterinarian in the case of animals, including non- human mammals) that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a care giver's expertise, but that include the knowledge that the subject is ill, or will be ill, as the result of a condition that is treatable by the compounds of the invention.
  • subject includes, but is not limited to, animals, plants, bacteria, viruses, parasites and any other organism or entity.
  • the subject can be a vertebrate, more specifically a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig or rodent), a fish, a bird or a reptile or an amphibian.
  • the subject can be an invertebrate, more specifically an arthropod (e.g., insects and crustaceans).
  • arthropod e.g., insects and crustaceans.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • treatment and “treating” is meant the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • palliative treatment that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder
  • preventative treatment that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder
  • supportive treatment that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • a cell can be in vitro.
  • a cell can be in vivo and can be found in a subject.
  • a "cell" can be a cell from any organism including, but not limited to, a bacterium.
  • the compounds described herein can be administered to a subject comprising a human or an animal including, but not limited to, a mouse, dog, cat, horse, bovine or ovine and the like, that is in need of alleviation or amelioration from a recognized medical condition.
  • an effective amount of a compound as provided herein is meant a nontoxic but sufficient amount of the compound to provide the desired result.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.
  • biocompatibility is a relative term, and some degree of immune response is to be expected even for polymers that are highly compatible with living tissue.
  • biocompatibility refers to the acute rejection of material by at least a portion of the immune system, i.e., a non-biocompatible material implanted into a subject provokes an immune response in the subject that is severe enough such that the rejection of the material by the immune system cannot be adequately controlled, and often is of a degree such that the material must be removed from the subject.
  • One simple test to determine biocompatibility is to expose a polymer to cells in vitro; biocompatible polymers are polymers that typically will not result in significant cell death at moderate
  • a biocompatible polymer may cause less than about 20% cell death when exposed to cells such as fibroblasts or epithelial cells, even if phagocytosed or otherwise uptaken by such cells.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent of a component is based on the total weight of the formulation or composition in which the component is included.
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a spacer or linker refers to one or more -OCH 2 CH 2 O- units in the spacer or linker, regardless of whether ethylene glycol was used to prepare the spacer or linker.
  • a sebacic acid residue in a spacer or linker refers to one or more -CO(CH 2 ) 8 CO- moieties in the linker or spacer, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the linker or spacer.
  • alkyl group as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, ft-propyl, isopropyl, w-butyl, isobutyl, /-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • a "lower alkyl” group is an alkyl group containing from one to six carbon atoms.
  • alkoxy as used herein is an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy” group may be defined as -OR where R is alkyl as defined above.
  • a "lower alkoxy” group is an alkoxy group containing from one to six carbon atoms.
  • alkenyl group as used herein is a hydrocarbon group of from 2 to 24 carbon atoms and structural formula containing at least one carbon-carbon double bond.
  • alkynyl group as used herein is a hydrocarbon group of 2 to 24 carbon atoms and a structural formula containing at least one carbon- carbon triple bond.
  • aryl group as used herein is any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc.
  • aromatic also includes “heteroaryl group,” which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy.
  • cycloalkyl group is a non-aromatic carbon- based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • heterocycloalkyl group is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.
  • aralkyl as used herein is an aryl group having an alkyl, alkynyl, or alkenyl group as defined above attached to the aromatic group.
  • An example of an aralkyl group is a benzyl group.
  • hydroxyalkyl group as used herein is an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above that has at least one hydrogen atom substituted with a hydroxyl group.
  • alkoxyalkyl group is defined as an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above that has at least one hydrogen atom substituted with an alkoxy group described above.
  • esteer as used herein is represented by the formula— C(0)OA, where A can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • carbonate group as used herein is represented by the formula -OC(0)OR, where R can be hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • carboxylic acid as used herein is represented by the formula -C(0)OH.
  • aldehyde as used herein is represented by the formula -
  • keto group as used herein is represented by the formula - C(0)R, where R is an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • ether as used herein is represented by the formula AOA 1 , where A and A 1 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • urethane as used herein is represented by the formula -OC(0)NRR', where R and R' can be, independently, hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or
  • sulfo-oxo group as used herein is represented by the formulas -S(0) 2 R, -OS(0) 2 R, or , -OS(0) 2 OR, where R can be hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • the disclosed prodrug compositions and components thereof, such as the hydrophilic spacer can, independently, possess two or more of the groups listed above.
  • the hydrophilic spacer is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can be substituted with a hydroxyl group, an alkoxy group, etc.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • the ester group can be incorporated within the backbone of the alkyl group.
  • the ester can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • the term “activity” refers to a biological activity.
  • the term “pharmacological activity” refers to the inherent physical properties of a peptide or polypeptide. These properties include but are not limited to half-life, solubility, and stability and other pharmacokinetic properties.
  • modified is often used herein to describe oligomers and polymers and means that a particular monomeric unit that would typically make up the pure oligomer or polymer has been replaced by another monomeric unit that shares a common polymerization capacity with the replaced monomeric unit.
  • diol residues for glycol in poly(ethylene glycol) in which case the poly(ethylene glycol) will be “modified” with the diol.
  • the poly(ethylene glycol) is modified with a mole percentage of the diol, then such a mole percentage is based upon the total number of moles of glycol that would be present in the pure polymer but for the modification.
  • the diol and glycol residues are present in equimolar amounts.
  • compositions and methods of delivering a drug to a liver cell or liver tissue in a subject are a prodrug of a drug where the drug, a hydrophilic linker, and a liver-targeted glycol ligand are conjugated together.
  • the hydrophilic linker contains or is coupled to the drug via a cleavable bond such that the cleavable bond is cleaved and the drug released after delivery into a target cell.
  • prodrugs comprising a drug moiety and a transport moiety covalently coupled to the drug moiety.
  • the transport moiety comprises a hydrophilic spacer covalently coupled to the drug moiety, and at least one liver-targeted glycol ligand covalently coupled to the hydrophilic spacer.
  • the hydrophilic spacer comprises a cleavable bond, where cleavage of the cleavable bond separates the drug moiety from the transport moiety.
  • the liver-targeted glycol ligand can be one or more ⁇ -D-galactose (Gal) moieties, N-acetylgalactoseamine (GalNAc) moieties, or combinations thereof.
  • the hydrophilic spacer can be selected from the group consisting of: a substituted branched or unbranched saturated or unsaturated alkyl chain, a substituted or unsubstituted branched or unbranched saturated or unsaturated alkoxy chain, a substituted or unsubstituted branched or unbranched saturated or unsaturated alkylamino chain, and a substituted or unsubstituted branched or unbranched saturated or unsaturated alkylthio chain.
  • the hydrophilic spacer can comprise ethylene glycol.
