Novel liposome compositions

• US 20060222696A1
• Filed: 03/08/2006
• Published: 10/05/2006
• Est. Priority Date: 03/10/2005
• Status: Active Grant

• Current Assignee: Mebiopharm Co., Ltd.
• Original Assignee: Mebiopharm Co., Ltd.
• Inventors: Fujisawa, Tadashi, Okada, Kazushi, Ibuki, Tadayuki, Kim, Donghyun
• Granted Patent: US 7,829,113 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present disclosure provides lipid-containing compositions, including targeted liposomes encapsulating drug, and pharmaceutical formulations thereof, as well as methods for the making and using the lipid-containing compositions, including the use of the targeted liposomes in the treatment of cancer and other diseases.

Claims

1. A targeted liposome comprising one or more phospholipids, an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, an encapsulated drug or labeled compound and, optionally, at least one additional lipid,

wherein the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine comprises a targeting ligand linked to a second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine; and

wherein

the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,

the second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 3,

wherein R¹, R², R⁵ and R⁶ are each, independently, an acyl group, and

m and p are, independently, an integer from 1 to 10; and

,

wherein the liposome does not comprise a non-derivatized phosphatidyl ethanolamine or polyethylene glycol, and wherein the targeting ligand is not an intact antibody.

2. The targeted liposome of claim 1, wherein the at least one additional lipid is present.

3. The targeted liposome of claim 2, wherein the at least one additional lipid is cholesterol or a cholesterol derivative.

4. The targeted liposome of claim 1, wherein the one or more phospholipids is selected from the group consisting of phosphatidylcholine, phosphatidic acid, phosphatidylserine and phosphatidylglycerol.

5. The targeted liposome of claim 1, wherein the one or more phospholipids is a neutral phospholipid.

6. The targeted liposome of claim 1, wherein the one or more phospholipids is a phosphatidylcholine.

7. The targeted liposome of claim 6, wherein the phosphatidylcholine includes a moiety of a saturated fatty acid.

8. The targeted liposome of claim 6, wherein the one or more phospholipids is DMPC, DSPC, POPC or DPPC.

9. The targeted liposome of claim 7, wherein the at least one additional lipid is present.

10. The targeted liposome of claim 9, the at least one additional lipid is cholesterol or a cholesterol derivative.

11. The targeted liposome of claim 10, wherein the liposome comprises DMPC and cholesterol, DSPC and cholesterol, POPC and cholesterol, or DPPC and cholesterol.

12. The targeted liposome of claim 10, wherein the liposome comprises DMPC and cholesterol.

13. The targeted liposome of claim 1, wherein the targeting ligand is selected from the group consisting of transferrin, folic acid, hyaluronic acid, a sugar chain, and a fragment of a monoclonal antibody.

14. The targeted liposome of claim 13, wherein the targeting ligand is selected from the group consisting of transferrin, folic acid, hyaluronic acid and a sugar chain.

15. The targeted liposome according to claim 14, wherein the targeting ligand is transferrin.

16. The targeted liposome according to claim 15, wherein the transferrin is in a holo-form but not in an apo-form.

17. The targeted liposome according to claim 1, wherein the mean diameter of the liposome is from about 50 nm to about 250 nm.

18. The liposome of claim 1, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl, and m and p are 3.

19. The targeted liposome of claim 18, wherein the one or more phospholipids is DMPC or DSPC, and the at least one additional lipid is present and is cholesterol.

20. The targeted liposome of claim 1, wherein m and p are each, independently, an integer from 2 to 4.

21. The targeted liposome of claim 1, wherein m and p are equal and are an integer from 2 to 4.

22. The targeted liposome of claim 21, wherein m and p are equal and are 3.

23. The targeted liposome of claim 1, wherein R¹, R², R⁵ and R⁶ are each, independently, oleoyl, stearoyl, palmitoyl or myristoyl.

