Platinum complexes and uses thereof

Abstract

The disclosure generally relates to compositions comprising therapeutic agent complexes and to methods of making and using the compositions. In particular embodiments, the disclosure provides compositions comprising platinum-based drug complexes and to methods of making and using these compositions.

1 . A liposome composition comprising a liposome encapsulating (a) a complex of a platinum-based chemotherapeutic agent or a salt thereof and one or more polyglutamates or (b) a complex of a platinum-based chemotherapeutic agent or a salt thereof and a cyclodextrin;
 and one or more pharmaceutically acceptable carriers; and a pegylated liposome.   
     
     
         2 . The liposome composition of  claim 1 , wherein the platinum-based chemotherapeutic agent is cisplatin or a cisplatin analog, or wherein the platinum-based chemotherapeutic agent is a member selected from the group: cisplatin, oxaliplatin, stratoplatin, paraplatin, platinol, cycloplatin, dexormaplatin, spiroplatin picoplatin, nedaplatin, triplatin, tetraplatin, lipoplatin, lobaplatin, ormaplatin, zeniplatin, platinum-triamine, traplatin, enloplatin, JM-216, 254-S, NK 121, CI-973, DWA 2114R, NDDP, and dedaplatin. 
     
     
         3 . (canceled) 
     
     
         4 . The liposome composition of  claim 1 , wherein the liposome encapsulates a complex of a platinum-based chemotherapeutic agent or a salt thereof and a cyclodextrin, and wherein the cyclodextrin is a derivatized or underivatized beta-cyclodextrin. 
     
     
         5 . The liposome composition of  claim 4 , wherein the cyclodextrin is a derivatized beta-cyclodextrin, optionally wherein
 the cyclodextrin (CD) is a hydroxypropyl beta-CD (HP-beta-CD), or a sulfobutyl ether beta-CD ((SBE)-beta-CD); or   the cyclodextrin is a derivatized beta-cyclodextrin comprising:
 (a) 1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more 2-hydroxylpropyl-3- group substitutions of hydroxy groups; or 
 (b) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more sulfoalkyl ether group substitutions of hydroxy groups; or 
   the cyclodextrin is a derivatized beta-cyclodextrin comprising: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more sulfobutyl ether group substitutions of hydroxy groups.   
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The liposome composition of  claim 5 , wherein:
 the cyclodextrin is a derivatized beta-cyclodextrin of Formula III:   
       
         
           
           
               
               
           
         
         wherein R equals:
 (a) (H) 21-X  or (—(CH 2 ) 4 —SO 3 Na) x , and x=1.0-10.0, 1.0-5.0, 6.0-7.0 or 8.0-10.0; 
 (b) (H) 21-X  or (—(CH 2 CH(OH)CH 3 ) x , and x=1.0-10.0, 1.0-5.0, 6.0-7.0 or 8.0-10.0; 
 (c) (H) 21-X  or (sulfoalkyl ether) x , and x=1.0-10.0, 1.0-5.0, 6.0-7.0 or 8.0-10.0; or 
 (d) (H) 21-X  or (—(CH 2 ) 4 —SO 3 Na) x , and x=1.0-10.0, 1.0-5.0, 6.0-7.0 or 8.0-10.0; 
 
         the cyclodextrin is a derivatized cyclodextrin of Formula I: 
       
       
         
           
           
               
               
           
         
         
           wherein: n is 4, 5, or 6; and
 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each, independently, —H, a straight chain or branched C 1 -C 8 - alkylene group, a 2-hydroxylpropyl-3- group; 
 or an optionally substituted straight-chain or branched C 1 -C 6  group, wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  is a straight-chain or branched C 1 -C 8 - alkylene group or a 2-hydroxylpropyl-3- group; or 
 
         
         cyclodextrin is a derivatized cyclodextrin of Formula II: 
       
       
         
           
           
               
               
           
         
         
           wherein: n is 4, 5, or 6; and
 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each, independently, —O— or a —O—(C 2 -C 6  alkylene)-SO 3   −  group; wherein at least one of R 1  and R 2  is independently a —O—(C 2 -C 6  alkylene)—SO 3   −  group; and S 1 , S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8 , and S 9  are each, independently, a —H or a H or a pharmaceutically acceptable cation. 
 