  • the hydrophilic spacer has of a length of 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or 3 atoms.
  • the drug moiety is covalently coupled to the hydrophilic spacer of the transport moiety via the cleavable bond.
  • the cleavable bond is a bond selected from the group consisting of: an ester, an amide, and a carbonate.
  • the cleavable bond is an internal bond in the hydrophilic spacer.
  • the cleavable bond is hydrolyzable.
  • the drug moiety is a cancer therapeutic.
  • the cancer therapeutic is sorafenib.
  • the drug moiety is selected from the group consisting of temozolomide, sorafenib, erlotinib, gefitinib, imatinib, pazopanib, rapamycin, raloxifene, lasofoxifene, basedoxifene, resveratrol, curcumin, etoposide, camptothecin, CPT-11, topotecan, irinotecan, exatecan, lurtecan, DB67, BNP1350, ST1481, CKD602, paclitaxel, docetaxel, vincristine, vinblastine, fingolimod, raltegravir, elvitegravir, MK-2408, lersivirine, daunorubicin, doxorubicin, epirubicin, and idarubic
  • the disclosed prodrug compositions generally include a drug moiety and a transport moiety covalently coupled to the drug moiety.
  • the transport moiety generally includes a hydrophilic spacer and at least one glycol ligand of a receptor.
  • the hydrophilic spacer is generally covalently coupled to the drug moiety and to the glycol ligand.
  • the hydrophilic spacer generally includes a cleavable bond, where cleavage of the cleavable bond separates the drug moiety from the transport moiety.
  • Components other the drug moiety, hydrophilic spacer, glycol moiety, and cleavable bond can be part of the transport moiety. Generally, such other components should not eliminate, and preferably do not diminish, the properties and functions useful to the function of the prodrug composition.
  • the hydrophilic spacer serves as a bridge connecting a glycol ligand to a drug moiety.
  • the hydrophilic spacer also includes or is flanked by a cleavable bond and provides favorable solution and stability characteristics.
  • a hydrophilic spacer of sufficient length and solubility can increase the solubility of the prodrug composition, the half-life or stability of the prodrug composition in the subject, or a combination thereof.
  • the hydrophilic spacer can be any chemical composition that accomplishes one or more of these functions or features.
  • Preferred hydrophilic spacers are oligomers of hydrophilic and biocompatible monomers.
  • hydroxybutyrate oligomers glycerol sebacate oligomers, glycolide oligomers, lactide oligomers, caprolactone oligomers, alkylene glycol oligomers, alkylene oxide oligomers, lysine oligomers, ethylene imine oligomers, acrylic acid oligomers, urethane oligomers, trimethylene carbonate oligomers, acrylic acid oligomers, beta amino esters oligomers, oligomeric derivatives or synthetic forms of natural polymers such as hyaluronic acid, chondroitin sulfate, carboxymethylcellulose, and starch, and co-oligmers of monomers or dimers making up such oligomers are useful as the hydrophilic spacer.
  • the monomers, dimers, and other components of the hydrophilic spacer can be modified or unmodified forms of monomers, dimers, and other components.
  • glycol ligand is the targeting and/or internalization moiety of the disclosed prodrug compositions.
  • Sugar residues and carbohydrates principally as the glycol modifications of glycoproteins, are recognition and binding ligands of numerous cell surface receptors.
  • glycol ligands can mediate binding to their cognate receptors and internalization of the glycol ligand and attached moieties into the cell bearing the receptor.
  • glycol ligand-specific receptors appear on cells, tissues, and organs of interest, the glycol ligands can facilitate targeting and internalization to and into the cells, tissue, and organs of interest.
  • Glycol groups can include a number of sugar residues of heterogeneous structure. Such complex glycol groups can have a number of different receptor targets based on individual sugar residues of parts of the glycol group. Reducing the number of sugar residues used in the prodrug compositions both simplifies the structure and synthesis of the prodrug compositions, but can make the targeting more specific. It has been discovered single sugar residues can support efficient and specific targeting and internalization of compositions bearing the sugar residues. For example, a single galactose residue can effectively target a sorafenib prodrug composition to cells bearing the ASGP receptor.
  • single sugar residue By “single sugar residue,” “single glycol ligand,” and the like is meant that a single type of sugar moiety or glycol ligand is included on the prodrug composition, unless the context clearly indicates otherwise.
  • a given prodrug molecule have one single molecule or moiety of sugar residue or glycol ligand (which can be referred to as a single instance of the sugar residue or glycol ligand)
  • the disclosed prodrug compositions can have multiple molecules or moieties of sugar residue or glycol ligand.
  • reference to a "single sugar residue,” “single glycol ligand,” or the like means that each of the multiple molecules or moieties of the sugar residue or glycol ligand will be the same (for example, they will all be galactose moieties).
  • the glycol ligand can be coupled to any part of the prodrug composition. It is preferred if the glycol ligand is coupled to the hydrophilic spacer. It is also preferred that the glycol ligand be coupled such that it is available for binding to its cognate receptor. It is also preferred for the glycol ligand to be separated from the drug moiety when the cleavable bond is cleaved. Those of skill in the art can easily configure the prodrug composition and the glycol ligand to satisfy some or all of those preferences and other design options.
  • the transport moiety includes both the hydrophilic spacer and the glycol moiety.
  • the transport moiety excludes the drug moiety.
  • the transport moiety by virtue of the location of the cleavable bond flanking or in the hydrophilic spacer, also includes or is flanked by the cleavable bond.
  • Components other the hydrophilic spacer, glycol moiety, and cleavable bond can be part of the transport moiety. Generally, such other components should not eliminate, and preferably do not diminish, the properties and functions useful to the function of the prodrug composition.
  • the drug moiety can be any compound to be delivered to cells, tissues, or organs.
  • the drug moiety can be a therapeutic agent.
  • therapeutic agent means a molecule which has one or more biological activities in a normal or pathologic tissue.
  • a variety of therapeutic agents can be used as a drug moiety.
  • the therapeutic agent can be a cancer chemotherapeutic agent.
  • a cancer chemotherapeutic agent is a chemical agent that inhibits the proliferation, growth, life-span or metastatic activity of cancer cells.
  • a cancer chemotherapeutic agent can be, without limitation, sorafenib; a taxane such as docetaxel; an anthracyclin such as doxorubicin; an alkylating agent; a vinca alkaloid; an anti- metabolite; a platinum agent such as cisplatin or carboplatin; a steroid such as methotrexate; an antibiotic such as adriamycin; a isofamide; or a selective estrogen receptor modulator; an antibody such as trastuzumab.
  • Taxanes are chemotherapeutic agents useful in homing compositions.