24. The targeted liposome of claim 1, wherein R¹ and are R² are the same, and R⁵ and R⁶ are the same.

25. The targeted liposome of claim 1, wherein R¹, R², R⁵ and R⁶ are the same.

26. The targeted liposome of claim 18, wherein the targeting ligand is transferrin.

27. The targeted liposome of claim 26, wherein the drug is present.

28. The targeted liposome of claim 27, wherein the drug is oxaliplatin.

29. The targeted liposome of claim 28, wherein the at least one additional lipid is present and is cholesterol.

30. The targeted liposome of claim 26, where the labeled compound is present.

31. The targeted liposome according to claim 1, wherein the drug is an anticancer agent.

32. The targeted liposome according to claim 1, wherein the drug is a cytotoxic drug.

33. The targeted liposome according to claim 1, wherein the drug is a topoisomerase I inhibitor.

34. The targeted liposome according to claim 33, wherein the topoisomerase I inhibitor is topotecan or irinotecan.

35. The targeted liposome according to claim 1, wherein the drug is a vinca alkaloid.

36. The targeted liposome according to claim 35, wherein the vinca alkaloid is vincristine, vinblastine, vinleurosine, vinrodisine, vinorelbine or vindesine.

37. The targeted liposome according to claim 1, wherein the drug is a nucleic acid.

38. The targeted liposome according to claim 37, wherein the nucleic acid is an antisense oligonucleotide or a ribozyme.

39. The targeted liposome according to claim 1, wherein the drug is a platinum compound.

40. The targeted liposome according to claim 39, wherein the platinum compound is biplatin, cisplatin, carboplatin, ormaplatin, oxaliplatin, zeniplatin, enloplatin, lobaplatin or spiroplatin.

41. The targeted liposome according to claim 40, wherein the platinum compound is oxaliplatin.

42. The targeted liposome according to claim 41, wherein R¹, R², R¹ and R⁶ are oleoyl, m and p are 3, the targeting ligand is transferrin, the one or more phospholipids is DMPC, and the at least one additional lipid is present and is cholesterol.

43. The targeted liposome according to claim 1, wherein the drug is an alkylating agent.

44. The targeted liposome according to claim 1, wherein the drug is a taxane.

45. The targeted liposome according to claim 1, wherein the drug is a metabolic antagonist.

46. The targeted liposome according to claim 1, wherein the drug is an antitumour antibiotic.

47. The targeted liposome according to claim 1, wherein the drug is a hormone therapy drug.

48. The targeted liposome according to claim 1, wherein the drug is a molecular target drug.

49. The targeted liposome according to claim 41, wherein the oxaliplatin is dissolved in an aqueous solution of a sugar selected from the group consisting of trehalose, maltose, sucrose, mannose, lactose, mannitol, glycerol and dextrose.

50. The targeted liposome of claim 49, wherein the sugar is at a concentration of from about 1 to about 20% percent sugar (v/v).

51. The targeted liposome of claim 41, wherein the concentration of oxaliplatin is from about 0.1 mg/ml to about 25 mg/ml within the liposome.

52. The targeted liposome of claim 15, wherein the transferrin is in a holo-form.

53. The targeted liposome claim 1, wherein the liposome does not comprise a cationic lipid.

54. The targeted liposome of claim 1, wherein the liposome does not comprise an anionic lipid.

55. A method of making a targeted liposome of claim 1, comprising the steps of

a) mixing the one or more phospholipids, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, the at least one additional lipid, to form a lipid mixture;

b) adding a drug or labeled compound to the lipid mixture formed in step (a);

c) forming a liposome.

56. The method of claim 55, further comprising a step

(d) purifying the liposome of step (c).

57. The method of claim 55, wherein the drug in step (b) is in aqueous solution prior to mixing.

58. The method of claim 55, wherein step (c) comprises sonication or stirring.

59. The method of claim 55, wherein step (c) comprises extrusion.

60. A method of making a targeted liposome of claim 1, comprising the steps of

a) mixing the one or more phospholipids, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, the at least one additional lipid, to form a lipid mixture,

wherein the succinimidyl ester of the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 2,

wherein R³ and R⁴ are each, independently, an acyl group,

n is, independently, an integer from 1 to 10;

b) adding drug or labeled compound to the lipid mixture formed in step (a);

c) forming a liposome; and

,

d) linking a targeting ligand to the succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine.

