Liposomal Doxorubicin Circumvents PSC 833-Free Drug Interactions, Resulting in Effective Therapy of Multidrug-resistant Solid Tumors

摘要: Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadministration of chemosensitizers and anticancer drugs. The cyclosporin analogue SDZ PSC 833 [(3'-keto-Bmt1)-(Val2)-cyclosporin] (PSC 833) has been shown possess powerful chemosensitization properties in vitro, addition being intrinsically nontoxic. However, with drugs, such as daunorubicin, doxorubicin (DOX), Taxol, have resulted exacerbation drug toxicity, which is due altered pharmacokinetics. Here, we hypothesized optimization delivery, using liposomal carriers, may, by avoiding these adverse interactions, offer a significant advantage over nonencapsulated Toxicity studies were conducted normal BDF1 mice, i.v. DOX (free or liposome encapsulated) administration p.o. single multiple dosage regimens 15-day study period. 833, at dose 100 mg/kg, reduced maximum tolerated (MTD) i.v administered free 2.5-3-fold, single- multiple-dose regimens. In contrast, only 20% reduction MTD for encapsulated 100-nm 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol liposomes (55:45 molar lipid ratio) single-dose regimen had no effect on day 1, 5, 9 treatment schedule. Modest modulation P-glycoprotein-mediated MDR was observed murine P388/ADR solid tumor model when MTD. combined growth inhibition comparable drug-sensitive P388/WT tumors. This efficacy tumors dependent because alone provided significantly less antitumor activity. Pharmacokinetic tissue distribution data demonstrated exhibited plasma elimination presence absence whereas displayed rates 833. These results provide evidence can induce P-glycoprotein chemosensitize pharmacokinetics carriers used. suggests improved selectivity drugs formulations may avoid complications associated drug-MDR-reversing agent combinations enhance therapy multidrug-resistant