  • Useful taxanes include, without limitation, docetaxel (Taxotere; Aventis Pharmaceuticals, Inc.; Parsippany, N.J.) and paclitaxel (Taxol; Bristol-Myers Squibb; Princeton, N.J.). See, for example, Chan et al, J. Clin. Oncol.
  • the drug moiety can be a paclitaxel-loaded albumin nanoparticle such as abraxane.
  • a cancer chemotherapeutic agent useful in a homing composition also can be an anthracyclin such as doxorubicin, idarubicin or daunorubicin.
  • Doxorubicin is a commonly used cancer chemotherapeutic agent and can be useful, for example, for treating breast cancer (Stewart and Ratain, In:
  • doxorubicin has anti- angiogenic activity (Folkman, Nature Biotechnology 15:510 (1997); Steiner, In “Angiogenesis: Key principles-Science, technology and medicine,” pp. 449-454 (eds. Steiner et al; Birkhauser Verlag, 1992)), which can contribute to its effectiveness in treating cancer.
  • An alkylating agent such as melphalan or chlorambucil also can be a useful cancer chemotherapeutic agent.
  • a vinca alkaloid such as vindesine, vinblastine or vinorelbine; or an antimetabolite such as 5- fluorouracil, 5-fluorouridine or a derivative thereof can be a useful cancer chemotherapeutic agent.
  • a platinum agent also can be a useful cancer chemotherapeutic agent.
  • a platinum agent can be, for example, cisplatin or carboplatin as described, for example, in Crown, Seminars in Oncol. 28:28-37 (2001).
  • Other useful cancer chemotherapeutic agents include, without limitation, methotrexate, mitomycin-C, adriamycin, ifosfamide and ansamycins.
  • a cancer chemotherapeutic agent useful for treatment of breast cancer and other hormonally-dependent cancers also can be an agent that antagonizes the effect of estrogen, such as a selective estrogen receptor modulator or an anti-estrogen.
  • the selective estrogen receptor modulator, tamoxifen is a cancer chemotherapeutic agent that can be used in a conjugate for treatment of breast cancer (Fisher et al, J. Natl. Cancer Instit. 90: 1371-1388 (1998)).
  • the therapeutic agent can be an antibody such as a humanized monoclonal antibody.
  • the anti-epidermal growth factor receptor 2 (HER2) antibody, trastuzumab (Herceptin; Genentech, South San Francisco, Calif.) can be a therapeutic agent useful for treating HER2/neu overexpressing breast cancers (White et al, Annu. Rev. Med. 52: 125-141 (2001)).
  • Useful therapeutic agents also can be a cytotoxic agent, which, as used herein, can be any molecule that directly or indirectly promotes cell death.
  • Useful cytotoxic agents include, without limitation, small molecules, polypeptides, peptides, peptidomimetics, nucleic acid-molecules, cells and viruses.
  • useful cytotoxic agents include cytotoxic small molecules such as doxorubicin, docetaxel or trastuzumab;
  • antimicrobial peptides such as those described further below; pro-apoptotic polypeptides such as caspases and toxins, for example, caspase-8; diphtheria toxin A chain, Pseudomonas exotoxin A, cholera toxin, ligand fusion toxins such as DAB389EGF, ricinus communis toxin (ricin); and cytotoxic cells such as cytotoxic T cells.
  • pro-apoptotic polypeptides such as caspases and toxins, for example, caspase-8
  • diphtheria toxin A chain diphtheria toxin A chain, Pseudomonas exotoxin A, cholera toxin, ligand fusion toxins such as DAB389EGF, ricinus communis toxin (ricin); and cytotoxic cells
  • cytotoxic T cells such as cytotoxic T cells.
  • a therapeutic agent can be a therapeutic polypeptide.
  • a therapeutic polypeptide can be any polypeptide with a biologically useful function.
  • Useful therapeutic polypeptides encompass, without limitation, cytokines, antibodies, cytotoxic polypeptides; pro-apoptotic polypeptides; and anti-angiogenic polypeptides.
  • useful therapeutic polypeptides can be a cytokine such as tumor necrosis factor-a (TNF-a), tumor necrosis factor- ⁇ (TNF- ⁇ ), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interferon .alpha.
  • IFN-a interferon .gamma.
  • IFN- ⁇ interleukin-1
  • IL-2 interleukin-2
  • IL-3 interleukin-3
  • IL-4 interleukin-4
  • IL-6 interleukin-6
  • IL-7 interleukin-7
  • DC-CK1 dendritic cell chemokine 1
  • an anti-HER2 antibody or fragment thereof a cytotoxic polypeptide including a toxin or caspase, for example, diphtheria toxin A chain, Pseudomonas exotoxin A, cholera toxin, a ligand fusion toxin such as DAB389EGF or ricin; or an anti-angiogenic polypeptide such as angiostatin, endostatin, thrombospondin, platelet factor 4; anastellin; or one of those described further herein
  • a therapeutic agent can also be an anti-angiogenic agent.
  • anti-angiogenic agent means a molecule that reduces or prevents angiogenesis, which is the growth and development of blood vessels.
  • anti-angiogenic agents can be prepared by routine methods.
  • Such anti-angiogenic agents include, without limitation, small molecules; proteins such as dominant negative forms of angiogenic factors, transcription factors and antibodies; peptides; and nucleic acid molecules including ribozymes, antisense oligonucleotides, and nucleic acid molecules encoding, for example, dominant negative forms of angiogenic factors and receptors, transcription factors, and antibodies and antigen-binding fragments thereof. See, for example, Hagedom and Bikfalvi, Crit. Rev. Oncol.
  • VEGF Vascular endothelial growth factor
  • An anti-angiogenic agent can be, for example, an inhibitor or neutralizing antibody that reduces the expression or signaling of VEGF or another angiogenic factor, for example, an anti-VEGF neutralizing monoclonal antibody (Borgstrom et al, supra, 1999).
  • An anti-angiogenic agent also can inhibit another angiogenic factor such as a member of the fibroblast growth factor family such as FGF-1 (acidic), FGF-2 (basic), FGF- 4 or FGF-5 (Slavin et al, Cell Biol. Int. 19:431-444 (1995); Folkman and Shing, J. Biol. Chem.
  • an angiogenic factor such as angiopoietin-1, a factor that signals through the endothelial cell-specific Tie2 receptor tyrosine kinase (Davis et al, Cell 87: 1161-1169 (1996); and Suri et al, Cell 87: 1171-1180 (1996)), or the receptor of one of these angiogenic factors. It is understood that a variety of mechanisms can act to inhibit activity of an angiogenic factor including, without limitation, direct inhibition of receptor binding, indirect inhibition by reducing secretion of the angiogenic factor into the extracellular space, or inhibition of expression, function or signaling of the angiogenic factor.
