Dual-functionalized liposome by co-delivery of paclitaxel with sorafenib for synergistic antitumor efficacy and reversion of multidrug resistance

Meng Lei,Guanglan Ma,Sijia Sha,Xueyuan Wang,Haiting Feng,Yongqiang Zhu,Xiao Du

doi:10.1080/10717544.2019.1580797

Meng Lei, Guanglan Ma + Show 5 more

Open Access

https://doi.org/10.1080/10717544.2019.1580797

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Abstract

Multidrug resistance (MDR) remains one of the major reasons for inefficiency of many chemotherapeutic agents in cancer therapy. In this study, a D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and polylysine-deoxycholic acid copolymer (PLL-DA) co-modified cationic liposome coating with hyaluronic acid (HA) was constructed for co-delivery of paclitaxel (PTX) and chemosensitizing agent, sorafenib (SOR) to treat the MDR cancer. The multifunctional liposome (HA-TPD-CL-PTX/SOR) presented good stability against rat plasma and was capable of reversing surface zeta potential under acidic conditions in the presence of HAase. Additionally, experimental result confirmed that the PLL-DA copolymer would facilitate the endo-lysosomal escape of the liposome. In vitro study demonstrated that HA-TPD-CL-PTX/SOR could significantly enhance drug accumulation in resistant MCF-7/MDR cells by inhibiting the P-gp efflux, and effectively inhibited growth of tumor cells. Furthermore, the liposome showed an enhanced anticancer activity in vivo, with a tumor growth inhibition rate of 78.52%. In summary, HA-TPD-CL-PTX/SOR exhibited a great potential for effective therapy of resistant cancers by combining with chemotherapeutic agents and could be a promising nano-carrier for reversing MDR and improving the effectiveness of chemotherapy.

Highlights

The well-studied mechanism of multidrug resistance in cancer cells is the P-glycoprotein (P-gp), an overexpression of membrane protein belonging to ATP-binding cassette (ABC) transporters, which could effectively pump anticancer agents out of cells against a concentration gradient, thereby reducing the drug concentration in the target site and eventually diminishes therapeutical efficacy (Meads et al, 2009; Fletcher et al, 2010; Yin et al, 2012)
PLL was obtained by successful elimination of the Z group from PLL (Z) and reacted with carboxyl group of the deoxycholic acid (DA) by an acid-amine coupling reaction to prepare polylysine-deoxycholic acid copolymer (PLL-DA)
The new peaks appeared in the range of 1.8–2.2 ppm for PLL-DA were ascribed to the hydrogen protons of deoxycholic acid, and 0.62, as well as 0.76 ppm, were the characteristic peaks of methyl groups of DA, indicating the successful introduction of deoxycholic acid into PLL

Summary

Introduction

Cancer is still a major threat to human health. Conventional chemotherapy as the main method for the treatment of cancer has achieved no significant progress over the past 30 years. One of the well-known challenges is lack of selective accumulation in cancer cells leading to considerable damage to normal tissues (Renugalakshmi et al, 2011; Zhang et al, 2012). Another reason is the emergence of multidrug resistance (MDR), which occurred in over 50% of cases and has been a major obstacle for successful chemotherapy (Hu & Zhang, 2012). Reversal of P-gp mediated chemotherapeutics efflux to overcome MDR in cancer treatment has been a promising approach

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