         
       
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The liposome composition of  claim 9 , wherein the pharmaceutically acceptable cation is selected from: an alkali metal such as Li + , Na + , or K + ; an alkaline earth metal such as Ca +2 , or Mg+ 2 ; and ammonium ions and amine cations such as the cations of (C 1 -C 6 )-alkylamines, piperidine, pyrazine, (C 1 -C 6 )-alkanolamine, and (C 4 -C 8 )-cycloalkanolamine. 
     
     
         13 . The liposome composition of  claim 1 , wherein each liposome comprises between 100 to 100,000 complexes formed by the platinum-based chemotherapeutic agent or salt thereof. 
     
     
         14 . The liposome composition of  claim 1 , wherein the liposome has a diameter in the range of 20 nm to 200 nm or in the range of 80 nm to 120 nm. 
     
     
         15 . (canceled) 
     
     
         16 . The liposome composition of  claim 1 , wherein the polyethylene glycol of the liposome has a number average molecular weight (Mn) of 200 to 5000 daltons. 
     
     
         17 . (canceled) 
     
     
         18 . The liposome composition of  claim 1 , which comprises a steric stabilizer selected from the group consisting of polyethylene glycol (PEG); poly-L-lysine (PLL); monosialoganglioside (GM1); poly(vinyl pyrrolidone) (PVP); poly(acrylamide) (PAA); poly(2-methyl-2-oxazoline); poly(2-ethyl-2-oxazoline); phosphatidyl polyglycerol; poly[N-(2-hydroxypropyl) methacrylamide]; amphiphilic poly-N-vinylpyrrolidones; L-amino-acid-based polymer; and polyvinyl alcohol. 
     
     
         19 . The liposome composition of  claim 1 , wherein the liposome comprises at least one of an anionic lipid and a neutral lipid, or wherein the liposome comprises at least one is a member selected from the group: DSPE; DSPE-PEG-maleimide; DSPE-PEG-FITC; HSPC; HSPC-PEG; cholesterol; cholesterol-PEG; and cholesterol-maleimide. 
     
     
         20 . (canceled) 
     
     
         21 . The liposome composition of  claim 1 , wherein the liposome comprises oxidized phospholipids, optionally wherein the phospholipids are a member selected from the group consisting of phosphatidylserines, phosphatidylinositols, phosphatidyl-ethanolamines, phosphatidylcholines and 1-palmytoyl-2-arachidonoyl-sn-glycero-2-phosphate. 
     
     
         22 . The liposome composition of  claim 1 , wherein the liposome comprises oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylchloine (OxPAPC), optionally wherein the oxPAPCs are epoxyisoprostane-containing phospholipids, or wherein the oxPAPC is 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine (5,6-PEIPC), 1-palmitoyl-2-(epoxy-cyclo-pentenone)-sn-glycero-3-phosphorylcholine (PECPC) and/or 1-palmitoyl-2-(epoxy-isoprostane E2)-sn-glycero-4-phosphocholine (PEIPC). 
     
     
         23 . (canceled) 
     
     
         24 . The liposome composition of  claim 1 , wherein the liposome is anionic or neutral, or wherein the liposome is cationic. 
     
     
         25 . The liposome composition of  claim 1 , wherein the liposome has a zeta potential that is:
 (a) less than or equal to zero,   (b) between 0 to −150 mV or between −30 to −50 mV,   (c) greater than zero, or   (d) between 1 and 100 mV, between 5 to 60 mV, or between 10 to 50 mV.   
     
     
         26 . (canceled) 
     
     
         27 . The liposome composition of  claim 1 , wherein the pH of the internal phase of the liposome is between 2.5 and 7.5. 
     
     
         28 . (canceled) 
     
     
         29 . The liposome composition of  claim 1 , wherein the liposome internal phase comprises trehalose, optionally wherein the liposome comprises 5% to 20% weight of trehalose. 
     
     
         30 . The liposome composition of  claim 1 , which further comprises a targeting moiety attached to one or both of a PEG and the exterior of the liposome, and wherein the targeting moiety has a specific affinity for a surface antigen on a target cell of interest, optionally wherein the targeting moiety is attached to one or both of the PEG and the exterior of the liposome by a covalent bond herein. 
     
     
         31 . (canceled) 
     
     
         32 . The liposome composition of  claim 30 , wherein the targeting moiety is a polypeptide, optionally, wherein the targeting moiety is an antibody or a fragment of an antibody. 
     