  • a variety of other molecules also can function as anti-angiogenic agents including, without limitation, angiostatin; a kringle peptide of angiostatin; endostatin; anastellin, heparin-binding fragments of fibronectin; modified forms of antithrombin; collagenase inhibitors; basement membrane turnover inhibitors; angiostatic steroids; platelet factor 4 and fragments and peptides thereof; thrombospondin and fragments and peptides thereof; and doxorubicin (O'Reilly et al, Cell 79:315-328 (1994)); O'Reilly et al, Cell
  • anti-angiogenic agents include, for example, angiostatin, endostatin, metastatin and 2ME2 (EntreMed; Rockville, Md.); anti-VEGF antibodies such as Avastin (Genentech; South San Francisco, Calif); and VEGFR-2 inhibitors such as SU5416, a small molecule inhibitor of VEGFR-2 (SUGEN; South San Francisco, Calif.) and SU6668 (SUGEN), a small molecule inhibitor of VEGFR-2, platelet derived growth factor and fibroblast growth factor I receptor. It is understood that these and other anti-angiogenic agents can be prepared by routine methods and are encompassed by the term "anti- angiogenic agent" as used herein.
  • the homing compositions disclosed herein can also be used to site of inflammation.
  • Moieties useful for this purpose can include therapeutic agents belonging to several basic groups including anti-inflammatory agents which prevent inflammation, restenosis preventing drugs which prevent tissue growth, anti-thrombogenic drugs which inhibit or control formation of thrombus or thrombolytics, and bioactive agents which regulate tissue growth and enhance healing of the tissue.
  • useful therapeutic agents include but are not limited to steroids, fibronectin, anti-clotting drugs, anti-platelet function drugs, drugs which prevent smooth muscle cell growth on inner surface wall of vessel, heparin, heparin fragments, aspirin,
  • TP A tissue plasminogen activator
  • urokinase hirudin
  • streptokinase antiproliferatives
  • antiproliferatives metalhotrexate, cisplatin, fluorouracil, Adriamycin
  • antioxidants ascorbic acid, beta carotene, vitamin E
  • antimetabolites thromboxane inhibitors
  • non-steroidal and steroidal antiinflammatory drugs beta and calcium channel blockers
  • genetic materials including DNA and RNA fragments, complete expression genes, antibodies, lymphokines, growth factors, prostaglandins, leukotrienes, laminin, elastin, collagen, and integrins.
  • Useful therapeutic agents also can be antimicrobial peptides. This can be particularly useful to target a wound or other infected sites.
  • homing compositions comprising an
  • antimicrobial peptide where the homing composition is selectively internalized and exhibits a high toxicity to the targeted area.
  • Useful antimicrobial peptides can have low mammalian cell toxicity when not incorporated into the homing composition.
  • antimicrobial peptide means a naturally occurring or synthetic peptide having antimicrobial activity, which is the ability to kill or slow the growth of one or more microbes.
  • An antimicrobial peptide can, for example, kill or slow the growth of one or more strains of bacteria including a Gram-positive or Gram-negative bacteria, or a fungi or protozoa.
  • an antimicrobial peptide can have, for example, bacteriostatic or bacteriocidal activity against, for example, one or more strains of Escherichia coli, Pseudomonas aeruginosa or Staphylococcus aureus. While not wishing to be bound by the following, an antimicrobial peptide can have biological activity due to the ability to form ion channels through membrane bilayers as a consequence of self-aggregation.
  • An antimicrobial peptide is typically highly basic and can have a linear or cyclic structure. As discussed further below, an antimicrobial peptide can have an amphipathic .alpha. -helical structure (see U.S. Pat. No. 5,789,542; Javadpour et al., J. Med. Chem. 39:3107-3113 (1996); and Blondelle and Houghten, Biochem. 31 : 12688-12694 (1992)). An antimicrobial peptide also can be, for example, a ⁇ -strand/sheet-forming peptide as described in Mancheno et al, J. Peptide Res. 51 : 142-148 (1998).
  • An antimicrobial peptide can be a naturally occurring or synthetic peptide.
  • Naturally occurring antimicrobial peptides have been isolated from biological sources such as bacteria, insects, amphibians, and mammals and are thought to represent inducible defense proteins that can protect the host organism from bacterial infection.
  • Naturally occurring antimicrobial peptides include the gramicidins, magainins, mellitins, defensins and cecropins (see, for example, Maloy and Kari, Biopolymers 37: 105-122 (1995); Alvarez- Bravo et al, Biochem. J.
  • An antimicrobial peptide also can be an analog of a natural peptide, especially one that retains or enhances amphipathicity (see below).
  • An antimicrobial peptide incorporated into a homing composition can have low mammalian cell toxicity linked to Lyp-1. Mammalian cell toxicity readily can be assessed using routine assays.
  • mammalian cell toxicity can be assayed by lysis of human erythrocytes in vitro as described in Javadpour et al, supra, 1996.
  • An antimicrobial peptide having low mammalian cell toxicity is not lytic to human erythrocytes or requires concentrations of greater than 100 ⁇ for lytic activity, preferably concentrations greater than 200, 300, 500 or 1000 ⁇ .
  • homing compositions in which the antimicrobial peptide portion promotes disruption of mitochondrial membranes when internalized by eukaryotic cells.
  • an antimicrobial peptide preferentially disrupts mitochondrial membranes as compared to eukaryotic membranes.
  • Mitochondrial membranes like bacterial membranes but in contrast to eukaryotic plasma membranes, have a high content of negatively charged phospholipids.
  • An antimicrobial peptide can be assayed for activity in disrupting mitochondrial membranes using, for example, an assay for mitochondrial swelling or another assay well known in the art.
  • An antimicrobial peptide that induces significant mitochondrial swelling at, for example, 50 ⁇ , 40 ⁇ . ⁇ , 30 ⁇ , 20 ⁇ , 10 ⁇ , or less, is considered a peptide that promotes disruption of mitochondrial membranes.
  • Antimicrobial peptides generally have random coil conformations in dilute aqueous solutions, yet high levels of helicity can be induced by helix- promoting solvents and amphipathic media such as micelles, synthetic bilayers or cell membranes.
  • a-Helical structures are well known in the art, with an ideal a -helix characterized by having 3.6 residues per turn and a translation of 1.5 A per residue (5.4 A per turn; see Creighton, Proteins: Structures and Molecular Properties W. H Freeman, New York (1984)).
  • amphipathic a-helical structure polar and non-polar amino acid residues are aligned into an amphipathic helix, which is an a -helix in which the hydrophobic amino acid residues are predominantly on one face, with hydrophilic residues predominantly on the opposite face when the peptide is viewed along the helical axis.
