US2022117894A1PendingUtilityA1

Targeted polymerized nanoparticles for cancer treatment

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Assignee: LOS ANGELES CHILDRENS HOSPITALPriority: Apr 1, 2014Filed: Dec 28, 2021Published: Apr 21, 2022
Est. expiryApr 1, 2034(~7.7 yrs left)· nominal 20-yr term from priority
Inventors:Jon O. NagyTimothy TricheHyunggyoo Kang
A61K 45/06A61K 9/1271Y10S977/907A61K 33/243A61K 9/51A61K 31/475A61K 31/337A61P 43/00A61K 31/407A61K 31/713Y10S977/906A61K 9/1273A61K 31/4745A61K 31/704A61K 31/136A61K 31/7068A61K 31/573A61P 35/00Y10S977/773
64
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Claims

Abstract

The invention relates to a novel drug delivery vehicle. Various embodiments of the invention provide a hybrid polymerized liposomal nanoparticle comprising both polymerizable lipids and non-polymerizable lipids. Therapeutic agents can be loaded into the polymerized liposomal nanoparticle and targeting agents can be conjugated to the surface of the polymerized liposomal nanoparticle. Also described in the invention are methods, compositions and kits that utilize the hybrid polymerized liposomal nanoparticle to treat disease conditions such as various cancers.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A hybrid polymerized liposomal nanoparticle, comprising:
 a polymerizable lipid, wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain; and   a non-polymerizable lipid.   
     
     
         2 . The hybrid polymerized liposomal nanoparticle of  claim 1 , comprising:
 a polymerizable lipid (about 15-40 mol %), wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain; and   non-polymerizable lipids comprising:   a zwitterionically charged lipid (at least about 10 mol %);   a neutrally charged molecule (about 20-45 mol %); and   a negatively charged lipid (about 1-15 mol %).   
     
     
         3 . The hybrid polymerized liposomal nanoparticle of  claim 1 , comprising:
 a polymerizable lipid (about 15 mol %), wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain; and   non-polymerizable lipids comprising:   a zwitterionically charged lipid (about 51 mol %);   a neutrally charged molecule (about 32 mol %); and   a negatively charged lipid (about 2 mol %).   
     
     
         4 . The hybrid polymerized liposomal nanoparticle of  claim 1 ,  2  or  3 , wherein the PEGylated polymerizable lipid having a polymer chain is m-PEG2000-PCDA. 
     
     
         5 . The hybrid polymerized liposomal nanoparticle of  claim 1 , comprising:
 about 14 mol % h-PEG1PCDA,   about 51 mol % hydrogenated soy PC,   about 32 mol % cholesterol,   about 2 mol % m-PEG2000-DSPE, and   about 1 mol % m-PEG2000-PCDA.   
     
     
         6 . The hybrid polymerized liposomal nanoparticle of  claim 1 , comprising:
 about 14 mol % h-PEG1PCDA,   about 48 mol % hydrogenated soy PC,   about 32 mol % cholesterol,   about 2 mol % m-PEG2000-DSPE,   about 3 mol % mal-PEG2000-DSPE, and   about 1 mol % m-PEG2000-PCDA.   
     
     
         7 . The hybrid polymerized liposomal nanoparticle of  claim 1 , comprising:
 about 24 mol % h-PEG1PCDA,   about 41 mol % hydrogenated soy PC,   about 32 mol % cholesterol,   about 2 mol % m-PEG2000-DSPE, and   about 1 mol % m-PEG2000-PCDA.   
     
     
         8 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , wherein the polymerized liposomal nanoparticle is about 30-200 nm in size. 
     
     
         9 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , wherein the polymerized liposomal nanoparticle is UV treated for about 1-35 minutes after fabrication to polymerize the polymerizable lipid. 
     
     
         10 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , wherein the polymerized liposomal nanoparticle is prepared by overnight cooling at 5-10° C. immediately after extrusion but prior to polymerization. 
     
     
         11 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , wherein the polymerized liposomal nanoparticle has a circulation half-life of at least about 1 to at least about 4 hours. 
     
     
         12 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , wherein the polymerized liposomal nanoparticle is internalized into the endosome compartment of a cell after about 30 minutes. 
     
     
         13 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , comprising a neutrally charged molecule selected from cholesterol, ergosterol, hopanoids, phytosterol, stanol, and sterols, and functional derivatives thereof. 
     
