Delivery and activation through liposome incorporation of diaminocyclohexane platinum(II) complexes
AssigneeBoard of Regents, The University of Texas System
InventorsRoman Perez-Soler, Abdul R. Khokhar
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Abstract
Antitumor compositions are disclosed, as well as methods of preparing the compositions and methods of using them to inhibit tumor growth in mammals. The invention can take advantage of intraliposomal conversion of a platinum complex having the formula where R1 is diaminocycloalkyl, and R2 and R3 each have the formula where R4, R5, and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, into a complex having the formula R1—Pt—X2 (II) where X is halogen.
Claims54
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising the steps:
- (a) adjusting the pH of a composition comprising a liposome-entrapped first compound, so that the pH is made acidic, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms;
- and
- (b) after a predetermined time, adjusting the acidic pH of the composition of step (a) to a pH greater than 7.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising the steps:
- (a) adjusting the pH of a composition comprising a liposome-entrapped first compound, so that the pH is made acidic, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- R1—Pt—X2
- where R1 is as defined above and X is halogen;
- and
- (b) after a predetermined time, adjusting the acidic pH of the composition of step (a) to a pH greater than 7.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising comprising the steps:
- (a) adjusting the pH of a composition containing a liposome-entrapped first compound in the presence of sodium chloride, so that the pH is made acidic, said first compound having the formula
- where DACH is 1,2-diaminocyclohexane and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- DACH-Pt—Cl2
- where DACH is as defined above;
- and
- (b) after a predetermined time, adjusting the acidic pH of the composition of step (a) to a pH greater than 7.
A liposomal antitumor composition, comprising a platinum complex having the formula
- DACH-Pt—Cl2
- intercalated between the bilayers of a liposome, where DACH is diaminocyclohexane, and where the liposome comprises dioleyl phosphatidyl glycerol and is the product of a process comprising mixing chloroform solutions of lipids.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising adjusting the pH of a composition containing a liposome-entrapped first compound, so that the pH is made acidic, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, and where said liposome comprises dioleyl phosphatidyl glycerol and is the product of a process comprising mixing chloroform solutions of lipids.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising adjusting the pH of a composition containing a liposome-entrapped first compound, so that the pH is made acidic, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- R1—Pt—X2
- where R1 is as defined above and X is halogen, and where said liposome comprises dioleyl phosphatidyl glycerol and is the product of a process comprising mixing chloroform solutions of lipids.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising adjusting the pH of a composition containing a liposome-entrapped first compound in the presence of sodium chloride, so that the pH is made acidic, said first compound having the formula
- where DACH is 1,2-diaminocyclohexane and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- DACH-PtCl2
- where DACH is as defined above, and where said liposome comprises dioleyl phosphatidyl glycerol and is the product of a process comprising mixing chloroform solutions of lipids.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid that is dioleyl phosphatidyl glycerol, said liposome being the product of a process comprising mixing chloroform solutions of lipids, to produce a liposomal composition, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid that is dioleyl phosphatidyl glycerol, said liposome being the product of a process comprising mixing chloroform solutions of lipids, to produce a liposomal composition, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- R1—Pt—X2
- where R1 is as defined above and X is halogen.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid is dioleyl phosphatidyl glycerol, said liposome being the product of a process comprising mixing chloroform solutions of lipids, to produce a liposomal composition, said first compound having the formula
- where DACH is 1,2-diaminocyclohexane and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- DACH-Pt—Cl2
- where DACH is as defined above.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid that is dioleyl phosphatidyl glycerol, wherein said entrapping is done in the presence of sodium chloride or chloroform, to produce a liposomal composition, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid that is dioleyl phosphatidyl glycerol, wherein said entrapping is done in the presence of sodium chloride or chloroform, to produce a liposomal composition, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- R1—Pt—X2
- where R1 is as defined above and X is halogen.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid is dioleyl phosphatidyl glycerol, wherein said entrapping is done in the presence of sodium chloride or chloroform, to produce a liposomal composition, said first compound having the formula
- where DACH is 1,2-diaminocyclohexane and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- DACH-Pt—Cl2
- where DACH is as defined above.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising adjusting the pH of a composition containing a liposome-entrapped first compound, so that the pH is made acidic, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, where said liposome comprises dioleyl phosphatidyl glycerol, and where 20% of said first compound is transformed into said platinum complex.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising adjusting the pH of a composition containing a liposome-entrapped first compound, so that the pH is made acidic, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- R1—Pt—X2
- where R1 is as defined above and X is halogen, where said liposome comprises dioleyl phosphatidyl glycerol, and where 20% of said first compound is transformed into said platinum complex.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising adjusting the pH of a composition containing a lipo some-entrapped first compound in the presence of sodium chloride, so that the pH is made acidic, said first compound having the formula
- where DACH is 1,2-diaminocyclohexane and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- DACH-Pt—Cl2
- where DACH is as defined above, where said liposome comprises dioleyl phosphatidyl glycerol, and where 20% of said first compound is transformed into said platinum complex.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid that is dioleyl phosphatidyl glycerol to produce a liposomal composition, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, and where 20% of said first compound is transformed into said platinum complex.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid that is dioleyl phosphatidyl glycerol to produce a liposomal composition, said first compound having the formula
- where R1 is diaminocycloalkyl and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- R1—Pt—X2
- where R1 is as defined above and X is halogen, and where 20% of said first compound is transformed into said platinum complex.
A liposomal antitumor composition comprising a platinum complex, the composition formed by a method, the method comprising entrapping a first compound in a liposome comprising an acidic phospholipid is dioleyl phosphatidyl glycerol to produce a liposomal composition, said first compound having the formula
- where DACH is 1,2-diaminocyclohexane and R2 and R3 independently have the formula
- where R4, R5 and R6 are each independently hydrocarbon moieties having from 1 to about 10 carbon atoms, said platinum complex having the formula
- DACH-Pt—Cl2
- where DACH is as defined above, and where 20% of said first compound is transformed into said platinum complex.
Dependencies are inferred from the claim text.