  • Antimicrobial peptides of widely varying sequence have been isolated, sharing an amphipathic a-helical structure as a common feature (Saberwal et al, Biochim. Biophys. Acta 1197: 109-131 (1994)).
  • Analogs of native peptides with amino acid substitutions predicted to enhance amphipathicity and helicity typically have increased antimicrobial activity.
  • analogs with increased antimicrobial activity also have increased cytotoxicity against mammalian cells (Maloy et al, Biopolymers 37: 105-122 (1995)).
  • amphipathic a-helical structure means an a-helix with a hydrophilic face containing several polar residues at physiological pH and a hydrophobic face containing nonpolar residues.
  • a polar residue can be, for example, a lysine or arginine residue
  • a nonpolar residue can be, for example, a leucine or alanine residue.
  • An antimicrobial peptide having an amphipathic . alpha. - helical structure generally has an equivalent number of polar and nonpolar residues within the amphipathic domain and a sufficient number of basic residues to give the peptide an overall positive charge at neutral pH
  • a homing composition can contain one or more of such therapeutic agents and that additional components can be included as part of the composition, if desired.
  • additional components can be included as part of the composition, if desired.
  • it can be desirable in some cases to utilize an oligopeptide spacer between Lyp-1 and the therapeutic agent Fitzpatrick and Garnett, Anticancer Drug Des. 10: 1-9 (1995)).
  • thrombolytics include aspirin, anticoagulants, painkillers and tranquilizers, beta-blockers, ace-inhibitors, nitrates, rhythm- stabilizing drugs, and diuretics.
  • Agents that limit damage to the heart work best if given within a few hours of the heart attack.
  • Thrombolytic agents that break up blood clots and enable oxygen-rich blood to flow through the blocked artery increase the patient's chance of survival if given as soon as possible after the heart attack.
  • Thrombolytics given within a few hours after a heart attack are the most effective.
  • APSAC anisoylated plasminogen streptokinase activator complex
  • r-tPA recombinant tissue-type plasminogen activator
  • streptokinase streptokinase activator complex
  • the disclosed homing compositions can use any of these or similar agents.
  • the drug moiety is a cancer therapeutic.
  • the cancer therapeutic is sorafenib.
  • the drug moiety is selected from the group consisting of temozolomide, sorafenib, erlotinib, gefitinib, imatinib, pazopanib, rapamycin, raloxifene, lasofoxifene, basedoxifene, resveratrol, curcumin, etoposide, camptothecin, CPT-11, topotecan, irinotecan, exatecan, lurtecan, DB67, BNP1350, ST1481, CKD602, paclitaxel, docetaxel, vincristine, vinblastine, fingolimod, raltegravir, elvitegravir, MK-2408, lersivirine, daunorubicin, doxorubicin, epirubicin, and idarubic
  • Cleavable bonds are included in the prodrug compositions to facilitate separation of the drug moiety from the transport moiety.
  • the drug moiety is covalently coupled to the hydrophilic spacer of the transport moiety via the cleavable bond.
  • the cleavable bond is a bond selected from the group consisting of: an ester, an amide, and a carbonate.
  • the cleavable bond is an internal bond in the hydrophilic spacer.
  • the cleavable bond is hydrolyzable.
  • a cleavable bond can be useful for freeing the drug moiety at the site of targeting, for example.
  • the cleavable bond can be cleaved in any suitable way.
  • the cleavable bond can be cleaved enzymatically or non- enzymatically.
  • the cleaving enzyme can be supplied or can be present at a site where the composition is delivered, homes, travels or accumulates.
  • the enzyme can be present inside or in proximity to a cell to which the composition is delivered, homes, travels, or accumulates.
  • the composition can be brought into contact with a cleaving agent, can be placed in cleaving conditions, or both.
  • a cleaving agent is any substance that can mediate or stimulate cleavage of the cleavable bond.
  • a non-enzymatic cleaving agent is any cleaving agent except enzymes.
  • Cleaving conditions can be any solution or environmental conditions that can mediate or stimulate cleavage of the cleavable bond. For example, some labile bonds can be cleaved in acid conditions, alkaline conditions, in the presence of a reactive group, under reducing conditions, etc.
  • Non-enzymatic cleaving conditions are any cleaving conditions except the presence of enzymes.
  • Non-agent cleaving conditions are any cleaving conditions except the presence of cleaving agents.
  • a "protease-cleavable bond” refers to a cleavable bond that can be cleaved by a protease.
  • Useful proteases include proteases that may be present at the location where the disclosed compositions are delivered, target, home, etc. Examples of useful proteases include, for example, serine proteases (including, for example, plasmin and pasminogen activators), proprotein convertases (see, for example, Duckert et al, Prediction of proprotein convertase cleavage sites Protein engineering Design and Selection
  • Serine proteases are particularly useful for compositions targeted to cancer cells and tumors. Examples of proteases are also described in Hook, Proteolytic and cellular mechanisms in prohormone and proprotein processing, RG Austin
  • esterase-cleavable bond refers to a cleavable bond that can be cleaved by a protease.
  • Useful esterases include esterases that may be present at the location where the disclosed compositions are delivered, target, home, etc.
  • the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
  • each of the materials, compositions, components, etc. contemplated and disclosed as above can also be specifically and independently included or excluded from any group, subgroup, list, set, etc. of such materials.
  • the prodrug is taken into the cell, tissue, or organ by a receptor on the cell, tissue, or organ.
  • the glycol ligand of the prodrug compositions can be chosen based on a receptor present on the cell, tissue, or organ.
  • the general purpose of these method is to deliver the drug moiety into the on the cell, tissue, or organ so that the drug moiety can have an effect on the on the cell, tissue, or organ.
  • Some form of the methods deliver a drug to a liver cell or liver tissue in a subject by providing to the cell or tissue a prodrug having a glycol ligand that can bind a receptor on liver cells or tissue. Also disclosed are methods of treating a subject in need thereof by administering to the subject a prodrug having a glycol ligand that can bind a receptor on liver cells or tissue.
  • the prodrug is taken into the cell or tissue by an asialo- glycoprotein receptor (ASGP-R).
  • ASGP-R asialo- glycoprotein receptor
  • the subject suffers from hepatocellular carcinoma (HCC).
  • compositions and methods can be made and tested using techniques suitable to the drug, condition or disease, and glycol ligand used. This can be illustrated with examples of the disclosed prodrug compositions.
  • the example prodrug compositions are useful to improve both liver specificity and favorable pharmacokinetics of sorafenib.
  • liver-targeting glyco-ligands at the terminal end of a water-soluble chemical linker and finally attach this linker covalently to sorafenib via pH sensitive hydrazone or disulfide bonds (Figure 1A).