     
         14 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the PEG polymer chain comprises about 10-150, 10-50, 50-100, or 100-150 PEG units. 
     
     
         15 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the molecular weight of the PEG polymer chain is about 500-5000, 500-2000, or 2000-5000 Da. 
     
     
         16 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , wherein the PEGylated polymerizable lipid is about 0.1-1, 1-5, 5-10, or 10-15 mol %. 
     
     
         17 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the PEGylated polymerizable lipid is selected from the group consisting (PEG)n-10,12-pentacosadiynoic acid ((PEG)n-PCDA) derivatives, wherein n is the number of the PEG units in the PEG polymer chain and is about 10-150, 10-50, 50-100, or 100-150. 
     
     
         18 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the PEGylated polymerizable lipid is selected from the group consisting PEG(mw)-10,12-pentacosadiynoic acid (PEG(mw)-PCDA) derivatives, wherein mw is the molecular weight of the PEG polymer chain and is about 500-5000, 500-2000, or 2000-5000 Da. 
     
     
         19 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the PEGylated polymerizable lipid is PEG2000-10-12-pentacosadiynamide. 
     
     
         20 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the polymerizable lipid is about 15-40 mol %. 
     
     
         21 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the polymerizable lipid comprises an unsaturated lipid. 
     
     
         22 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the polymerizable lipid comprises a diacetylenic lipid. 
     
     
         23 . The hybrid polymerized liposomal nanoparticle of of any one of  claims 1 - 3 , wherein the polymerizable lipid comprises N-(5′-hydroxy-3′-oxypentyl)-10-12-pentacosadiynamide (h-PEG1-PCDA), N-(5′-sulfo-3′-oxypenty1)-10-12-pentacosadiynamide (sulfo-PEG1-PCDA), N-[methoxy(polyethylene glycol)-750]-10-12-pentacosadiynamide (m-PEG750-PCDA), or N-[maleimide(polyethylene glycol)-1500]-10-12-pentacosadiynamide (mal-PEG1500-PCDA), or a combination thereof. 
     
     
         24 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the non-polymerizable lipid is about 80-85 mol %. 
     
     
         25 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the non-polymerizable lipid is about 30-60 mol %. 
     
     
         26 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the non-polymerizable lipid comprises a saturated phospholipid. 
     
     
         27 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the non-polymerizable lipid comprises at least one PEGylated non-polymerizable lipid having a PEG polymer chain. 
     
     
         28 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the non-polymerizable lipid comprises L-α-phosphatidylcholine hydrogenated soy (hydrogenated soy PC), distearoylphosphatidylcholine (DSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (m-Peg2000-DSPE), or 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (mal-Peg2000-DSPE), or a combination thereof. 
     
     
         29 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the non-polymerizable lipid comprises L-α-phosphatidylcholine, PE-PEG2000-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000], or PE-PEG2000-biotin, or a combination thereof. 
     
     
         30 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , comprising a zwitterionically charged lipid at at least about 10 mol %. 
     
     
         31 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , comprising a zwitterionically charged lipid at about 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, or 80-90 mol %. 
     
     
         32 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , comprising a zwitterionically charged lipid at about 10-60 mol %. 
     
     
         33 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 3 , wherein the zwitterionically charged lipid comprises L-α-distearoylphosphatidylcholine. 
     
     
         34 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , further comprising a therapeutic agent loaded into the polymerized liposomal nanoparticle, wherein the therapeutic agent is selected from the group consisting of antineoplastic agents, blood products, biological response modifiers, anti-fungals, hormones, vitamins, peptides, anti-tuberculars, enzymes, anti-allergic agents, anti-coagulators, circulatory drugs, metabolic potentiators, antivirals, antianginals, antibiotics, antiinflammatories, antiprotozoans, antirheumatics, narcotics, opiates, cardiac glycosides, neuromuscular blockers, sedatives, local anesthetics, general anesthetics, radioactive compounds, radiosensitizers, immune checkpoint inhibitors, monoclonal antibodies, genetic material, antisense nucleic acids such as siRNA or RNAi molecules, and prodrugs. 
     
     
         35 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , further comprising a chemotherapeutic agent loaded into the polymerized liposomal nanoparticle. 
     
     
         36 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , further comprising two or more chemotherapeutic agents loaded into the polymerized liposomal nanoparticle. 
     
