Designer Podophyllotoxin Derivatives with Significantly Improved Safety by Targeting LAT1 for the Treatment of Esophageal Cancer

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.