Delivery of platinum (II) drugs with bulky ligands in trans-geometry for overcoming cisplatin drug resistance

Abstract

Drug resistance induced by increasing intracellular levels of detoxifying agents for conventional platinum(II) drugs such as metallothioneins (MTs) and glutathione (GSH) are the major obstacles for widely used platinum-based chemotherapeutic cancer treatment. Here, we developed trans-geometry platinum (II) drugs with sterically hindered bulky ligands PyPt which is able to hind the GSH attack of platinum drug to overcome cisplatin resistance. Moreover, the PyPt can self-assemble with biodegradable copolymer mPEG-PGA into uniform nanoparticles with PyPt drugs in the polymeric core and PEG as the shell, further protecting PyPt from GSH detoxification to further slow the reaction rate with GSH in vivo. This strategy was developed to bring benefit of not only increasing the solubility of sterically hindered platinum drugs but also combating cisplatin resistance. The M(PyPt) exhibited environment controlled releasing of Pt in tumor micro-environment which prohibited the division of cancer cells. Furthermore, due to the increasing solubility of nanoparticle encapsulated PyPt, the cellular uptake and cytotoxicity of M(PyPt) against both cancer resistance cells was enhanced compared to the cisplatin and PyPt through evaluating with flow cytometry and MTT, respectively. Thus, it was concluded that the M(PyPt) was capable to successfully overcome the cisplatin resistance in the drug-resistant cell line, indicating its potential application in the treatment of clinical cancers with strong cisplatin resistance. Hence the M(PyPt) strategy may represent a promising novel drug delivery system for the local treatment of drug resistance cancer.