Platinum(II) anticancer drug cisplatin is one of the most important chemotherapeutic agents in clinical use but is limited by its high toxicity and severe side effects. Platinum(IV) anticancer prodrugs can overcome these limitations by resisting premature aquation and binding to essential plasma proteins. Structure-activity relationship studies revealed a link between the efficacy of platinum(IV) complexes with the nature of their axial ligands, which can be modified to enhance the properties of the prodrug. The existing paradigm of employing platinum(IV) complexes with symmetrical axial carboxylate ligands does not fully exploit their vast potential. A new approach was conceived to control properties of platinum(IV) prodrugs using contrasting axial ligands via sequential acylation. We report a novel class of asymmetric platinum(IV) carboxylates based on the cisplatin template containing both hydrophilic and lipophilic ligands on the same scaffold designed to improve their aqueous properties and enhance their efficacy against cancer cells in vitro.
Platinum-based anticancer drugs constitute some of most effective chemotherapeutic regimes, but they are limited by high toxicities and severe side-effects arising from premature aquation and non-specific interactions. Macromolecular delivery agents can be used to shield platinum drugs from adventitious binding and as a platform to attach targeting groups, as a strategy to mitigate some of these limitations. An approach was conceived to utilise carbon nanotubes as a protective shell for stable platinum(IV) prodrugs entrapped within its inner cavities. An inert and strongly hydrophobic platinum(IV) complex was designed for entrapment within multiwalled carbon nanotubes via hydrophobic-hydrophobic interactions. Upon chemical reduction, the drug was converted to its cytotoxic and hydrophilic form and released from the carrier, via a drastic reversal in hydrophobicity, for DNA-binding. This simple method of hydrophobic entrapment and controlled release by chemical reduction and hydrophobicity reversal, exploiting the Pt(IV) scaffold as a prodrug, could form the basis of other delivery strategies for targeted delivery of platinum drugs into cancer cells.
A hydrophobic platinum(iv) prodrug was entrapped in tumour-targeting multiwalled carbon nanotubes for synchronous and ratiometric delivery of drug combinations.
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