  • ⁇ -D- galactose (Gal) or N-acetylgalactosamine (GalNAc) are used as sugar-ligands to target the asialo-glycoprotein (ASGP) receptors on hepatoma cells (Baenziger and Maynard, J. Biol. Chem. 1980, 255, 4607- 4613, Kim et al, Nucl. Med. Biol.
  • ASGP-R asialo-glycoprotein receptors
  • ASGP-R is expressed in plasma membrane in 80% of well-differentiated HCC samples analyzed by immuno-labeling in a cohort of 60 HCC patients (Trere et al, Br. J. Cancer 1999, 81, 404- 408). Aided by their high hepatocyte expression, specificity in recognition of Gal-terminal ligand, and role in receptor-mediated endocytosis, ASGP receptors can be used as hepatotropic targets for liver uptake of a variety of drugs encapsulated with sugar- decorated nanoparticles, such as liposomes, cyclodextrins and polymer linked oligonucleotides (Sliedregt et al, J. Med. Chem.
  • the disclosed prodrugs use single sugar residues for targeting to glycol receptors. Changing the targeting moiety from complex
  • oligosaccharides containing multiple sugar residues to single sugar moieties reduces the complexity of targeted drug-delivery compositions and makes design and use of prodrugs more streamlined and efficient.
  • galactose moieties are used as a glycol ligand targeting liver cells via ASGP-R.
  • the combination of this simple liver-targeted glycol ligand with a useful (but low solubility) drug, sorafenib, in a simple solubility-increasing conjugate is an example of a site specific sugar additive prodrug approach to sorafenib to produce more favorable pharmacokinetics of sorafenib (such as, water solubility, reduced toxicity, and improved tumor bioavailability) by specific targeting to liver cancer cells.
  • the modified version of the gly co-conjugated sorafenib can enhance liver targeting through ASGP-R mediated endocytosis and thus release higher drug concentration within the liver cancer cells compared to other normal cells via sensitive chemical linkers.
  • This approach to a prodrug conjugate can thus enhance the therapeutic potential of sorafenib.
  • the hydrophilic spacer short chain ethylene glycol in this illustration
  • sorafenib Unfavorable pharmacokinetics and toxicity profile of sorafenib hampers its optimal performance in treating liver cancer. It was realized the therapeutic potential of sorafenib could be improved by using a site specific sugar additive prodrug approach involving single Gal/GalNAc ligand attached to the terminal end of a short chain PEG-sorafenib conjugate.
  • the resulting glycoconjugated sorafenib analog has (1) enhanced delivery to liver cancer cells through ASGP-R mediated endocytosis, and (2) improved pharmacokinetics by modifying its water solubility, tumor bioavailability and reduced unwanted toxicities. No prior attempt has been made to improve therapeutic potential of sorafenib by taking advantage of liver cell specific expression of sugar receptors (ASGP-R).
  • a number of synthetic-galactose terminal ligands for attachment to a drug carrier have previously been developed to make use of hepatocyte targeting. Most of these drug carriers contain complex polymeric functional groups and multiple sugar residues. It was discovered that specific liver targeting of a reporter luciferase can be achieved by using cationic lipid conjugated to a single galactose head group. We have designed and synthesized Based on this discovery, a series of cationic glycolipids conjugated to single sugar (both cyclic-and open sugar head) were designed and synthesized (Mukthavaram et al, Biomaterials 2009, 30, 2369-2384). The number of spacer units between sugar and the quarternized nitrogen atom were varied in these conjugates.
  • glycolipids 3 & 6 (having five and one spacer units, respectively) were found to be equally effective in selective targeting of reporter luciferase construct to mouse livers. It was also discovered that this observed enhanced liver specific reporter gene delivery was mediated via liver specific ASGP-R.
  • the disclosed liver-targeted prodrug compositions a designed to make use of these discoveries and this delivery path.
  • a strategy for targeting sorafenib specifically to liver by conjugating single sugar residue to sorafenib was developed.
  • the disclosed sorafenib prodrug strategy an example of which is shown in Figure 1A, can improve the therapeutic efficacy of sorafenib by changing its pharmacokinetics and liver specificity.
  • the strategy overcomes limitations associated with sorafenib and can improve the therapeutic effectiveness of other drugs, especially hydrophobic drugs and those with toxicity problems.
  • the strategy modifies the pharmacokinetics and liver specificity of sorafenib.
  • a pH sensitive hydrazine linker that could be further linked water soluble liver specific sugar ligands was covalently attached at specific position of sorafenib (Figure 3B). This location is consistent with the crystal structure of wild type B-Raf-sorafenib complex (PDB: 1UWH; Wan et al, Cell 2004, 116, 855-867).
  • Figure 3C shows the example gly co-conjugated sorafenib analogs 1 -6.
  • the number of glycoconjugates is double because for each of the six glycoconjugates one form uses galactose (Gal) as the liver-specific ligand and one form uses N- acetyl-galactosamine (GalNAc).
  • Gal galactose
  • GalNAc N- acetyl-galactosamine
  • a pH sensitive hydrazone linker is used that can covalently couple the transport moiety (sugar ligand and hydrophilic linker).
  • Glycoconjugates 1 & 2 illustrate an ethylene glycol hydrophobic linker while glycoconjugates 3 & 4 illustrate a hydrophilic spacer made up of ethylene glycol and an acyl spacer.
  • Prodrug designs like that of glycoconjugates 3 & 4 with an acyl component can be used to increase the lifetime of the prodrug under
  • a disulfide linker is used as a useful alternative to the hydrazone linker. Because the concentration of thiol-disulfide exchange reactions with intracellular reducing molecules, especially glutathione (GSH), in tumor cells (2-8 mM) is much higher than that in blood plasma (1- 2 ⁇ ), using a disulfide bond as the cleavable bond allows for selective separation of the drug in tumor cells (Balendiran et al, Cell Biochem. Funct. 2004, 22, 343-352).
  • the disclosed prodrug compositions can efficiently deliver sorafenib to liver cells through ASGP-R receptor mediated endocytosis, thus increasing therapeutic potential of the drug in treating liver cancers (Figure IB).
  • the hydrazone linker glycoconjugates 1-4 can be synthesized as outlined in schemes 1 & 2 ( Figures 4-7).
  • the intermediate compounds 7, 8 and 9 can be synthesized by adapting procedures reported previously (Babic et al, Molecules. 2012, 77, 1124-1137). Briefly, the starting material picolinic acid is first converted to the acid chloride using the thionyl chloride method to yield the desired product 7, amidation of the acid chloride 7 with methyl amine and triethyl amine under room temperature will yields amide of 8, Then 8 will couple with 4-aminophenol to yield ether of 9 using potassium tert-butoxide in the presence of potassium carbonate.