61. The method of claim 60, further comprising a step

(e) purifying the liposome of step (d).

62. The method of claim 60, wherein the drug in step (b) is in aqueous solution prior to mixing.

63. The method of claim 60, wherein step (c) comprises sonication or stirring.

64. The method of claim 60, wherein step (c) comprises extrusion.

65. A method for treating cancer comprising a) administering a targeted liposome according to claim 1 to an individual in need thereof in an amount effective to treat cancer, wherein the targeted liposome comprises a drug, and the drug is an anticancer agent.

66. A method of diagnosis comprising the steps of

a) administering a targeted liposome according to claim 1 to an individual in need thereof in an amount effective for detection, wherein the targeted liposome comprises a labeled compound;

and

b) detecting the labeled compound.

67. A pharmaceutical formulation comprising a targeted liposome according to claim 1 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, or preservatives.

68. A transferrin-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, where the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 3,

69. The transferrin-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine of claim 68, wherein p is an integer from 2 to 4.

70. The transferrin-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine of claim 69, p is 3.

71. The transferrin-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine of claim 69, wherein R⁵ and R⁶ are each, independently, oleoyl, stearoyl, palmitoyl or myristoyl.

72. The transferrin-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine of claim 69, wherein R⁵ and R⁶ are the same.

73. The transferrin-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine of claim 69, wherein R⁵ and R⁶ are oleoyl or stearoyl.

74. The transferrin-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine of claim 69, wherein R⁵ and R⁶ are oleoyl or stearoyl and p is 3.

75. A pharmaceutical formulation comprising the transferrin-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine of claim 69 or 74 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, or preservatives.

76. A blank liposome comprising one or more phospholipids, an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and,

optionally, at least one additional lipid,

wherein the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine comprises a targeting ligand linked to a second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine; and

wherein

the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,

the second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 3,

wherein R¹, R², R⁵ and R⁶ are each, independently, an acyl group, and

m and p are, independently, an integer from 1 to 10; and

,

wherein the liposome does not comprise a non-derivatized phosphatidyl ethanolamine or polyethylene glycol, and wherein the targeting ligand is not an intact antibody.

77. The blank liposome of claim 76, wherein the at least one additional lipid is present.

78. The blank liposome of claim 77, wherein the at least one additional lipid is cholesterol or a cholesterol derivative.

79. The blank liposome of claim 76, wherein the one or more phospholipids is selected from the group consisting of phosphatidylcholine, phosphatidic acid, phosphatidylserine and phosphatidylglycerol.

80. The blank liposome of claim 76, wherein the one or more phospholipids is a neutral phospholipid.

81. The blank liposome of claim 76, wherein the one or more phospholipids is a phosphatidylcholine.

82. The blank liposome of claim 81, wherein the phosphatidyl choline includes a moiety of a saturated fatty acid.

83. The blank liposome of claim 81, wherein the one or more phospholipids is DMPC, DSPC, POPC or DPPC.

84. The blank liposome of claim 83, wherein the liposome comprises at least one additional lipid.

85. The blank liposome of claim 84, the at least one additional lipid is cholesterol or a cholesterol derivative.

86. The blank liposome of claim 85, wherein the mixture comprises DMPC and cholesterol, DSPC and cholesterol, POPC and cholesterol, or DPPC and cholesterol.

87. The blank liposome of claim 86, wherein the mixture comprises DMPC and cholesterol.

88. The blank liposome of claim 76, wherein the targeting ligand is selected from the group consisting of transferrin, folic acid, hyaluronic acid, a sugar chain, and a fragment of a monoclonal antibody.

89. The blank liposome of claim 88, wherein the targeting ligand is selected from the group consisting of transferrin, folic acid, hyaluronic acid and a sugar chain.

91. The blank liposome according to claim 88, wherein the targeting ligand is transferrin.

93. The blank liposome according to claim 76, wherein the mean diameter of the liposome is from about 50 nm to about 250 nm.

94. The blank liposome of claim 76, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl, and m and p are 3.

95. The blank liposome of claim 94, wherein the one or more phospholipids is DMPC or DSPC, and the at least one additional lipid is present and is cholesterol.

