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.
Highlights
The triethylene glycol monomethyl ether (TEG-OMe)-initiated polymers are referred as BPCL
The results clearly demonstrate the polymer nanoparticles resistance to drug detoxification against GSH and ensure efficient cisplatin administration to the nucleus of the cell to enhance cell death
The core of the particles was fixed at 75 nm and the hydrophilic PEG shell was varied by varying the PEG chain length in the ring-opening polymerization (ROP) process
Summary
Paper poly(isobutylene-maleic acid)[14] and polyacrylates[15,16,17,18,19,20] are some of the important polymer systems that have been explored for cisplatin conjugation. In these cases, the aquo cisplatin complex was conjugated with a carboxylic acid functionality in the polymer backbone to preserve the drug in its active form prior to delivery. Despite the above examples observed the importance of platinum drug delivery, the stability of cisplatin drugs in the polymer scaffolds against detoxification by cytoplasmic thiol species such as GHS has not been addressed. New efforts are required to develop polymer–cisplatin conjugates that are resistant to detoxification against cytoplasmic thiols (like GSH) for accomplishing efficient treatment against breast cancer that are found to be over-expressed by GSH
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