  • the intermediate compound 9 is conjugated to pre-synthesized hydrazide linker 10 (as shown in scheme lb ( Figure 5): briefly, the O-glycosylation of 10 was performed through oxazoline or acetal intermediate as the glycosyl donor, to favour the stereo selective formation of the ⁇ -anomer, then coupled to tert- Butyl carbazate in the presence of reacted triphosgene, followed by removal of t-Bu group with TFA in the presence of activated molecular sieves in the dark forming stable hydrazone bond 11, which was readily reacted with isocyanate followed by deprotection acetyl groups with NaOCH 3 in methanol to yield final glycoconjugates 1 & 2 (scheme 1 ; Figure 4).
  • the O-glycosylation thiol intermediate 17 can be mixed with excess of acyl hydrazide linker 18 in anhydrous methanol containing triethyl amine to get the desired hydrazide linker 14.
  • the disulfide linker glycoconjugates 5 & 6 can be synthesized as outlined in scheme 3 ( Figure 8). Briefly, the intermediate 8 can be treated with triphosgene, followed by treatment with 2,2'-dithiolethanol, to afford 19, which can then be reacted with O-glycosyl terminated chlorine 16 in the presence of NaH to yield intermediate 20, which can be coupled with 4- aminophenol to yield the ether of 21 using potassium tert-butoxide in the presence of potassium carbonate. The intermediate 21 can be readily reacted with isocyanate followed by deprotection acetyl groups with NaOCH 3 in methanol to yield final the glycoconjugates 5 & 6.
  • the intermediates and final compounds can be characterized with standard analytical techniques (NMR, Mass spectrometry). The final purity of the compounds can also be confirmed by CHN elemental analysis. Other standard or useful characterization techniques can also be used.
  • the disclosed prodrugs can be made using suitable synthetic techniques.
  • the efficiency and kinetics of drug separation from the prodrug composition can be assessed using suitable techniques, which can be tailored to the particular drug, cleavable bond, and cell or tissue target.
  • one aspect of therapeutic effectiveness is based on the amount of the drug released from the prodrug composition.
  • the cleavage kinetics of the cleavable bonds e.g., hydrazone and disulfide bonds
  • free drug release from the prodrug compositions can be assessed by using in vitro conditions similar to the expected in vivo conditions.
  • the hydrazone linker in glycoconjugates 1-4 is considered an acidic pH sensitive group, which is known to be activated and cleaved at pH 5 at mature endosome ( Figure 9) and ideally should not be released at physiological pH 7.4 during systemic delivery (Rodrigues et al, Bioorg. Med. Chem. 1999, 7, 2517-2524, Patil et al, Int. J. Mol. Sci. 2012, 13, 11681-11693).
  • the disulfide bonds in glycoconjugates 5 & 6 are stable in the mildly oxidizing extracellular milieu, may be prone to rapid cleavage through thiol-disulfide exchange reactions with intracellular reducing molecules, especially with glutathione (GSH) (Raina and Missiakas, Annu. Rev. Microbiol. 1997, 51, 179-202, Gilbert, Methods Enzymol. 1995, 251, 8- 28).
  • GSH glutathione
  • Assessment of the kinetics of the cleavable bonds used can be using any suitable techniques. Examples include the dialysis method of Opanasopit et al. (J. Control Release 2005, 104, 313-321) as well as HPLC or LC-MS.
  • Released drug can be measured by isolating the free drug after reaction and measure the percentage of free drug by using, for example, HPLC-UV or LC-MS. Examples of such procedures are described by Blanchet et al. (J. Pharm. Biomed. Anal. 2009, 49, 1109-1114) and Bobin-Dubigeon et al. (Ther. DrugMonit. 2011, 33, 705-710). Similarly, the pH dependence of the thiol-mediated disulfide bond cleavage can be assessed, for example, in the presence of 5 mM of GSH at different time as per the procedure of Lee et al. (J. Am. Chem. Soc. 2012, 134, 1316-1322).
  • the disclosed prodrug compositions can improve one or more of the components of the absorbtion, distribution, metabolism, and excretion (ADME) profile for the drug involved.
  • ADME absorbtion, distribution, metabolism, and excretion
  • Assessment of ADME is well known and can be applied to the disclosed prodrug compositions.
  • solubility, Caco2 permeability, plasma protein binding, and hERG toxicity can be assessed for the prodrug compositions.
  • sorafenib prodrug compositions can be assessed using sorafenib prodrug compositions and, for example, human HCC cell lines (such as HepG2 and Huh7).
  • Useful control cells for this include HeLa cell line (null for ASGP-R expression) and a normal mouse myoblast cell line (such as C2C12). Techniques for use of these cell lines are known (see, e.g., Mukthavaram et al., Biomaterials 2009, 30, 2369-2384, Mahidhar et al, J. Med. Chem. 2004, 47, 3938- 3948, and Mahidhar et al., J. Med. Chem. 2004, 47, 5721-5728).
  • Another measure of the effectiveness of the disclosed prodrug conjugates is the kinetics of uptake by target cells.
  • ASGP-R endocytosis and the receptor bound drug thereof
  • ASGP-R endocytosis can be assessed for prodrug compositions that use galactose as the glycol ligand using cell lines without or with ASGP-R expression.
  • a prodrug composition to be tested can be labeled, such as with fluorescent label such as dansyl. This fluorescence is useful in tracking the prodrug compositions inside or outside the cells in a bound or unbound form with ASGP-R ( Figure 1 IB).
  • the disclosed prodrugs as well as the parent drug can be dansylated.
  • dansylation of sorafenib prodrug by animation reaction between dansyl ethylene di-amine and gly co-conjugate in the presence of base is shown in Figure 11 A.
  • ASGP-R endocytosis can be followed via fluorescent labeling of ASGP-R, such as via CY5 -conjugated secondary antibodies (excitation/emission:649/666nm) bound to anti-ASGP-R primary antibodies.
  • the endocytosis, co-localization of fluorescence from the labeled prodrug compositions and from ASGP-R immunofluorescence can be tracked, for example, by video lapse microscopy on a real time basis.
  • ASGP-R positive HCC cell lines can be used for these studies involving prodrugs for HCC, with HeLa (null for ASGP-R) as negative control. A higher endocytosis, co- localization of fluorescence should be observed from prodrug compositions than from the parent drug.
  • Uptake by target cells can also be assessed using engineered cells and cell lines.
  • ASGP-R-mediated uptake can be assessed by knocking down ASGP-R protein from positive HCC cell lines and overexpressing ASGP-R protein in negative HeLa cells.
  • a reverse observation of inhibited endocytosis in HCC cells and positive higher endocytosis in HeLa cells of glycoderivatives is expected.
