Understanding the Role of Axial Ligands in Modulating the Biopharmaceutical Outcomes of Cisplatin(IV) Derivatives.

Abstract

Cisplatin is a platinum (Pt)-based anticancer drug with broad-scale clinical utility. However, due to its hydrophilic nature and high kinetic reactivity, it offers numerous drug delivery challenges. Limitations such as severe systemic toxicities, chemoresistance, extensive cisplatin-plasma protein interaction, and limited cellular drug uptake reduce the therapeutic impact of cisplatin therapy. Cisplatin(IV) prodrug formation can effectively resolve these challenges. The selection of axial ligands could play a key role in determining the fate of cisplatin(IV) prodrugs by modulating the therapeutic and biopharmaceutical outcomes of therapy. Hereby, three cisplatin(IV) derivatives were developed utilizing valproate, tocopherol, and chlorambucil as axial ligands, and their biopharmaceutical performance was compared along with cisplatin. The impact of cisplatin(IV) derivative formation on their kinetic stability, drug-albumin interaction, cytotoxicity profile, cellular uptake pattern, self-assembling behavior, hemotoxicity, and tumor biodistribution pattern was analyzed to establish the correlation between the structural properties of cisplatin(IV) agents and their biopharmaceutical outcomes. The kinetic inertness of the designed cisplatin(IV) compounds helped in minimizing their plasma protein interactions and ensuring their stability in the blood environment. The lipophilicity enhancement due to Pt(IV) prodrug formation critically helped in enhancing the cellular drug uptake and reduced the dependence on transporters for drug uptake. The lipophilicity and activity of axial ligands were the key drivers governing the biopharmaceutical performance of the Pt(IV) derivatives. The properties of the axial ligand, such as its therapeutic activity, chemical backbone, and functional groups present in its structure, were the critical factors determining their plasma protein interaction, cellular uptake, anticancer activity, and self-assembly pattern. Cisplatin(IV) derivative formation further improved the amount of platinum accumulated in tumors after intravenous injection compared to free cisplatin therapy (2.7-5.4 folds increment) and reduced drug-erythrocyte interactions. Overall, the results highlighted the potential of cisplatin(IV) agents in resolving cisplatin drug delivery challenges and denoted the critical role of axial ligand selection in Pt(IV) prodrug designing.

• Authors: Tushar Date, Kaushik Kuche, Rohan Ghadi, Pradeep Kumar, Sanyog Jain
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 19 Issue 5 Pg. 1325-1337 (05 02 2022) ISSN: 1543-8392 [Electronic] United States
• PMID: 35437994 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biological Products
• Ligands
• Prodrugs
• Platinum
• Cisplatin

Topics

• Antineoplastic Agents (chemistry, therapeutic use)
• Biological Products
• Cell Line, Tumor
• Cisplatin (chemistry, pharmacology, therapeutic use)
• Ligands
• Platinum (chemistry)
• Prodrugs (chemistry)
• Tissue Distribution