The severe toxicity of podophyllotoxin and its analogs primarily constrains their clinical application. We designed and synthesized a series of novel podophyllotoxin derivatives that target tumor-specific transporters to enhance tumor selectivity and reduce systemic toxicity. Among the new analogs, B11 as a LAT1-targeted amino acid conjugate, exhibited significantly greater anticancer activity against Eca109 cells than etoposide and with an ideal druggability profile. B11 achieved a 64.6% TGI versus 30.6% for etoposide in mice bearing Eca109 xenografts in a single drug treatment. The MTD studies showed a more than 4-fold improvement for B11 in animal tolerability compared to etoposide. Pharmacokinetic experiments revealed that B11 can achieve a higher drug distribution in tumors and minimize drug concentration in vital organs. Mechanistic studies indicated that B11 could accumulate in tumor cells in a LAT1-dependent manner and exert its antitumor effects by cytoskeleton disruption.
Jia et al. (Tue,) studied this question.