Preparation, characterization, and biological analysis of liposomal formulations of vincristine.
Vincristine is a dimeric Catharanthus alkaloid derived from the Madagascan periwinkle that acts by binding to tubulin and blocking metaphase in actively dividing cells. While vincristine is widely used in the treatment of a number of human carcinomas, its use is associated with dose-limiting neurotoxicity, manifested mainly as peripheral neuropathy. It is known that the therapeutic activity of vincristine can be significantly enhanced after its encapsulation in appropriately designed liposomal systems. Enhanced efficacy is also associated with a slight decrease in drug toxicity. Thus, the therapeutic index of vincristine can be enhanced significantly through the use of a liposomal delivery system. Vincristine may be encapsulated into liposomes of varying lipid composition by several techniques, including passive loading, pH gradient loading, and ionophore-assisted loading. However, most research has focused on the encapsulation of vincristine in response to a transbilayer pH gradient, which actively concentrates the drug within the aqueous interior of the liposome. This chapter details the preparation and evaluation of liposomal vincristine. Specifically, we elaborate on the components (choice of lipids, molar proportions, etc.), methods (preparation of liposomes, drug loading methods, etc.), critical design features (size, surface charge, etc.), and key biological endpoints (circulation lifetime, bioavailability, efficacy measurements) important to the development of a formulation of vincristine with enhanced therapeutic properties.
Waterhouse
Dawn N
DN
Department of Advanced Therapeutics, British Columbia Cancer Agency, British Columbia, Canada.
Madden
Thomas D
TD
Cullis
Pieter R
PR
Bally
Marcel B
MB
Mayer
Lawrence D
LD
Webb
Murray S
MS
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007476:Ionophores / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D014750:Vincristine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D007476:Ionophores; D008055:Lipids; D008081:Liposomes; D014750:Vincristine