     
         37 . The hybrid polymerized liposomal nanoparticle of  claim 35  or  36 , wherein the chemotherapeutic agent is doxorubicin, irinotecan, cis-platin, topotecan, vincristine, mytomicin, paxlitaxol, cytarabine, mitoxantrone, Ara-C (cytarabine), VP-16 (etoposide), or siRNA, or a combination thereof. 
     
     
         38 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , further comprising a targeting agent conjugated to the surface of the polymerized liposomal nanoparticle. 
     
     
         39 . The hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 , further comprising two or more targeting agents conjugated to the surface of the polymerized liposomal nanoparticle. 
     
     
         40 . The hybrid polymerized liposomal nanoparticle of  claim 38  or  39 , wherein the targeting agent is an anti-CD19 antibody, anti-CD34 antibody, anti-CD99 antibody, anti-CD117 antibody, anti-CD166 antibody, or anti-CA19-9 antibody, or a combination thereof. 
     
     
         41 . The hybrid polymerized liposomal nanoparticle of  claim 38  or  39 , wherein the targeting agent is a peptide capable of specifically binding to a cell surface molecule. 
     
     
         42 . The hybrid polymerized lipid nanoparticle of  claim 41 , wherein the cell surface molecule is a cell membrane protein selected from the group consisting of structural proteins, cell adhesion molecules, membrane receptors, carrier proteins and channel proteins. 
     
     
         43 . The hybrid polymerized lipid nanoparticle of  claim 41 , wherein the cell surface molecule is Activated Leukocyte Adhesion Molecule (CD-166), carbohydrate antigen 19-9 (CA19-9), Alphafetoprotein (AFP), Carcinoembryonic antigen (CEA), Ovarian cancer antigen (CA-125), breast cancer antigens (MUC-1 and epithelial tumor antigen (ETA)), Tyrosinase malignant melanoma antigen and Melanoma-associated antigen (MAGE), abnormal antigenic products of ras, p53, Ewing sarcoma antigen (CD-99), leukemia antigens (CD-19 and CD-117), Vascular Endothelial Growth Factor (VEGF), Epithelial Growth Factor Receptor (EGFR), Her2/neu, or prostate-specific membrane antigen (PSMA). 
     
     
         44 . The hybrid polymerized liposomal nanoparticle of  claim 38  or  39 , wherein the targeting agent is selected from a group consisting of diabodies, antibodies, ligands, proteins, peptides, carbohydrates, vitamins, nucleic acids and combinations thereof. 
     
     
         45 . The hybrid polymerized liposomal nanoparticle of  claim 38  or  39 , wherein the targeting agent enhances endocytosis or cell membrane fusion. 
     
     
         46 . The hybrid polymerized liposomal nanoparticle of  claim 38  or  39  further comprising an agent conjugated to the surface that will elicit an immune response as a treatment for cancer. 
     
     
         47 . The hybrid polymerized lipid nanoparticle of  claim 46 , wherein the cell surface molecule is a cell membrane protein selected from the group consisting of E6 and E7 proteins that are detectable in all Human Papilloma Virus (HPV)-positive pre-cancerous and cancer cells or mucin glycoproteins based on tumor associated MUC1 and MUC4 glycoproteins. 
     
     
         48 . A method of loading a therapeutic agent into a hybrid polymerized liposomal nanoparticle, comprising:
 providing a hybrid polymerized liposomal nanoparticle comprising a polymerizable lipid and a non-polymerizable lipid, wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain;   establishing an ion gradient across the membrane of the polymerized liposomal nanoparticle;   providing a therapeutic agent; and   incubating the therapeutic agent with the polymerized liposomal nanoparticle, thereby loading the therapeutic agent into the polymerized liposomal nanoparticle.   
     
     
         49 . The method of  claim 48 , wherein the ion gradient is an ammonium sulfate gradient and/or pH gradient. 
     
     
         50 . The method of  claim 48 , wherein the PEG polymer chain comprises about 10-150, 10-50, 50-100, or 100-150 PEG units. 
     
     
         51 . The method of  claim 48 , wherein the molecular weight of the PEG polymer chain is about 500-5000, 500-2000, or 2000-5000 Da. 
     
