Synthesis and Investigation of a Novel Platinum(II) Complex Targeting Biotin Receptor-Positive Tumors: In Vitro Evaluation in Cisplatin-Sensitive and -Resistant Cells, Mass Cytometry Profiling, Pharmacokinetics, In Vivo Efficacy, and SMVT-Mediated Uptake.

内容摘要

This study presents the synthesis and biological evaluation of two DAPA-conjugated platinum-(II) complexes, PMX114 and PMX118, designed as structural analogues of cisplatin and carboplatin. Comparative cytotoxicity assays in cisplatin-sensitive and cisplatin-resistant A2780 ovarian cancer cells showed that PMX114 maintained activity in the resistant cell line, with a resistance index close to unity, although its absolute IC50 values remained higher than those of cisplatin in the sensitive strain. Mass cytometry analysis confirmed substantially greater intracellular platinum accumulation with PMX114 relative to carboplatin. Pharmacokinetic profiling of PMX114 in mice informed subsequent in vivo efficacy studies in xenograft models, in which both PMX114 and carboplatin significantly reduced tumor volumes. At equimolar doses, PMX114 (75 mg/kg) produced a numerically greater reduction in tumor burden than carboplatin (60 mg/kg), although this difference did not reach statistical significance. Guided by the structural design of the complexes, additional studies examined whether PMX114 engages biotin-receptor-mediated uptake. Cancer cell lines with differential biotin receptor expression were treated with PMX114 and compared with carboplatin. Mass cytometry revealed markedly higher intracellular platinum accumulation with PMX114, and pretreatment with excess biotin attenuated uptake, implicating SMVT-mediated transport. PMX118 demonstrated similar uptake behavior but exhibited substantially weaker cytotoxicity in initial assays; therefore, subsequent mechanistic and in vivo studies focused on PMX114. Collectively, these findings support PMX114 as a promising candidate for further development as a biotin-targeted platinum-(II) chemotherapeutic with potential advantages in resistant tumor settings.