EFFECT OF POLYCATION COMPLEXATION ON METHOTREXATE RETENTION IN LIPOSOMES
Abstract
The methotrexate-DEAE-dextran complex was studied and compared with plain methotrexate (MTX) in dipalmitoyl phosphatidyl choline (DPPC) liposomes and natural pure egg lecithin liposomes, both in lyophilized and non-lyophilized systems. In the lyophilized system, the percent of entrapment of MTX in the MTX-DEAE-dextran liposomes was about 55% higher than the plain MTX liposome system for DPPC liposomes and 24% higher in pure egg lecithin liposomes. In the non-lyophilized system, the complex liposome showed a 64% higher entrapment than in the free MTX liposome for DPPC liposomes but a 55% lower entrapment in the pure egg lecithin system. The kinetic permeability of MTX from both the lyophilized and non-lyophilized DPPC liposome systems was studied at 37(DEGREES)C and pH 7.4. Both DPPC liposome systems appeared to show a biphasic first order kinetic release of MTX from the liposomes. The non-lyophilized liposome system had first phase release time of about 40 hours, whereas the lyophilized system was about 15 hours. In the non-lyophilized system, the MTX-DEAE-dextran liposome had a half-life approximately 2.5 times longer than the MTX-liposome system in the first phase and a half-life of approximately 7 times longer than the MTX liposome in the second diffusional phase. The lyophilized complex liposome system showed a half-life only 2 times longer in the first phase and 4 times longer in the second phase than the free MTX liposome system. The desorption kinetics were separated from the diffusion process in the first phase by graphing. In the desorption process, the MTX-DEAE-dextran complex liposome showed a half-life similar to the MTX liposome system in lyophilized system and a half-life approximately 15 times longer in non-lyophilized system. A kinetic analysis of the MTX-DEAE-dextran liposome data revealed that 18% of MTX was bound on the surface, whereas MTX liposome data showed 33% MTX surface bound in the lyophilized system. A similar analysis for the non-lyophilized system showed 13% MTX bound on the MTX-DEAE-dextran liposome surface, with 23% MTX bound on the MTX-liposome surface. In cytotoxicity studies, MTX-DEAE-dextran liposome systems and MTX liposome systems, both in the lyophilized and the non-lyophilized form, showed the same effectiveness as a solution of the free drug against L1210 mouse leukemia cells.
Degree
Ph.D.
Subject Area
Pharmaceuticals
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