Lipid-based platinum compounds and nanoparticles

Abstract

The present disclosure is in relation to the field of nanotechnology and cancer therapeutics. In particular, the present disclosure relates to platinum based compounds comprising platinum moiety, linker moiety and lipid moiety and corresponding nanoparticles thereof. The disclosure further relates to synthesis of said platinum based compounds, nanoparticles and compositions comprising said platinum based compounds/nanoparticles. The disclosure also relates to methods of managing cancer by employing aforesaid carbene compounds, platinum based compounds, nanoparticles and compositions thereof.

What is claimed is: 
     
         1 . A compound comprising:
 (a) a platinum moiety; and   (b) a lipid connected to said platinum moiety.   
     
     
         2 . The compound of  claim 1 , (i) wherein the compound comprises a carbonyl moiety; or (ii) wherein the platinum moiety comprises a platinum atom that is conjugated to said lipid via covalent bond, coordinate bond or a combination thereof; or (iii) further comprising at least one linker between the platinum moiety and the lipid. 
     
     
         3 . The compound of  claim 1 , wherein the carbonyl moiety is a carboxylic acid that is succinic acid, malonic acid, oxalic acid, keto acid, or a combination thereof 
     
     
         4 . The compound of  claim 1 , wherein the compound is of Formula (VIII):
   Q-linker-lipid  (VIII)
   
       wherein:
 Q is 
 
       
         
           
           
               
               
           
         
         
           X 3  is (CH 2 ) n , CH 2 —NH and C 4 H 8 ; 
           X 4  is CO or —CH—CH 3 ; 
           Z is a platinum containing compound, wherein the platinum forms a part of the ring; and 
           n is 0, 1, or 2. 
         
       
     
     
         5 . The compound of  claim 1 , wherein the linker is:
 (i) —X—CH 2 —X 2 —X 1 —, wherein:
 X is NH; 
 X 1  is C(O)O, C(O)NH, O(CH 2 )—O, NH, or O; 
 X 2  is (CH 2 ) n  or C(O); and 
 n is 0, 1, 2, 3, 4, or 5; 
   (ii) —(CH 2 ) n O—, —(CH 2 ) n NHC(O)O—, —(CH 2 ) n OC(O)NH—, —(CH 2 ) n C(O)NH(CH 2 ) m O—, —(CH 2 ) n O(CH 2 ) m O—, —(CH 2 ) n OC(O)—, (CH 2 ) n NHC(O)(CH 2 ) m O—, or —(CH 2 ) n C(O)O—; wherein, n and m are, independently, 0, 1, 2, 3, 4, or 5;   (iii) —X 3 —X 4 X 5 —X 6 , wherein:
 X 3  is CH, CH 2 , or O; and 
 X 4 , X 5  and X 6  are, independently, —CH 2 O— or O; or 
   (iv) a combination of (i)-(iii).   
     
     
         6 . The compound of  claim 1 , wherein the compound has (i) increased cellular uptake of platinum relative to cisplatin or oxaliplatin in cancer cells or the compound has a higher accumulation of platinum in a tumor relative to cisplatin or oxaliplatin at an equivalent dosage amount of amount of cisplatin or oxaliplatin; or (ii) a higher accumulation of platinum in a tumor relative to cisplatin or oxaliplatin at an equivalent dosage amount of amount of cisplatin or oxaliplatin. 
     
     
         7 . The compound of  claim 1 , that is of Formula (VIII):
   Q-linker-lipid  (VIII)
   
       wherein:
 Q is 
 
       
         
           
           
               
               