96. The blank liposome of claim 76, wherein m and p are each independently, an integer from 2 to 4.

97. The blank liposome of claim 76, wherein m and p are equal and are an integer from 2 to 4.

98. The blank liposome of claim 97, wherein m and p are equal and are 3.

99. The blank liposome of claim 76, wherein R¹, R², R⁵ and R⁶ are each, independently, oleoyl, stearoyl, palmitoyl or myristoyl.

100. The blank liposome of claim 76, wherein R¹ and are R² are the same, and R⁵ and R⁶ are the same.

101. The blank liposome of claim 76, wherein R¹, R², R⁵ and R⁶ are the same.

102. The blank liposome of claim 94, wherein R¹, R², R⁵ and R⁶ are oleoyl.

103. The blank liposome of claim 94, wherein the targeting ligand is transferrin.

104. The blank liposome of claim 103, wherein the transferrin is in a holo-form.

105. The blank liposome claim 76, wherein the liposome does not comprise a cationic lipid.

106. The blank liposome of claim 76, wherein the liposome does not comprise an anionic lipid.

107. A method of making a blank liposome of claim 76, comprising the steps of

a) mixing the one or more phospholipids, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, the at least one additional lipid, to form a lipid mixture; and

b) forming a liposome.

108. The method of claim 107, further comprising a step

(c) purifying the liposome of step (b).

109. The method of claim 107, wherein step (b) comprises sonication or stirring.

110. The method of claim 107, wherein step (b) comprises extrusion.

111. A method of making a blank liposome of claim 76, comprising the steps of

a) mixing the one or more phopsholipids, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and a succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, the at least one additional lipid, to form a lipid mixture,

wherein the succinimidyl ester of the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 2,

wherein R³ and R⁴ are each, independently, an acyl group,

n is, independently, an integer from 1 to 10;

b) forming a liposome; and

,

c) linking a targeting ligand to the succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine to form a targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine.

112. The method of claim 111, further comprising a step

(d) purifying the liposome of step (c).

113. The method of claim 111, wherein step (b) comprises sonication or stirring.

114. The method of claim 111, wherein step (b) comprises extrusion.

115. The method of claim 111, wherein the targeting ligand is transferrin.

116. A method of preparing a therapeutic liposome, comprising the step of

a) encapsulating a drug into a blank liposome of claim 76.

117. A method of preparing a diagnostic liposome, comprising the step of

a) encapsulating a labeled compound into a blank liposome of claim 76.

118. A method of preparing a therapeutic liposome, comprising the step of

a) encapsulating a drug into a blank liposome of claim 87.

119. A method of preparing a diagnostic liposome, comprising the step of

a) encapsulating a labeled compound into a blank liposome of claim 87.

120. A pharmaceutical formulation comprising a blank liposome according to claim 76 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, or preservatives.

90. The blank liposome according to claim or 89, wherein the targeting ligand is transferrin.

92. The blank liposome according to claim 90, wherein the transferrin is in a holo-form but not in an apo-form.

121. A lipid mixture comprising a mixture of one or more phospholipids, an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, at least one additional lipid,

wherein

the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,

the succinimidyl ester of the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanol amine is represented by Formula 2,

wherein R¹, R², R³ and R⁴ are each, independently, an acyl group,

m and n are, independently, an integer from 1 to 10; and

,

wherein the mixture does not comprise a non-derivatized phosphatidyl ethanolamine or polyethylene glycol.

122. The lipid mixture of claim 121, wherein the at least one additional lipid is present.

123. The lipid mixture of claim 122, wherein the at least one additional lipid is cholesterol or a cholesterol derivative.

124. The lipid mixture of claim 121, wherein the one or more phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidic acid, phosphatidylserine and phosphatidylglycerol.

125. The lipid mixture of claim 121, wherein the one or more phospholipids is a neutral phospholipid.

126. The lipid mixture of claim 124, wherein the one or more phospholipids is a phosphatidylcholine.

127. The lipid mixture of claim 126, wherein the one or more phospholipids is DMPC, DSPC, POPC or DPPC.

128. The lipid mixture of claim 126, wherein the at least one additional lipid is present.

129. The lipid mixture of claim 128, the at least one additional lipid is cholesterol or a cholesterol derivative.

130. The lipid mixture of claim 129, wherein the mixture comprises DMPC and cholesterol, DSPC and cholesterol, POPC and cholesterol, or DPPC and cholesterol.

