Issue 26, 2017

Hypoxia-induced tumor cell resistance is overcome by synergistic GAPDH-siRNA and chemotherapy co-delivered by long-circulating and cationic-interior liposomes

Abstract

Chemotherapeutic drug resistance of tumor cells under hypoxic conditions is caused by the inhibition of apoptosis by autophagy and drug efflux via adenosine triphosphate (ATP)-dependent transporter activation, among other factors. Here, we demonstrate that disrupting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression can reduce the autophagy and ATP levels in tumor cells. To test whether GAPDH knockdown is sufficient to overcome drug resistance, a nanocarrier (asymmetry-membrane liposome) was designed to encapsulate GAPDH-siRNA with a low dose of paclitaxel (PTX). Liposomes were prepared using novel cryogenic inner–outer dual reverse phase emulsion liposome manufacturing technology to obtain a high loading of siRNA. The results of dynamic light scattering (DLS) indicated that the liposomes had an average hydrodynamic diameter of 250.5 nm and polydispersity index (PDI) of 0.210, which was confirmed by (Transmission Electron Microscope) TEM images. In in vitro tests, the siRNA liposomes presented a high specificity in the suppression of GAPDH expression and significant synergy in cytotoxicity with co-delivery of PTX against tumor cells (HeLa and MCF-7) under hypoxic conditions. Moreover, in vivo studies (a HeLa tumor xenograft model using female BALB/c nude mice) demonstrate that the liposomes could not only increase the concentration of drugs in tumors over time but also successfully boosted the chemotherapeutic efficacy of PTX (synergistic therapy with GAPDH-siRNA). Tumor cells appeared to lose their resistance against PTX therapy, becoming more sensitive to PTX when GAPDH-siRNA was simultaneously administered in long-circulating liposomes. Consequently, the novel delivery of GAPDH-siRNA using nanotargeted liposomes provides a useful and potential tool to overcome multidrug resistant (MDR) tumors and presents a bright prospect compared with the traditional chemotherapeutic strategies in clinic cancer therapy.

Graphical abstract: Hypoxia-induced tumor cell resistance is overcome by synergistic GAPDH-siRNA and chemotherapy co-delivered by long-circulating and cationic-interior liposomes

Article information

Article type
Paper
Submitted
14 Apr 2017
Accepted
01 Jun 2017
First published
07 Jun 2017

Nanoscale, 2017,9, 9190-9201

Hypoxia-induced tumor cell resistance is overcome by synergistic GAPDH-siRNA and chemotherapy co-delivered by long-circulating and cationic-interior liposomes

J. Guan, J. Sun, F. Sun, B. Lou, D. Zhang, V. Mashayekhi, N. Sadeghi, G. Storm, E. Mastrobattista and Z. He, Nanoscale, 2017, 9, 9190 DOI: 10.1039/C7NR02663C

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements