Co-delivery of Doxorubicin and PSC 833 (Valspodar) by Stealth Nanoliposomes for Efficient Overcoming of Multidrug Resistance

Abstract

-Purpose. This study was aimed at developing co-encapsulated stealth nanoliposomes containing PSC 833, an efficient MDR modulator, and doxorubicin (DOX) in order to increase the effectiveness and decrease adverse effects of the anticancer drug. Methods. In attempt to increase the encapsulation efficiency of drugs, different methods for liposome preparation were tested and the effect of different parameters such as drug to lipid molar ratio, cholesterol mole percent and lipid compositions, were investigated. The final product with a lipid composition of EPC:DSPE-PEG2000:Chol (60:5:30 %mol) was prepared by thin layer film hydration method. After preparation of empty liposomes, DOX and PSC 833 were loaded using ammonium sulfate gradient and remote film loading methods, respectively. Physical characteristics of optimized liposomes (DOX/PSC-L) such as particle size, zeta potential, encapsulation efficiency, in-vitro drugs release and stability were evaluated. Furthermore, in vitro cytotoxicity study of various liposomal formulations as well as drugs, solutions against resistant human breast cancer cell line, T47D/TAMR-6, was evaluated using MTT assay. Results. The best formulation showed a narrow size distribution with average diameter of 91.3 ± 0.2 nm with zeta potential of -6 ± 1.2, the encapsulation efficiency for DOX and PSC 833 were more than 95% and 65.5%, respectively. In DOX-resistant T47D/TAMR-6 cells, dual-agent stealth liposomes showed significantly greater cytotoxicity (P < 0.05) than free DOX and liposomal DOX plus free PSC 833 treatments. Conclusions. Co-encapsulation of DOX and PSC 833 presents a promising anticancer formulation, capable of effective reversal of drug resistance, and should be explored further in therapeutic studies with animal tumor xenograft models.

Nanomedicine therapeutic approaches to overcome cancer drug resistance

“…Further, liposomal anti-MRP-1 and anti-Bcl2 siRNA in combination with Doxorubicin were used to suppress pump and non-pump mediated cellular resistance and to cause death in MDR lung cancer cells [116]. Finally, stealth liposomes containing PSC 833 (Valspodar, a cyclosporin A analogue that is more effective) and Doxorubicin were able to reverse MDR in the Doxorubicin-resistant human breast cancer cell line T47D/TAMR-6 [117]. …”

Co-delivery nanoparticles of anti-cancer drugs for improving chemotherapy efficacy

“…Thus, co-administration of a chemotherapeutic agent with P-gp inhibitors, including verapamil (VER), cyclosporine A, tariquida, and valspodar (PSC833), is used as a promising approach for treating MDR cancer (Bajelan et al, 2012;Sriraman et al, 2015).…”

Niosomal carriers enhance oral bioavailability of&nbsp;carvedilol: effects of bile salt-enriched vesicles and carrier surface charge&nbsp;

“…Similar results were found in our previous studies of liposomal formulations. 36,37 The increase in EE can be rationalized by proposing that Chol increases the microviscosity of the membrane by abolishing the gel-toliquid phase transition of the surfactant bilayer, resulting in a more stable and hydrophobic bilayer 38 that retards permeation and prevents leakage of hydrophobic drugs entrapped in the bilayer. 39 In contrast, subsequent intercalation of Chol would reduce drug entrapment by competing with the drug for the bilayer, thus preventing incorporation of the amphiphilic or lipophilic drug into the vesicles.…”