Simultaneous delivery of Paclitaxel and Bcl-2 siRNA via pH-Sensitive liposomal nanocarrier for the synergistic treatment of melanoma.

Teegala Lakshminarayan Reddy,Utpal Bhadra,S Gopal Reddy,J S Yadav,B V Subba Reddy,Manika Pal Bhadra,Koteswara Rao Garikapati

doi:10.1038/srep35223

Abstract

pH-sensitive drug carriers that are sensitive to the acidic (pH = ~6.5) microenvironments of tumor tissues have been primarily used as effective drug/gene/siRNA/microRNA carriers for releasing their payloads to tumor cells/tissues. Resistance to various drugs has become a big hurdle in systemic chemotherapy in cancer. Therefore delivery of chemotherapeutic agents and siRNA’s targeting anti apoptotic genes possess advantages to overcome the efflux pump mediated and anti apoptosis-related drug resistance. Here, we report the development of nanocarrier system prepared from kojic acid backbone-based cationic amphiphile containing endosomal pH-sensitive imidazole ring. This pH-sensitive liposomal nanocarrier effectively delivers anti-cancer drug (Paclitaxel; PTX) and siRNA (Bcl-2), and significantly inhibits cell proliferation and reduces tumor growth. Tumor inhibition response attributes to the synergistic effect of PTX potency and MDR reversing ability of Bcl-2 siRNA in the tumor supporting that kojic acid based liposomal pH-sensitive nanocarrier as efficient vehicle for systemic co-delivery of drugs and siRNA.

Highlights

IntroductionWe report the development of nanocarrier system prepared from kojic acid backbone-based cationic amphiphile containing endosomal pH-sensitive imidazole ring
PH-sensitive drug carriers that are sensitive to the acidic microenvironments of tumor tissues have been primarily used as effective drug/gene/siRNA/microRNA carriers for releasing their payloads to tumor cells/tissues
Chemotherapy is often considered the primary treatment for various cancers, some serious doselimiting side-effects are seen in most cases over a period of time[1,2]

Summary

Introduction

We report the development of nanocarrier system prepared from kojic acid backbone-based cationic amphiphile containing endosomal pH-sensitive imidazole ring This pH-sensitive liposomal nanocarrier effectively delivers anti-cancer drug (Paclitaxel; PTX) and siRNA (Bcl-2), and significantly inhibits cell proliferation and reduces tumor growth. Research over a period of time has shown the delivery of small molecule therapeutics and its subsequent release in response to external stimuli such as temperature, light[11,12], redox reagents[13], ultrasound[10], pH, enzymes, etc Among these stimulation systems, the pH-responsive system is of particular interest for cancer therapy as both the tumor microenvironment (pH 6.8) and endosomes (pH 5.0) has more acidic pH compared to normal tissues (pH 7.4), enabling the carriers to release therapeutic agents in a pH-dependent manner[14,15,16]. Studies have established the promising role of cationic amphiphiles with endosomal pH-sensitive histidine groups in increasing the drug delivery efficacy of cationic liposomes[15]

Methods

Results

Discussion

Conclusion