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.

Combination of DNA Damage, Autophagy, and ERK Inhibition: Novel Evodiamine-Inspired Multi-Action Pt(IV) Prodrugs with High-Efficiency and Low-Toxicity Antitumor Activity

“…In the current study, the 12C-aliphatic chain in the EVO–Pt­(IV) compound 10 was proved to increase lipophilicity and ERK-1 affinity, which further resulted in significant platinum accumulation, proliferation inhibition, and ERK signaling suppression in MCF-7 cells. In addition, the introduction of an aliphatic chain could further regulate the pharmacokinetic behavior of the Pt­(IV) prodrug, especially the tissue distribution . Based on the result of the human serum albumin (HSA) binding assay (Figure S50), the significant HSA binding property of compound 10 could regulate its tissue distribution, which may contribute to the decrease in kidney platinum accumulation and nephrotoxicity.…”

“…Based on the result of the human serum albumin (HSA) binding assay (Figure S50), the significant HSA binding property of compound 10 could regulate its tissue distribution, which may contribute to the decrease in kidney platinum accumulation and nephrotoxicity. On the other hand, the increased HSA binding could further serve as an important way to improve tumor targeting of Pt­(IV) agents, − thereby enhancing the distribution in tumor tissue and eventually inducing the in vivo antitumor effect. − Finally, the remarkable suppression in ERK expression and phosphorylation by compound 10 might be a critical mechanism that contributes to the decrease in nephrotoxicity in MCF-7 xenografted BALB/c nude mice. Collectively, the current results suggested that functionalizing platinum-based agents with EVO by the Pt­(IV) strategy could produce impressive in vivo antitumor activity and attenuate nephrotoxicity, which represents an effective modality for cancer treatment.…”

“…In addition, the introduction of an aliphatic chain could further regulate the pharmacokinetic behavior of the Pt(IV) prodrug, especially the tissue distribution. 78 Based on the result of the human serum albumin (HSA) binding assay (Figure S50), the significant HSA binding property of compound 10 could regulate its tissue distribution, which may contribute to the decrease in kidney platinum accumulation and nephrotoxicity. On the other hand, the increased HSA binding could further serve as an important way to improve tumor targeting of Pt(IV) agents, 78−80 thereby enhancing the distribution in tumor tissue and eventually inducing the in vivo antitumor effect.…”

Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties

“…In contrast to the four-coordinate Pt(II) compounds, the low-spin d 6 octahedral complex structure tends to be saturated, displaying higher kinetic inertness to ligand substitution reactions. This minimizes adverse reactions with biomolecules (e.g., undesired interactions between Pt(II) and proteins or intracellular thiols) before DNA binding occurs [3,[24][25][26][27].…”

Synergistic chemotherapy/photothermal therapy for cancer treatment using a co-delivery system of cisplatin and novel conjugated polymers

“…10,11 To mitigate cisplatin's side effects, researchers have modified cisplatin ligands and altered different leaving groups, leading to the development of new divalent platinum drugs such as carboplatin, oxaliplatin, nedaplatin, and picoplatin, 12,13 as well as the design of Pt(IV) prodrug complexes with two axial ligands. [14][15][16][17] These platinum drug derivatives have to some extent reduced cisplatin's side effects but still cannot avoid certain drawbacks associated with small-molecule drugs, such as poor water solubility, ineffective accumulation at tumor sites, and low bioavailability. With the recent development of "polymeric nanomedicine" in recent years, 18,19 there is potential to provide technical avenues for overcoming this challenge.…”