Comparative Study on Covalent and Noncovalent Endogenous Albumin-Binding β-Glucuronidase-Activated SN38 Prodrugs for Antitumor Efficacy

Albumin-binding prodrugs have been explored to overcome the limitations of small-molecule anticancer chemotherapy agents, such as inadequate physiological and pharmaceutical compatibility, as well as rapid renal clearance. Herein, we investigated two endogenous albumin-binding prodrugs, <b>M-g-SN38</b> and <b>S-g-SN38</b>, forming macromolecular conjugates. Both prodrugs exhibited robust stability in murine and human plasma, crucial for their therapeutic potential. Selective activation by β-glucuronidase ensures minimal toxicity in their inactive state. Notably, <b>M-g-SN38</b> exhibited higher cellular uptake, a longer circulation half-life, and enhanced tumor accumulation compared to <b>S-g-SN38</b>, suggesting its greater potential for improved antitumor efficacy. In vivo, <b>M-g-SN38</b> exhibited significant antitumor activity, leading to profound tumor reduction and, in many cases, marked depletion and complete eradication in all treated mice in the HCT116 xenograft model. Furthermore, <b>M-g-SN38</b> also demonstrated pronounced antitumor efficacy in the BxPC-3 xenograft model. Together, these findings provide new insights for the development of albumin-binding prodrugs.