           
         
         
           wherein:
 X is NH or N(CH 2 COO − ); and 
 Z is a platinum containing compound, wherein the platinum forms a part of the ring; 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 X is S + , C, S + ═O, N + H, or P═O; 
 X 1  is —CH, —CH 2  or —CH 2 O; 
 X 2  is C═O; and 
 Z is a platinum containing compound, wherein the platinum forms a part of the ring; 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 X 1  is (CH 2 ) n ; 
 X 2  is C═O; 
 Z is a platinum containing compound, wherein the platinum forms a part of the ring; and 
 n is 0, 1, or 2; 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 R 1 , R 2  and R 3  are, independently, halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, -linker-lipid, or a combination thereof; 
 or R 1  and R 2  together with the Pt atom or R 2  and R 3  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; 
 or R 1  and R 2  together with the Pt atom and R 2  and R 3  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; or 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 R 1 , R 2 , R 3 , R 4  and R 5  are, independently, halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, -linker-lipid, or a combination thereof; 
 or R 1  and R 2  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; 
 or R 3  and R 4  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; and 
 
         
         the linker is one of (a)-(d):
 (a) —X—CH 2 —X 2 —X 1 —, wherein:
 X is NH; 
 X 1  is C(O)O, C(O)NH, O(CH 2 )O, NH, or O; 
 X 2  is (CH 2 ) n  or C(O); and 
 n is 0, 1, 2, 3, 4, or 5; 
 
 (b) —(CH 2 ) n O—, —(CH 2 ) n NHC(O)O—, —(CH 2 ) n OC(O)NH—, —(CH 2 ) n C(O)NH(CH 2 ) m O—, —(CH 2 ) n O(CH 2 ) m O—, —(CH 2 ) n OC(O)—, —(CH 2 ) n NHC(O)(CH 2 ) m O—, or —(CH 2 ) n C(O)O—; wherein n and m are, independently, 0, 1, 2, 3, 4, or 5; 
 (c) —X 3 —X 4 X 5 —X 6 —, wherein:
 X 3  is CH, CH 2 , or O; and 
 X 4 , X 5  and X 6  are, independently, the same or different and are —CH 2 O— or O; or 
 
 (d) a combination of (i), (ii), or (iii). 
 
       
     
     
         8 . The compound of  claim 1 , that is of Formula (VIII):
   Q-linker-lipid  (VIII)
   
       wherein:
 Q is 
 
       
         
           
           
               
               
           
         
         
           wherein:
 X is NH or N(CH 2 COO − ); and 
 Z is a platinum containing compound, wherein the platinum forms a part of the ring; 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 X is S + , C, S + ═O, N + H, or P═O; 
 X 1  is —CH, —CH 2  or —CH 2 O; 
 X 2  is C═O; and 
 Z is a platinum containing compound, wherein the platinum forms a part of the rings 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 X 1  is (CH 2 ) n ; 
 X 2  is C═O; 
 Z is a platinum containing compound, wherein the platinum forms a part of the ring; and 
 n is 0, 1, or 2; 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 R 1 , R 2  and R 3  are, independently, halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, -linker-lipid, or a combination thereof; 
 or R 1  and R 2  together with the Pt atom or R 2  and R 3  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; 
 or R 1  and R 2  together with the Pt atom and R 2  and R 3  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; or 
 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 R 1 , R 2 , R 3 , R 4  and R 5  are, independently, halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, -linker-lipid, or a combination thereof; 
 or R 1  and R 2  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; 
 or R 3  and R 4  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; and 
 
         
         the linker is a bond, ethylene diamine, ethylene glycol, diethylene glycol, 1,3-propanediol, glycine, beta alanine, —O—, —CH 2 ONHCH 2 CH 2 NHC(O)—, —NHCH 2 CH 2 NHC(O)O—, —NHCH 2 CH 2 —, —NHCH 2 CH 2 O—, —NHCH 2 C(O)—, —NHCH 2 C(O)O—, —NHCH 2 C(O)OCH 2 CH 2 CH 2 —, —NHCH 2 C(O)OCH 2 CH 2 CH 2 O—, —NHCH 2 C(O)NH—, —CH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 CH 2 NHC(O)—, —CH 2 CH 2 NHC(O)O—, —CH 2 CH 2 O—, —CH 2 C(O)NHCH 2 CH 2 —, —CH 2 C(O)NHCH 2 CH 2 O—, —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 OCH 2 CH 2 O—, —CH 2 C(O)—, —CH 2 C(O)O—, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 O—, ═CH—CH═CH 2 —, ═CH—CH═CHCH 2 O—, —CH═CHCH 2 —, —CH═CHCH 2 O—, —OCH 2 CH 2 O—, —CH 2 —, —CH 2 O—, —NHC(O)CH 2 —, —NHC(O)CH 2 O—, —C(O)CH 2 —, —C(O)CH 2 O—, —OC(O)CH 2 —, —OC(O)CH 2 O—, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 —, —OC(O)CH 2 CH 2 C(O)NHCH 2 CH 2 —, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 O—, —OC(O)CH 2 CH 2 C(O)NHCH 2 CH 2 O—, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)—, —OC(O)CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)—, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)O—, —OC(O)CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)O—, or a combination thereof. 
       
