Stereochemical Optimization Boosts the Chemotherapeutic Efficacy of Isomeric Bile Salt-Aquated Cisplatin Nanocomplexes

Abstract Cisplatin (CDDP) requires a rate-limiting intracellular aquation to generate aquated cisplatin (aqCDDP) for DNA binding and exertion of oncostatic effects. On this basis, three isomeric bile salt-aqCDDP nanocomplexes (12α-SDC@CDDP, 7α-SCDC@CDDP, and 7β-SUDC@CDDP) were constructed to directly deliver aqCDDP. Although 7β-SUDC@CDDP exhibited the optimal pharmacokinetics, poor cellular uptake resulted in limited tumor accumulation and insufficient antitumor activity. For 7α-SCDC@CDDP, the nonspecific distribution in the liver and lung resulted in suboptimal antitumor activity. Notably, 12α-SDC@CDDP demonstrated 3-fold higher tumor accumulation than CDDP solution and the best antitumor activity owing to its highest cellular uptake. These results revealed that the stereochemical configuration of the hydroxyl group on bile salts regulated the trade-off between systemic circulation and cellular internalization, with 12α-hydroxylation favoring uptake and 7β-hydroxylation favoring circulation. These findings provided guiding implications for future bile salt–platinum nanomedicine design, particularly through stereochemical regulation to improve therapeutic performance.