Fabrication and Intracellular Delivery of Doxorubicin/Carbonate Apatite Nanocomposites: Effect on Growth Retardation of Established Colon Tumor

Sharif Hossain,Amranul Haque,Ezharul Hoque Chowdhury,Toshihiro Akaike,Yuichiro Doki,Hajime Hirose,Masaki Mori,Hirofumi Yamamoto,Xin Wu,Efstathios Karathanasis

doi:10.1371/journal.pone.0060428

Abstract

In continuing search for effective treatments of cancer, the emerging model aims at efficient intracellular delivery of therapeutics into tumor cells in order to increase the drug concentration. However, the implementation of this strategy suffers from inefficient cellular uptake and drug resistance. Therefore, pH-sensitive nanosystems have recently been developed to target slightly acidic extracellular pH environment of solid tumors. The pH targeting approach is regarded as a more general strategy than conventional specific tumor cell surface targeting approaches, because the acidic tumor microclimate is most common in solid tumors. When nanosystems are combined with triggered release mechanisms in endosomal or lysosomal acidic pH along with endosomolytic capability, the nanocarriers demonstrated to overcome multidrug resistance of various tumors. Here, novel pH sensitive carbonate apatite has been fabricated to efficiently deliver anticancer drug Doxorubicin (DOX) to cancer cells, by virtue of its pH sensitivity being quite unstable under an acidic condition in endosomes and the desirable size of the resulting apatite-DOX for efficient cellular uptake as revealed by scanning electron microscopy. Florescence microscopy and flow cytometry analyses demonstrated significant uptake of drug (92%) when complexed with apatite nanoparticles. In vitro chemosensitivity assay revealed that apatite-DOX nanoparticles executed high cytotoxicity in several human cancer cell lines compared to free drugs and consequently apatite-DOX-facilitated enhanced tumor inhibitory effect was observed in colorectal tumor model within BALB/cA nude mice, thereby shedding light on their potential applications in cancer therapy.

Highlights

Contemporary cancer therapy, with respect to drug delivery, has begun an evolution from traditional methodology
Since the central problem in conventional cancer chemotherapy is the severe toxic side effects of anticancer drugs on healthy tissues and invariably the side effects impose dose reduction, treatment delay, or discontinuation of therapy [1], delivery of specific drugs into the cancer cells to achieve high cytotoxicity with minimal side effect is a desirable objective for offering a potential approach for cancer therapy
The enhanced permeability and retention (EPR) effect can only enhance the accumulation of nanoparticles in tumor tissues; the poor cellular internalization as well as insufficient intracellular drug release always limits the dosages of anticancer drugs to the level below the therapeutic window, which hampers the efficacy of cancer chemotherapy [7,8]

Summary

Introduction

Contemporary cancer therapy, with respect to drug delivery, has begun an evolution from traditional methodology. Since the central problem in conventional cancer chemotherapy is the severe toxic side effects of anticancer drugs on healthy tissues and invariably the side effects impose dose reduction, treatment delay, or discontinuation of therapy [1], delivery of specific drugs into the cancer cells to achieve high cytotoxicity with minimal side effect is a desirable objective for offering a potential approach for cancer therapy To achieve these goals, the current focus is on the development of novel carriers with prolonged blood circulation time for both existing and incoming new drugs in order to achieve high efficacy in killing cancer cells and minimizing the side effects, while defining better therapeutic targets in various cancer cells [2,3]. Simple preparation of an efficient intracellular stimuli responsive drug delivery system is highly expected

Methods

Results

Conclusion