     
     
         9 . A compound of Formula (V): 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1 , X 2 , X 3  and X 4  are, independently, O, P, S, Se, N, C, O-A, O—B, DACH, halide, chelated dicarboxylato linkage group, non-chelated dicarboxylato linkage group, or a combination thereof; 
 A and B are, independently, C, P, S, N, or a combination thereof; and 
 X 4  is optional. 
 
     
     
         10 . A nanoparticle containing a compound of  claim 1 , optionally further comprising a co-lipid, stabilizer, or a combination thereof. 
     
     
         11 . The nanoparticle of  claim 10 , wherein ratio of the compound to co-lipid and/or stabilizer ranges from 99:1 to 1:99 (w/w), (mol/mol) or (vol/vol). 
     
     
         12 . The nanoparticle of  claim 10 , wherein the nanoparticle comprises (i) soy-phosphatidyl choline and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] as co-lipids, and wherein the ratio of the compound and the co-lipids ranges from about 1:1:0.01 to about 1:4:3; or (ii) L-α-phosphatidylcholine, hydrogenated (soy) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt) as co-lipids, and wherein the ratio of the compound and the co-lipids ranges from about 1:1:0.01 to about 1:4:3. 
     
     
         13 . The nanoparticle of  claim 10 , wherein the nanoparticle has (i) increased cellular uptake of platinum relative to cisplatin or oxaliplatin in cancer cells or the nanoparticle has a higher accumulation of platinum in a tumor relative to cisplatin or oxaliplatin at an equivalent dosage amount of amount of cisplatin or oxaliplatin; or (ii) a higher accumulation of platinum in a tumor relative to cisplatin or oxaliplatin at an equivalent dosage amount of amount of cisplatin or oxaliplatin. 
     
     
         14 . A nanoparticle containing a compound of  claim 10 . 
     
     
         15 . A pharmaceutical composition comprising a nanoparticle of  claim 14  and an excipient. 
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 1  and an excipient. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the excipient is a granulating agent, binding agent, lubricating agent, disintegrating agent, sweetening agent, glidant, anti-adherent, anti-static agent, surfactant, anti-oxidant, gum, coating agent, coloring agent, flavouring agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agent, or a combination thereof. 
     
     
         18 . The pharmaceutical composition of  claim 16 , that is formulated into a dosage form that is an injectable, tablet, lyophilized powder, liposomal suspension, or a combination thereof. 
     
     
         19 . A method of treating or managing cancer in a subject, the method comprising administering a therapeutically effective amount of a compound of  claim 1  to a subject in need thereof. 
     
     
         20 . The method of  claim 19 , wherein the cancer is breast, head and neck, ovarian, testicular, pancreatic, oral-esophageal, gastrointestinal, liver, gall bladder, lung, melanoma, skin, sarcoma, blood, brain, glioblastoma, tumor of neuroectodermal origin, or a combination thereof. 
     
     
         21 . A method for preparing a compound of  claim 1 , comprising conjugating the lipid with the platinum moiety to obtain said compound. 
     
     
         22 . A method for preparing the nanoparticle of  claim 10 , comprising reacting a platinum compound comprising platinum moiety and a lipid connected to said platinum moiety with a co-lipid in presence of solvent. 
     
     
         23 . A compound that is