Exploring the Structure-Activity Relationships of Albumin-Targeted Picoplatin-Based Platinum(IV) Prodrugs

Area of Science:

• Medicinal Chemistry
• Cancer Therapeutics
• Drug Delivery

Background:

• Platinum(II) complexes are standard cancer treatments but face challenges with side effects and resistance.
• Picoplatin, a platinum(II) analog, was developed to overcome glutathione-induced resistance.
• The anticancer potential of picoplatin prodrugs and tumor-targeting strategies remains largely unexplored.

Purpose of the Study:

• To synthesize novel picoplatin(II) derivatives and their platinum(IV) prodrugs.
• To evaluate the synthesis and properties of albumin-targeting platinum(IV) prodrugs.
• To assess the in vitro and in vivo anticancer efficacy of these novel platinum complexes.

Main Methods:

• Synthesis of picoplatin(II) derivatives and platinum(IV) prodrugs with oxalate, cyclobutane dicarboxylate, albumin-targeting maleimide, or succinimide moieties.
• Assessment of reaction kinetics with glutathione (GSH) and reduction with ascorbic acid.
• In vitro cytotoxicity assays (MTT) and in vivo studies using CT26 tumor-bearing mice.

Main Results:

• Picoplatin derivatives exhibited slower reactions with GSH compared to cisplatin, carboplatin, and oxaliplatin.
• Platinum(IV) prodrugs showed varying stability, with picoplatin(IV) being highly unstable.
• Albumin-binding platinum(IV) complexes demonstrated prolonged circulation and enhanced tumor accumulation in mice.
• Maleimide-functionalized PicoCarbo(IV) and picoplatin(II) significantly inhibited tumor growth, while other prodrugs were largely inactive.

Conclusions:

• Albumin-targeting strategies can enhance the tumor accumulation of platinum prodrugs.
• The bulky 2-picoline ligand in picoplatin may impede the activation of platinum(IV) prodrugs when conjugated to albumin.
• Further research is needed to optimize picoplatin-based platinum(IV) prodrugs for enhanced anticancer efficacy.