131. The lipid mixture of claim 130, wherein the mixture comprises DMPC and cholesterol.

132. The lipid mixture of claim 121, wherein m and n are each independently, an integer from 2 to 4.

133. The lipid mixture of claim 121, wherein m and n are equal and are an integer from 2 to 4.

134. The lipid mixture of claim 133, wherein m and n are equal and are 3.

135. The lipid mixture of claim 121, wherein R¹, R², R³ and R⁴ are each, independently, oleoyl, stearoyl, palmitoyl or myristoyl.

136. The lipid mixture of claim 121, wherein R¹ and are R² are the same, and R³ and R⁴ are the same.

137. The lipid mixture of claim 121, wherein R¹, R², R³ and R⁴ are the same.

138. The lipid mixture of claim 137, wherein R¹, R², R³ and R⁴ are oleoyl or stearoyl.

139. The lipid mixture of claim 138, wherein m and n are 3, where the one or more phospholipids is DMPC or DSPC and the at least one additional lipid is present and is cholesterol.

163. A method of making the lipid mixture of claim 121, comprising the step of mixing the one or more phospholipids, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and the succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine.

164. A method of making the lipid mixture of claim 122, comprising the step of mixing the one or more phospholipids, the at least one additional lipid, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and the succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine.

140. A lipid mixture comprising a mixture of one or more phospholipids, an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, at least one additional lipid,

wherein

the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,

the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine comprises a targeting ligand linked to a second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine; and

wherein the second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 3,

wherein R¹, R², R⁵ and R⁶ are each, independently, an acyl group,

m and p are, independently, an integer from 1 to 10; and

,

wherein the mixture does not comprise a non-derivatized phosphatidyl ethanolamine or polyethylene glycol, and wherein the targeting ligand is not an intact antibody.

141. The lipid mixture of claim 140, wherein the at least one additional lipid is present.

142. The lipid mixture of claim 141, wherein the at least one additional lipid is cholesterol or a cholesterol derivative.

143. The lipid mixture of claim 140, wherein the one or more phospholipids is selected from the group consisting of phosphatidylcholine, phosphatidic acid, phosphatidylserine and phosphatidylglycerol.

144. The lipid mixture of claim 140, wherein the one or more phospholipids is a neutral phospholipid.

145. The lipid mixture of claim 143, wherein the one or more phospholipids is a phosphatidylcholine.

146. The lipid mixture of claim 145, wherein the one or more phospholipids is DMPC, DSPC, POPC or DPPC.

147. The lipid mixture of claim 145, wherein the at least one additional lipid is present.

148. The lipid mixture of claim 147, the at least one additional lipid is cholesterol or a cholesterol derivative.

149. The lipid mixture of claim 148, wherein the mixture comprises DMPC and cholesterol, DSPC and cholesterol, POPC and cholesterol, or DPPC and cholesterol.

150. The lipid mixture of claim 149, wherein the mixture comprises DMPC and cholesterol.

151. The lipid mixture of claim 140, wherein m and p are each independently, an integer from 2 to 4.

152. The lipid mixture of claim 140, wherein m and p are equal and are an integer from 2 to 4.

153. The lipid mixture of claim 152, wherein m and p are equal and are 3.

154. The lipid mixture of claim 140, wherein R¹, R², R⁵ and R⁶ are each, independently, oleoyl, stearoyl, palmitoyl or myristoyl.

155. The lipid mixture of claim 140, wherein R¹ and are R² are the same, and R⁵ and R⁶ are the same.

156. The lipid mixture of claim 140, wherein R¹, R², R⁵ and R⁶ are the same.

157. The lipid mixture of claim 156, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl.

158. The lipid mixture of claim 140, wherein the targeting ligand is selected from the group consisting of transferrin, folic acid, hyaluronic acid, a sugar chain, and a fragment of a monoclonal antibody.