     
         52 . The method of  claim 48 , wherein the PEGylated polymerizable lipid is about 0.1-1, 1-5, 5-10, or 10-15 mol %. 
     
     
         53 . The method of  claim 48 , wherein the PEGylated polymerizable lipid is selected from the group consisting (PEG)n-10,12-pentacosadiynoic acid ((PEG)n-PCDA) derivatives, wherein n is the number of the PEG units in the PEG polymer chain and is about 10-150, 10-50, 50-100, or 100-150. 
     
     
         54 . The method of  claim 48 , wherein the PEGylated polymerizable lipid is selected from the group consisting PEG(mw)-10,12-pentacosadiynoic acid (PEG(mw)-PCDA) derivatives, wherein mw is the molecular weight of the PEG polymer chain and is about 500-5000, 500-2000, or 2000-5000 Da. 
     
     
         55 . The method of  claim 48 , wherein the PEGylated polymerizable lipid is PEG2000-10-12-pentacosadiynamide. 
     
     
         56 . The method of  claim 48 , wherein the therapeutic agent is doxorubicin, irinotecan, cis-platin, topotecan, vincristine, mytomicin, paxlitaxol, cytarabine, mitoxantrone, Ara-C (cytarabine), VP-16 (etoposide), or siRNA, or a combination thereof. 
     
     
         57 . A method of conjugating a targeting agent to a hybrid polymerized liposomal nanoparticle, comprising:
 providing a lipid micelle;   providing a targeting agent;   conjugating the targeting agent to the lipid micelle;   providing a hybrid polymerized liposomal nanoparticle comprising a polymerizable lipid and a non-polymerizable lipid, wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain; and   incubating the polymerized liposomal nanoparticle with the lipid micelle conjugated with the target agent, thereby transferring the targeting agent to the polymerized liposomal nanoparticle.   
     
     
         58 . A method of conjugating a targeting agent to a hybrid polymerized liposomal nanoparticle, comprising:
 providing a targeting agent with a free thiol group;   providing a hybrid polymerized liposomal nanoparticle comprising a polymerizable lipid and a non-polymerizable lipid, wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain, at least one maleimide terminated PEGylated lipid; and   incubating the polymerized liposomal nanoparticle with the target agent containing the free thiol, thereby covalently conjugating the targeting agent to the polymerized liposomal nanoparticle.   
     
     
         59 . The method of  claim 57  or  58 , wherein the targeting agent is an anti-CD19 antibody, anti-CD34 antibody, anti-CD99 antibody, anti-CD117 antibody, anti-CD166 antibody, or anti-CA19-9 antibody, or a combination thereof. 
     
     
         60 . The method of  claim 57  or  58 , wherein the targeting agent is a peptide capable of specifically binding to a surface marker on a cancerous cell. 
     
     
         61 . The method of  claim 57 , wherein the targeting agent is conjugated to the lipid micelle through a reaction between a thiol group on the targeting agent and a maleimide group on the lipid micelle. 
     
     
         62 . The method of  claim 58 , wherein the targeting agent is conjugated to the polymerized liposome outer surface through a reaction between a thiol group on the targeting agent and a maleimide group on the outer polymerized liposome surface. 
     
     
         63 . The method of  claim 57  or  58 , wherein the PEG polymer chain comprises about 10-150, 10-50, 50-100, or 100-150 PEG units. 
     
     
         64 . The method of  claim 57  or  58 , wherein the molecular weight of the PEG polymer chain is about 500-5000, 500-2000, or 2000-5000 Da. 
     
     
         65 . The method of  claim 57  or  58 , wherein the PEGylated polymerizable lipid is about 0.1-1, 1-5, 5-10, or 10-15 mol %. 
     
     
         66 . The method of  claim 57  or  58 , wherein the PEGylated polymerizable lipid is selected from the group consisting (PEG)n-10,12-pentacosadiynoic acid ((PEG)n-PCDA) derivatives, wherein n is the number of the PEG units in the PEG polymer chain and is about 10-150, 10-50, 50-100, or 100-150. 
     
     
         67 . The method of  claim 57  or  58 , wherein the PEGylated polymerizable lipid is selected from the group consisting PEG(mw)-10,12-pentacosadiynoic acid (PEG(mw)-PCDA) derivatives, wherein mw is the molecular weight of the PEG polymer chain and is about 500-5000, 500-2000, or 2000-5000 Da. 
     
