Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy.

Chandran Murugan,Srinivasan Sivasubramanian,Atanu Bhattacharyya,Raju Vivek,Ramar Thangam,Kathirvel Rayappan,Palani Gunasekaran,Ramasamy Bhanumathi,Ramasamy Thirumurugan,Krishnamurthy Shanthi,Soundarapandian Kannan

doi:10.1038/srep34053

Abstract

Combination therapy of multiple drugs through a single system is exhibiting high therapeutic effects. We investigate nanocarrier mediated inhibitory effects of topotecan (TPT) and quercetin (QT) on triple negative breast cancer (TNBC) (MDA-MB-231) and multi drug resistant (MDR) type breast cancer cells (MCF-7) with respect to cellular uptake efficiency and therapeutic mechanisms as in vitro and in vivo. The synthesized mesoporous silica nanoparticle (MSN) pores used for loading TPT; the outer of the nanoparticles was decorated with poly (acrylic acid) (PAA)-Chitosan (CS) as anionic inner-cationic outer layer respectively and conjugated with QT. Subsequently, grafting of arginine-glycine-aspartic acid (cRGD) peptide on the surface of nanocarrier (CPMSN) thwarted the uptake by normal cells, but facilitated their uptake in cancer cells through integrin receptor mediated endocytosis and the dissociation of nanocarriers due to the ability to degrade of CS and PAA in acidic pH, which enhance the intracellular release of drugs. Subsequently, the released drugs induce remarkable molecular activation as well as structural changes in tumor cell endoplasmic reticulum, nucleus and mitochondria that can trigger cell death. The valuable CPMSNs may open up new avenues in developing targeted therapeutic strategies to treat cancer through serving as an effective drug delivery podium.

Highlights

Combination therapy of multiple drugs through a single system is exhibiting high therapeutic effects
To enable cancer cell targeting of the drug loaded nanoparticles, cRGD peptide was covalently conjugated to the outer layer of Poly acrylic acid (PAA)-CS as results that the formed capped pH-responsive MSNs (CPMSNs) nanocarrier
On pore blocking, the pore volume of mesoporous silica nanoparticle (MSN)-NH2 was still large enough for drug loading (Fig. 2G). These results demonstrated that the drug molecule TPT was successfully loaded into the pores of MSN-NH2 that were subsequently functionalized with polymer PAA-CS, QT and cRGD peptides to obtain multifunctional tumor targeting CPMSNs

Summary

Introduction

Combination therapy of multiple drugs through a single system is exhibiting high therapeutic effects. In the present study, the PAA-CS polymers capped pH-responsive MSNs (CPMSNs) are designed with the properties of both targeted and combinatorial drug delivery against triple negative breast cancer cells (TNBCs). The MSNs functionalized with polymers (PAA-CS) that serve as gatekeeper as well as drug carrier and the conjugation of cRGD to the external surface of the polymer capped MSNs, assists targeted drug delivery through recognizing over expressed integrin receptor αvβ[3] on tumor cell surface and improves shelf life of the synthesized nanosystem in vivo. Studies are performed to investigate the pH response drug release kinetics, stability, targeting and cellular uptake efficiency, bioavailability, synchronized delivery of co-encapsulated drugs, toxicity and anticancer capability of multifunctional CPMSNs using MDA-MB-231 and MCF-7 breast cancer cells along with HBL-100 cells (Control)

Methods

Results

Conclusion