Characterization and Therapeutic Effect of a pH Stimuli Responsive Polymeric Nanoformulation for Controlled Drug Release.

Maria Victoria Cano-Cortes,Jose Antonio Laz-Ruiz,Rosario Maria Sanchez-Martin,Juan Jose Diaz-Mochon

doi:10.3390/polym12061265

Abstract

Despite the large number of polymeric nanodelivery systems that have been recently developed, there is still room for improvement in terms of therapeutic efficiency. Most reported nanodevices for controlled release are based on drug encapsulation, which can lead to undesired drug leakage with a consequent reduction in efficacy and an increase in systemic toxicity. Herein, we present a strategy for covalent drug conjugation to the nanodevice to overcome this drawback. In particular, we characterize and evaluate an effective therapeutic polymeric PEGylated nanosystem for controlled pH-sensitive drug release on a breast cancer (MDA-MB-231) and two lung cancer (A549 and H520) cell lines. A significant reduction in the required drug dose to reach its half maximal inhibitory concentration (IC50 value) was achieved by conjugation of the drug to the nanoparticles, which leads to an improvement in the therapeutic index by increasing the efficiency. The genotoxic effect of this nanodevice in cancer cells was confirmed by nucleus histone H2AX specific immunostaining. In summary, we successfully characterized and validated a pH responsive therapeutic polymeric nanodevice in vitro for controlled anticancer drug release.

Highlights

Nanomedicine for cancer therapy has become a promising therapeutic approach to overcome the various limitations of conventional small molecule chemotherapeutics by improving drug internalization and selective intracellular accumulation in cancer cells, easing the toxicity to normal tissues [1,2]
This controlled release can be achieved by implementing a stimulus-sensitive approach involving a two-step process: first, the nanosystem is preferentially accumulated at the target site through the enhanced permeability and retention (EPR) effect; the drug-loaded nanoparticles are directly activated by an external or internal stimulus to produce the local release of the drug [7,8]
Following a previously described protocol, a 500 nm monodisperse population of polystyrene amino-functionalized NPs (1) with 2% divinylbenzene (DVB) crosslinking were synthesized by dispersion polymerization [25]

Summary

Introduction

Nanomedicine for cancer therapy has become a promising therapeutic approach to overcome the various limitations of conventional small molecule chemotherapeutics by improving drug internalization and selective intracellular accumulation in cancer cells, easing the toxicity to normal tissues [1,2]. One of the main advantages offered by nanoparticles (NPs) is their ability to release drugs in a controlled manner [6] This controlled release can be achieved by implementing a stimulus-sensitive approach involving a two-step process: first, the nanosystem is preferentially accumulated at the target site through the EPR effect; the drug-loaded nanoparticles are directly activated by an external (light, temperature, etc.) or internal (pH, enzymatic, redox, etc.) stimulus to produce the local release of the drug [7,8]. The pH in most solid tumors is between 6 and 7 [9] This pH difference opened a new pathway for the release of tumor-specific drugs in tumors and simultaneously reduces undesirable effects in healthy tissues. Several examples of pH-sensitive nanodevices such as amorphous calcium carbonate–silica nanoparticles (core/shell), N- (2-hydroxypropyl) ethacrylamide (HPMA), dendrimers, and gold nanoparticles have been reported [10,11,12,13,14]

Methods

Results

Conclusion