  • Engineering can be accomplished using any suitable method.
  • over and underexpression of protein can be accomplished, for example, using a lentiviral delivery of cDNA and shRNA, respectively.
  • Further confirmation of receptor-mediated uptake can be assessed by using an inhibitor of the receptor.
  • okadaic acid an inhibitor of ASGP-R endocytosis, can be used for assessing ASGP-R-mediated uptake.
  • the biodistribution of the drug in the subject and the concentration of the drug in target cells can be assessed using any suitable method.
  • the effect of a prodrug composition as compared to the parent drug can be assessed by the effect of these on a suitable cell culture.
  • cytotoxicity of selected sorafenib prodrug compositions and parent sorafenib, as reflected by inhibited cell growth can be determined by WST-1 based viability testing in human hepatoma cell lines.
  • cell viability assays can be performed in HCC cell lines and normal mouse myoblast cell line according to published procedure (Yenugonda et al, Bioorg. Med. Chem. 2011, 19, 2714-2725, Yenugonda et al, Cancer Biol. Ther. 2012, 13, 925-934).
  • cell survival can be estimated 24 and 48 h after the addition of sorafenib prodrug and sorafenib alone using WST-1 reduction assay.
  • the IC50 value (the concentration yielding 50% growth inhibition) can be interpolated from the graph of the log of compound concentration versus the fraction of surviving cells.
  • Sorafenib is the first oral multi-kinase inhibitor that blocks several receptor tyrosine kinase signaling (such as VEGFR, PDGFR, c-Kit and RET) and inhibits downstream
  • Such measurements can be made by comparing the activities of mentioned signaling proteins in lysates developed from cells treated with control parent sorafenib or sorafenib prodrug compositions using activity specific phospho-antibodies in immunoblot will be compared head to head for.
  • Suitable phosphor-antibodies are
  • Statistical analysis and P value determination can be done by two tailed paired t-test with a confidence interval of 95% for determination of the significance differences between treatment groups and are calculated using Sigma Plot software. P ⁇ 0.05 is considered to be significant.
  • the disclosed prodrug compositions can be formulated and administered in any suitable manner. Generally, the formulation will depend on the route of administration.
  • the dosages or amounts of the prodrug compositions described herein are large enough to produce the desired effect in the method by which delivery occurs.
  • the dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like.
  • the dosage will vary with the age, condition, sex and extent of the disease in the subject and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician based on the clinical condition of the subject involved.
  • the dose, schedule of doses and route of administration can be varied.
  • the efficacy of administration of a particular dose of the prodrug compositions according to the methods described herein can be determined by evaluating the particular aspects of the medical history, signs, symptoms, and objective laboratory tests that are known to be useful in evaluating the status of a subject for the treatment of HCC or other diseases and/or conditions. These signs, symptoms, and objective laboratory tests will vary, depending upon the particular disease or condition being treated or prevented, as will be known to any clinician who treats such patients or a researcher conducting experimentation in this field.
  • a subject's physical condition is shown to be improved (e.g., a tumor has partially or fully regressed)
  • the progression of the disease or condition is shown to be stabilized, or slowed, or reversed, or (3) the need for other medications for treating the disease or condition is lessened or obviated, then a particular treatment regimen will be considered efficacious.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject along with the selected drug moiety, compound, or prodrug composition without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the
  • prodrug compositions can be used therapeutically in combination with a pharmaceutically acceptable carrier.
  • the prodrug compositions described herein can be conveniently formulated into pharmaceutical compositions composed of one or more of the prodrug compositions in association with a pharmaceutically acceptable carrier. See, e.g., Remington 's Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co., Easton, PA, which discloses typical carriers and
  • compositions that can be used in conjunction with the preparation of formulations of the prodrug compositions described herein and which is incorporated by reference herein. These most typically would be standard carriers for administration of compositions to humans.
  • humans and non-humans including solutions such as sterile water, saline, and buffered solutions at physiological pH.
  • Other prodrug compositions will be administered according to standard procedures used by those skilled in the art.
  • compositions described herein can include, but are not limited to, carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • compositions can also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like.
  • prodrug compositions and pharmaceutical compositions described herein can be administered to the subject in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated.
  • a prodrug composition or pharmaceutical composition described herein can be administered as an ophthalmic solution and/or ointment to the surface of the eye.
  • a prodrug composition or pharmaceutical composition can be administered to a subject vaginally, rectally, intranasally, orally, by inhalation, or parenterally, for example, by intradermal, subcutaneous, intramuscular, intraperitoneal, intrarectal, intraarterial, intralymphatic, intravenous, intrathecal and intratracheal routes.
  • Parenteral administration if used, is generally characterized by injection.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • a more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See, e.g., U.S. Patent No.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions which can also contain buffers, diluents and other suitable additives.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Formulations for topical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be necessary or desirable.
  • compositions for oral administration can include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders can be desirable.
  • prodrug composition includes a plurality of such prodrug compositions
  • prodrug composition is a reference to one or more prodrug
  • Ranges may be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, also specifically contemplated and considered disclosed is the range from the one particular value and/or to the other particular value unless the context specifically indicates otherwise. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another, specifically contemplated embodiment that should be considered disclosed unless the context specifically indicates otherwise. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint unless the context specifically indicates otherwise.
  • prodrug composition disclosed herein is intended to be and should be considered to be specifically disclosed herein. Further, every component or part that can be identified within this disclosure is intended to be and should be considered to be specifically disclosed herein. As a result, it is specifically contemplated that any prodrug composition, or component of prodrug compositions can be either specifically included for or excluded from use or included in or excluded from a list of prodrug compositions. 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 method and compositions described herein. Such equivalents are intended to be encompassed by the following claims.

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Abstract

La présente invention concerne des compositions et des méthodes d'administration d'un médicament à une cellule hépatique ou à un tissu hépatique chez un sujet. Sous certaines formes, la composition est un promédicament d'un médicament conjuguant le médicament, un lieur hydrophile, et un ligand de type glycol ciblant le foie. Le lieur hydrophile contient ou est couplé au médicament par l'intermédiaire d'une liaison clivable de façon que la liaison clivable soit clivée et que le médicament soit libéré après administration dans une cellule cible.
PCT/US2016/064216 2015-11-30 2016-11-30 Compositions de promédicaments ciblant le foie et leurs méthodes d'utilisation WO2017095924A1 (fr)

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CN108187063A (zh) * 2018-01-09 2018-06-22 沈阳药科大学 白蛋白结合型抗肿瘤药-马来酰亚胺分子前药

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CN108187063A (zh) * 2018-01-09 2018-06-22 沈阳药科大学 白蛋白结合型抗肿瘤药-马来酰亚胺分子前药

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