Applications of liposome technology in modulating p-glycoprotein mediated multidrug resistance

This thesis tested the hypothesis that the inadequate tumor delivery of anticancer agents and selectivity of PGP modulation are primarily responsible for the attenuated therapy of extravascular MDR solid tumors overexpressing PGP. PSC 833 was selected as the MDR modulator for in vivo applications, based on potency, extent of MDR reversal and latent modulating activity. Whereas co-administration of PSC 833 with non-encapsulated DOX required a 3-fold reduction in anticancer drug dose due to increased toxicity, the toxicity of DOX encapsulated in 100 nm diameter DSPC/Chol vesicles was comparable in the presence and absence of PSC 833. Efficacy studies in P388/ADR solid tumor bearing mice revealed that co-administration of non-encapsulated DOX and PSC 833 at the maximum tolerated dose (MTD) resulted in modest MDR modulation and antitumor activity. However, significant tumor growth suppression was observed when DSPC/Chol DOX was co-administered with PSC 833. Pharmacokinetic studies indicated a PSC 833-induced increase in terminal elimination phase and a concomitant 10-fold increase in plasma DOX AUC following treatment with non-encapsulated DOX whereas minimal pharmacokinetic alterations were observed with DOX encapsulated in DSPC/Chol liposomes. The relative toxicities and degree of MDR reversal were also examined using leaky and non-leaky liposomal DOX in the presence and absence of PSC 833. While PSC 833 necessitated a 3-fold dose reduction for the leaky EPC/Chol DOX in the multiple dosing schedule, no dose reductions were required for the non-leaky PEG-DSPE/DSPC/Chol DOX. In human breast carcinoma MDR xenograft tumor bearing mice, co-administration of EPC/Chol DOX and PSC 833 resulted in modest modulation and antitumor activity. However, co-administration of PSC 833 with non-leaky liposomal DOX resulted in significant tumor growth suppression comparable to that obtained using drug sensitive tumors. PSC 833 caused a 2.6-fold increase in plasma DOX AUC when co-administered with EPC/Chol DOX, whereas PSC 833 did not alter the pharmacokinetics of DOX encapsulated in sterically stabilized liposomes. The renal (CLr) and biliary (CLb) clearances of non-encapsulated DOX were found to be significantly inhibited by PSC 833. While the CLr and CLb of the EPC/Chol and PEG-DSPE/DSPC/Chol DOX were considerably lower than for non-encapsulated drug, PSC 833 co-administration resulted in minor inhibitions of CLr and CLb for the EPC/Chol DOX formulation. PEG-DSPE/DSPC/Chol DOX clearances were unaltered by the MDR modulator. These results confirmed the ability of liposome encapsulation to modify the distribution and metabolism of DOX in a manner that alleviates the effects of PSC 833 on DOX pharmacokinetics observed using non-encapsulated drug.Pharmaceutical Sciences, Faculty ofGraduat