159. The lipid mixture of claim 158, wherein the targeting ligand is selected from the group consisting of transferrin, folic acid, hyaluronic acid and a sugar chain.

160. The lipid mixture according to claim 159, wherein the targeting ligand is transferrin.

161. The lipid mixture according to claim 160, wherein the transferrin is in a holo-form but not in an apo-form.

162. The lipid mixture of claim 141, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl, m and p are 3, the one or more phospholipids is DMPC or DSPC, the at least one additional lipid is cholesterol, and the targeting ligand is transferrin.

165. A method of making the lipid mixture of claim 140, comprising the step of mixing the one or more phospholipids, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine.

166. A method of making the lipid mixture of claim 141, comprising the step of mixing the one or more phospholipids, the at least one additional lipid, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine.

167. A liposome-containing composition comprising liposomes comprising one or more phospholipids, an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, at least one additional lipid,

wherein

the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,

the succinimidyl ester of the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 2,

wherein R¹, R², R³ and R⁴ are each, independently, an acyl group,

m and n are, independently, an integer from 1 to 10; and

,

wherein the composition does not comprise a non-derivatized phosphatidyl ethanolamine or polyethylene glycol.

168. The liposome-containing composition of claim 167, wherein the at least one additional lipid is present.

169. The liposome-containing composition of claim 168, wherein the at least one additional lipid is cholesterol or a cholesterol derivative.

170. The liposome-containing composition of claim 167, wherein the one or more phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidic acid, phosphatidylserine and phosphatidylglycerol.

171. The liposome-containing composition of claim 167, wherein the one or more phospholipids is a neutral phospholipid.

172. The liposome-containing composition of claim 170, wherein the one or more phospholipids is a phosphatidylcholine.

173. The liposome-containing composition of claim 172, wherein the one or more phospholipids is DMPC, DSPC, POPC or DPPC.

174. The liposome-containing composition of claim 173, wherein R¹, R², R³ and R⁴ are oleoyl or stearoyl, and m and n are 3.

175. The liposome-containing composition of claim 173, wherein the at least one additional lipid is present.

176. The liposome-containing composition of claim 175, the at least one additional lipid is cholesterol or a cholesterol derivative.

177. The liposome-containing composition of claim 176, wherein the liposomes comprise DMPC and cholesterol, DSPC and cholesterol, POPC and cholesterol, or DPPC and cholesterol.

178. The liposome-containing composition of claim 177, wherein the liposomes comprise DMPC and cholesterol.

179. The liposome-containing composition of claim 167, wherein m and n are each independently, an integer from 2 to 4.

180. The liposome-containing composition of claim 167, wherein m and n are equal and are an integer from 2 to 4.

181. The liposome-containing composition of claim 180, wherein m and n are equal are 3.

182. The liposome-containing composition of claim 167, wherein R¹, R², R³ and R⁴ are each, independently, oleoyl, stearoyl, palmitoyl or myristoyl.

183. The liposome-containing composition of claim 167, wherein R¹ and are R² are the same, and R³ and R⁴ are the same.

184. The liposome-containing composition of claim 167, wherein R¹, R², R³ and R⁴ are the same.

185. The liposome-containing composition of claim 184, wherein R¹, R², R³ and R⁴ are oleoyl or stearoyl.

186. The liposome-containing composition of claim 167, further comprising a solution.

187. The liposome-containing composition of claim 186, wherein the solution is an aqueous solution or a mixture of an aqueous solution and a water-miscible solvent.

215. The liposome-containing composition of any one of claims 167, 168, 173, 188, 189 or 194 further comprising a drug.

216. The liposome-containing composition according to claim 215, wherein the drug is an anticancer agent.

217. The liposome-containing composition according to claim 215, wherein the drug is a cytotoxic drug.

218. The liposome-containing composition according to claim 215, wherein the drug is a topoisomerase I inhibitor.

219. The liposome-containing composition according to claim 218, wherein the topoisomerase I inhibitor is topotecan or irinotecan.

220. The liposome-containing composition according to claim 215, wherein the drug is a vinca alkaloid.

221. The liposome-containing composition according to claim 220, wherein the vinca alkaloid is vincristine, vinblastine, vinleurosine, vinrodisine, vinorelbine or vindesine.

