Platinum (Pt) (IV) prodrugs have emerged as a promising class of drug candidates that were designed to overcome the toxicity and resistance issues associated with Pt(II) chemotherapeutics. They can be reduced by bio-reductants, such as ascorbic acid and in hypoxic environments in vivo to release the corresponding cytotoxic Pt(II) species. Targeted delivery of these agents can be achieved using microbubbles (MBs), which can encapsulate, embed, or adsorb drug molecules.(1) At a higher intensity of ultrasound (US) than that is used for imaging, MBs undergo oscillation and collapse (inertial cavitation), facilitating site specific drug release.(2) Use of MBs as a drug delivery system bypasses the dose limiting side effects and resistance associated with platinum drugs. Previous work successfully demonstrated incorporation of a biotin functionalised oxaliplatin Pt(IV) prodrug onto the MB shell through a biotin-avidin interaction.(2)
The main objective of this study is to establish a targeted, formulation-integrated strategy by incorporating lipid-functionalised Pt(IV) complexes directly into the MB shell during self-assembly. To date, a library of Pt(IV) prodrugs have been developed, including derivatives of cisplatin, carboplatin and oxaliplatin. Target compounds were functionalised at the axial position with lipids such as tetradecanoic acid to enhance lipophilicity and facilitate incorporation into the MB structure. Structural characterisation by ¹H NMR spectroscopy and HR mass spectrometry confirmed successful synthesis of target compounds.
Next steps will be focused on incorporation of our Pt(IV) conjugates into MBs and investigation of their application in ultrasound-targeted microbubble destruction (UTMD)-mediated drug delivery. The overall goal is to establish a one-step, formulation-integrated platform for platinum-based chemotherapy with improved tumour selectivity and reduced systemic toxicity.