Abstract
Biodegradable and tumor-micro-environmental responsive polymers are desired for targeted anticancer drug delivery. In this regard, development of pH sensitive drug delivery system to carry anticancer drugs to tumor is considered to be a promising strategy. This type of delivery system targets the acidic extracellular microenvironment as well as the intracellular organelles of solid tumors. In the present study, a novel hydroxypropyl methacrylamide (HPMA)-based polymer, p(HPMA)-p(HPMA-NH-N-DOX)-b-mPEG(P6) has been developed for the delivery of anticancer drug, Doxorubicin (DOX). The monomer, HPMA was conjugated to DOX via pH-responsive hydrazone linker to form HPMA-NH-N-DOX, which was further reacted along with free HPMA in the radical polymerization reaction using mPEG2–4,4-azobis-(4-cyanopentanoic acid) (mPEG2-ABCPA) as a macro-initiator. The synthesized polymers were characterized by gel permeation chromatography (GPC), proton nuclear magnetic resonance (1HNMR), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray crystallographic analysis. The self-assembled polymer-drug conjugate-nanoparticles (P6-NPs) were further analysed for particle size, zeta potential, drug release at varied pH conditions (pH 5.5, 6.5, and 7.4) and in the in vitro cell experiments, including cellular uptake and cytotoxicity studies. The cellular uptake and anticancer activity of the synthesized P6-NPs were carried out in murine mammary carcinoma cell line (4 T1), and human breast cancer cell lines (MCF-7) using confocal microscopy, flow cytometry and MTT assay, respectively. Dynamic light scattering and scanning electron microscopy revealed well-defined nanostructure of P6-NPs with a size of ~150 nm. Faster release of the drug (DOX) from Dox-polymer conjugate nano-assembly (P6-NPs) at the intra-tumoral (pH 6.5) and intracellular pH (pH 5.5) was observed compared to the release of DOX at physiological pH (pH 7.4). P6-NPs demonstrated higher cellular uptake and similar cytotoxicity compared to free DOX in both, MCF-7 and 4T1 cell lines. The results confirmed the formation of nanoparticles, pH-responsiveness and anticancer activity of the DOX-conjugated polymer. The newly developed polymeric system is promising to be used for DOX-mediated treatment in solid tumors.
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