222. The liposome-containing composition according to claim 215, wherein the drug is a nucleic acid.

223. The liposome-containing composition according to claim 222, wherein the nucleic acid is an antisense oligonucleotide or a ribozyme.

224. The liposome-containing composition according to claim 215, wherein the drug is a platinum compound.

225. The liposome-containing composition according to claim 224, wherein the platinum compound is biplatin, cisplatin, carboplatin, ormaplatin, oxaliplatin, zeniplatin, enloplatin, lobaplatin or spiroplatin.

226. The liposome-containing composition according to claim 225, wherein the platinum compound is oxaliplatin.

227. The liposome-containing composition according to claim 226, wherein, when present, the at least one additional lipid is cholesterol or a cholesterol derivative.

228. The liposome-containing composition according to claim 227, wherein the at least one or more phospholipid is DMPC or DSPC.

229. The liposome-containing composition according to claim 227, wherein the one or more phospholipids is a neutral phospholipid.

230. The liposome-containing composition according to claim 229, wherein when the liposome comprises an additional lipid, the lipid is cholesterol or a cholesterol derivative.

231. The liposome-containing composition according to claim 226, wherein the one or more phospholipids is a phosphatidylcholine.

232. The liposome-containing composition according to claim 226, wherein the concentration of oxaliplatin is from about 0.1 mg/ml to about 25 mg/ml within the liposome.

233. The liposome-containing composition according to claim 215, wherein the drug is an alkylating agent.

234. The liposome-containing composition according to claim 215, wherein the drug is a taxanes.

235. The liposome-containing composition according to claim 215, wherein the drug is a metabolic antagonist.

236. The liposome-containing composition according to claim 215, wherein the drug is an antitumour antibiotic.

237. The liposome-containing composition according to claim 215, wherein the drug is a hormone therapy drug.

238. The liposome-containing composition according to claim 215, wherein the drug is a molecular target drug.

239. The liposome-containing composition according to claim 226, wherein the oxaliplatin is dissolved in an aqueous solution of a sugar selected from the group consisting of trehalose, maltose, sucrose, lactose, mannose, mannitol, glycerol and dextrose.

240. The liposome-containing composition according to claim 215, wherein, when present, the targeting ligand is transferrin.

241. The liposome-containing composition according to claim 215, wherein the one or more phospholipid is DMPC or DSPC, R¹, R² and, where present, R⁵ and R⁶ are oleoyl or stearoyl, m and, where present, p are 3, the at least one additional lipid, where present, is cholesterol, the drug is oxaliplatin, and the targeting ligand, where present, is transferrin.

242. The liposome-containing composition of claim 239, wherein the sugar is at a concentration of from about 1 to about 20% percent sugar (v/v).

243. The liposome-containing composition of any one of claims 167, 168, 173, 188, 189 or 194, further comprising a labeled compound.

244. The liposome-containing composition of claim 243, wherein the labeled compound comprises a radioisotopic moiety.

245. A method of making the liposome-containing composition claim 215, comprising the steps of

a) mixing the one or more phospholipid lipids, and the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and,

where present, the succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine or targeting-factor modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, where present, at least one additional lipid, to form a lipid mixture; and

b) adding a drug to the lipid mixture formed in step (a); and

,

c) forming a liposome containing composition.

246. A method of making the liposome-containing composition claim 243, comprising the steps of

a) mixing the one or more phospholipid lipids, and the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and,

where present, the succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine or the targeting-factor modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, where present, the at least one additional lipid, to form a lipid mixture; and

b) adding a labeled compound to the lipid mixture formed in step (a).

c) forming a liposome containing composition.

252. The method of claim 245, wherein in step (a) the at least one additional lipid is present.

253. The method of claim 252, wherein in step (a) the succinimidyl ester of an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is present.