     
         68 . The method of  claim 57  or  58 , wherein the PEGylated polymerizable lipid is PEG2000-10-12-pentacosadiynamide. 
     
     
         69 . A method of treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of a condition in a subject, comprising:
 providing a hybrid polymerized liposomal nanoparticle comprising a polymerizable lipid and a non-polymerizable lipid, wherein the polymerizable lipid comprises at least one PEGylated polymerizable lipid having a PEG polymer chain and wherein a therapeutic agent is loaded into the polymerized liposomal nanoparticle and; and   administering a therapeutically effective amount of the hybrid polymerized liposomal nanoparticle to the subject, thereby treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of the condition in the subject.   
     
     
         70 . The method of  claim 69 , wherein the condition is a cancer. 
     
     
         71 . The method of  claim 69 , wherein the condition is any one or more of Ewing sarcoma, Burkitt lymphoma, osteosarcoma, neuroblastoma, glioma, ALL, CML, AML or MDS. 
     
     
         72 . The method of  claim 69 , wherein the subject is a human. 
     
     
         73 . The method of  claim 69 , wherein the PEG polymer chain comprises about 10-150, 10-50, 50-100, or 100-150 PEG units. 
     
     
         74 . The method of  claim 69 , wherein the molecular weight of the PEG polymer chain is about 500-5000, 500-2000, or 2000-5000 Da. 
     
     
         75 . The method of  claim 69 , wherein the PEGylated polymerizable lipid is about 0.1-1, 1-5, 5-10, or 10-15 mol %. 
     
     
         76 . The method of  claim 69 , wherein the polymerized liposomal nanoparticle further comprises a targeting agent conjugated to the surface of the polymerized liposomal nanoparticle. 
     
     
         77 . The method of  claim 69 , wherein the therapeutic agent is doxorubicin, irinotecan, cis-platin, topotecan, vincristine, mytomicin, paxlitaxol, cytarabine, mitoxantrone, Ara-C (cytarabine), VP-16 (etoposide), or siRNA, or a combination thereof. 
     
     
         78 . The method of  claim 69 , wherein the polymerized liposomal nanoparticle is administered intravascularly, intravenously, intraarterially, intratumorally, intramuscularly, subcutaneously, intranasally, intraperitoneally, or orally. 
     
     
         79 . The method of  claim 69 , wherein the polymerized liposomal nanoparticle is administered once, twice, three or more times. 
     
     
         80 . The method of  claim 69 , wherein the polymerized liposomal nanoparticle is administered 1-3 times per day, 1-7 times per week, or 1-9 times per month. 
     
     
         81 . The method of  claim 69 , wherein the polymerized liposomal nanoparticle is administered for about 1-10 days, 10-20 days, 20-30 days, 30-40 days, 40-50 days, 50-60 days, 60-70 days, 70-80 days, 80-90 days, 90-100 days, 1-6 months, 6-12 months, or 1-5 years. 
     
     
         82 . The method of  claim 69 , wherein the polymerized liposomal nanoparticle is administered to deliver the therapeutic agent at about 0.001 to 0.01, 0.01 to 0.1, 0.1 to 0.5, 0.5 to 5, 5 to 10, 10 to 20, 20 to 50, 50 to 100, 100 to 200, 200 to 300, 300 to 400, 400 to 500, 500 to 600, 600 to 700, 700 to 800, 800 to 900, or 900 to 1000 mg per kg body weight of the subject. 
     
     
         83 . The method of  claim 69 , wherein the polymerized liposomal nanoparticle is administered to deliver the therapeutic agent at about 0.001 to 0.01, 0.01 to 0.1, 0.1 to 0.5, 0.5 to 5, 5 to 10, 10 to 20, 20 to 50, 50 to 100, 100 to 200, 200 to 300, 300 to 400, 400 to 500, 500 to 600, 600 to 700, 700 to 800, 800 to 900, or 900 to 1000 mg per m2 body surface area of the subject. 
     
     
         84 . A pharmaceutical composition comprising the hybrid polymerized liposomal nanoparticle of any one of  claims 1 - 7 . 
     
     
         85 . The pharmaceutical composition of  claim 84 , further comprising a pharmaceutically acceptable excipient. 
     
     
         86 . The pharmaceutical composition of  claim 84 , further comprising a pharmaceutically acceptable carrier.

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