Core–shell polymer nanoparticles for prevention of GSH drug detoxification and cisplatin delivery to breast cancer cells

Abstract

Platinum drug delivery against the detoxification of cytoplasmic thiols is urgently required for achieving efficacy in breast cancer treatment that is over expressed by glutathione (GSH, thiol-oligopeptide). GSH-resistant polymer-cisplatin core-shell nanoparticles were custom designed based on biodegradable carboxylic functional polycaprolactone (PCL)-block-poly(ethylene glycol) diblock copolymers. The core of the nanoparticle was fixed as 100 carboxylic units and the shell part was varied using various molecular weight poly(ethylene glycol) monomethyl ethers (MW of PEGs = 100-5000 g mol(-1)) as initiator in the ring-opening polymerization. The complexation of cisplatin aquo species with the diblocks produced core-shell nanoparticles of 75 nm core with precise size control the particles up to 190 nm. The core-shell nanoparticles were found to be stable in saline solution and PBS and they exhibited enhanced stability with increase in the PEG shell thickness at the periphery. The hydrophobic PCL layer on the periphery of the cisplatin core behaved as a protecting layer against the cytoplasmic thiol residues (GSH and cysteine) and exhibited <5% of drug detoxification. In vitro drug-release studies revealed that the core-shell nanoparticles were ruptured upon exposure to lysosomal enzymes like esterase at the intracellular compartments. Cytotoxicity studies were performed both in normal wild-type mouse embryonic fibroblast cells (Wt-MEFs), and breast cancer (MCF-7) and cervical cancer (HeLa) cell lines. Free cisplatin and polymer drug core-shell nanoparticles showed similar cytotoxicity effects in the HeLa cells. In MCF-7 cells, the free cisplatin drug exhibited 50% cell death whereas complete cell death (100%) was accomplished by the polymer-cisplatin core-shell nanoparticles. Confocal microscopic images confirmed that the core-shell nanoparticles were taken up by the MCF-7 and HeLa cells and they were accumulated both at the cytoplasm as well at peri-nuclear environments. The present investigation lays a new foundation for the polymer-based core-shell nanoparticles approach for overcoming detoxification in platinum drugs for the treatment of GSH over-expressed breast cancer cells.

Temperature, pH, and reduction triple‐stimuli‐responsive inner‐layer crosslinked micelles as nanocarriers for controlled release

“…When the hydrophobic segment of amphiphilic block copolymer is certain, the length of the hydrophilic segment will affect the size of the micelle. As reported by Surnar et al ., polymer–cisplatin core–shell nanoparticles exhibited increased size and enhanced stability with the increase in PEG shell thickness at the periphery. As we all know, the hydrophilic shell, such as polyethylene glycol (PEG), can effectively prevent anticancer drugs in the core from prematurely interacting with the biological environment, protect the drug from premature degradation, and minimize nonspecific protein adsorption during blood circulation and capture by the reticuloendothelial system .…”

Electrohydrodynamic encapsulation of cisplatin in poly (lactic-co-glycolic acid) nanoparticles for controlled drug delivery

“…Encapsulation within a lipidic or polymeric particle protects the drug from degradation in the biological environment and, in particular, nanoscale formulations have shown promise for cellular targeting and prolonged circulation times 9,10 .…”

Electrohydrodynamic fabrication of core&ndash;shell PLGA nanoparticles with controlled release of cisplatin for enhanced cancer treatment

“…5 In recent years, the continued search for effective cancer treatment has led to the emergence of many nanosized vectors for the delivery of chemotherapeutics, for example, liposomes 6 and polymeric particles, 7,8 which aim to reduce premature interaction with the biological environment and improve cellular targeting. 9,10 Importantly, the physicochemical properties of nanovectors influence their efficacy as drug delivery systems. Therefore, this structure-activity relationship can be harnessed to engineer nanomaterials as chemotherapeutic delivery agents for improved antitumor efficacy.…”