254. The method of claim 252, wherein in step (a) the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is present.

188. A liposome-containing composition comprising liposomes comprising one or more phospholipids, an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, and, optionally, at least one additional lipid,

wherein

the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,

the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine comprises a targeting ligand linked to a second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine; and

wherein the second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 3,

wherein R¹, R², R⁵ and R⁶ are each, independently, an acyl group,

m and p are, independently, an integer from 1 to 10; and

,

wherein the composition does not comprise a non-derivatized phosphatidyl ethanolamine or polyethylene glycol, and wherein the targeting ligand is not an intact antibody.

189. The liposome-containing composition of claim 188, wherein the at least one additional lipid is present.

190. The liposome-containing composition of claim 189, wherein the at least one additional lipid is cholesterol or a cholesterol derivative.

191. The liposome-containing composition of claim 188, wherein the one or more phospholipids is selected from the group consisting of phosphatidylcholine, phosphatidic acid, phosphatidylserine and phosphatidylglycerol.

192. The liposome-containing composition of claim 188, wherein the one or more phospholipids is a neutral phospholipid.

193. The liposome-containing composition of claim 191, wherein the one or more phospholipids is a phosphatidylcholine.

194. The liposome-containing composition of claim 193, wherein the one or more phospholipids is DMPC, DSPC, POPC or DPPC.

195. The liposome-containing composition of claim 193, wherein the at least one additional lipid is present.

196. The liposome-containing composition of claim 195, the at least one additional lipid is cholesterol or a cholesterol derivative.

197. The liposome-containing composition of claim 196, wherein the liposomes comprise DMPC and cholesterol, DSPC and cholesterol, POPC and cholesterol, or DPPC and cholesterol.

198. The liposome-containing composition of claim 197, wherein the liposomes comprise DMPC and cholesterol.

199. The liposome-containing composition of claim 188, wherein m and p are each independently, an integer from 2 to 4.

200. The liposome-containing composition of claim 188, wherein m and p are equal and are an integer from 2 to 4.

201. The liposome-containing composition of claim 200, wherein m and p are equal are 3.

202. The liposome-containing composition of claim 188, wherein R¹, R², R⁵ and R⁶ are each, independently, oleoyl, stearoyl, palmitoyl or myristoyl.

203. The liposome-containing composition of claim 188, wherein R¹ and are R² are the same, and R⁵ and R⁶ are the same.

204. The liposome-containing composition of claim 188, wherein R¹, R², R⁵ and R⁶ are the same.

205. The liposome-containing composition of claim 188, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl.

206. The liposome-containing composition of claim 188, wherein the targeting ligand is selected from the group consisting of transferrin, folic acid, hyaluronic acid, a sugar chain, and a fragment of a monoclonal antibody.

207. The liposome-containing composition of claim 206, wherein the targeting ligand is selected from the group consisting of transferrin, folic acid, hyaluronic acid and a sugar chain.

208. The liposome-containing composition according to claim 206, wherein the targeting ligand is transferrin.

209. The liposome-containing composition according to claim 208, wherein the transferrin is in a holo-form but not in an apo-form.

210. The liposome-containing composition of claim 194, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl, the at least one additional lipid is present and is cholesterol, and the targeting ligand is transferrin.

211. The liposome-containing composition of claim 210, wherein the one or more phospholipids is DMPC or DSPC.

212. The liposome-containing composition of claim 188, further comprising a solutin.

213. The liposome-containing composition of claim 212, wherein the solution is an aqueous solution or a mixture of an aqueous solution and a water-miscible solvent.

214. The liposome-containing composition of claim 189, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl, the one or more phospholipids is DMPC or DSPC, the at least one additional lipid cholesterol, and the targeting ligand is transferrin.

247. A method of making the liposome-containing composition of claim 188, comprising the steps of

a) mixing the one or more phospholipids, the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and, optionally, at least one additional lipid, to form a lipid mixture; and

b) adding solvent to the mixture formed in step (a) to form a liposome-containing composition.

248. The method of claim 247, wherein the mixing step (a) is performed in the presence of an organic solvent.

249. The method of claim 247, wherein the solvent in step (b) is an aqueous solution or a mixture of aqueous solution and a water-miscible solvent.

250. The method of claim 247, wherein step (b) comprises sonication or stirring.

251. The method of claim 247, wherein step (b) comprises extrusion.