     
         33 . The liposome composition of  claim 30 , wherein the targeting moiety binds the surface antigen with an equilibrium dissociation constant (Kd) in a range of 0.5×10 −10  to 10×10 −6  as determined using BIACORE® analysis. 
     
     
         34 . The liposome composition of  claim 30 , wherein the targeting moiety specifically binds one or more folate receptors selected from the group: folate receptor alpha (FR-α), folate receptor beta (FR-β), and folate receptor delta (FR-δ). 
     
     
         35 . The liposome composition of  claim 30 , wherein the targeting moiety comprises one or more members selected from the group: an antibody, a humanized antibody, an antigen binding fragment of an antibody, a single chain antibody, a single-domain antibody, a bi-specific antibody, a synthetic antibody, a pegylated antibody, and a multimeric antibody. 
     
     
         36 . The liposome composition of  claim 30  wherein each PEGylated liposome comprises from 30 to 500 targeting moieties or 30 to 200 targeting moieties. 
     
     
         37 . The liposome composition of  claim 30 , wherein the liposome does not comprise a targeting moiety attached to one or both of a PEG and the exterior of the liposome. 
     
     
         38 . (canceled) 
     
     
         39 . The liposome composition of  claim 1 , wherein the liposome further comprises a second complex formed by a therapeutic agent or a salt thereof, and one or more polylglutamate molecules or a cyclodextrin, optionally, the therapeutic agent of the second complex is gemcitabine or doxorubicin, or a salt thereof. 
     
     
         40 . (canceled) 
     
     
         41 . The liposome composition of  claim 1 , further comprising one or more of an immunostimulatory agent, a detectable marker and a maleimide, wherein the immunostimulatory agent, the detectable marker or the maleimide is attached to the PEG or the exterior of the liposome, optionally wherein the immunostimulating agent is at least one member selected from the group: a protein immunostimulating agent; a nucleic acid immunostimulating agent; a chemical immunostimulating agent; a hapten; and an adjuvant, or at least one selected from the group: a fluorescein; a fluorescein isothiocyanate (FITC); a DNP; a beta glucan; a beta-1,3-glucan; and a beta-1,6-glucan 
     
     
         42 . (canceled) 
     
     
         43 . The liposome composition of  claim 1 , which further comprises at least one cryoprotectant selected from the group consisting of mannitol; trehalose; sorbitol; and sucrose. 
     
     
         44 . A method of killing a hyperproliferative cell comprising contacting a hyperproliferative cell with the liposome composition of  claim 1 , optionally wherein the hyperproliferative cell is a cancer cell. 
     
     
         45 . A method for treating or preventing disease in a subject needing such treatment or prevention, the method comprising administering an effective amount of the liposome composition of  claim 1  to a subject in need thereof, optionally wherein the disease is cancer and the subject has or at risk of having cancer. 
     
     
         46 . The method of  claim 45 , wherein the cancer is a member selected from the group: lung cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, head and neck cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, esophageal cancer, cervical cancer, liver cancer, kidney cancer, biliary duct cancer, gallbladder cancer, bladder cancer, sarcoma (e.g., osteosarcoma), brain cancer, central nervous system cancer, and melanoma; and a hematologic malignancy such as for example, a leukemia, a lymphoma and other B cell malignancies, myeloma and other plasma cell dyscrasias. 
     
     
         47 . A method of delivering a liposome composition to a tumor expressing an antigen on its surface, the method comprising: administering the liposome composition of  claim 30  to a subject having a tumor expressing the antigen bound by the liposome targeting moiety in an amount to deliver a therapeutically effective dose of the liposome composition to the tumor, optionally wherein the administration is parenteral or intravenous. 
     
     
         48 . A method for treating cancer that comprises administering an effective amount of the liposome composition of  claim 30  to a subject having or at risk of having a cancer cell that expresses on its surface the antigen bound by the liposome targeting moiety, optionally wherein the administration is parenteral or intravenous. 
     
     
         49 . A maintenance therapy that comprises administering an effective amount of the liposome composition of  claim 1  to a subject that is undergoing or has undergone cancer therapy, optionally wherein the administration is parenteral or intravenous. 
     
     
         50 . A pharmaceutical composition comprising the liposome composition of  claim 1 .