Dendrimer-Mediated Delivery Enhances Therapeutic Efficacy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant breast cancer subtypes due to poor drug bioavailability, systemic toxicity, and rapid resistance development. Camptothecin (Campto), a potent topoisomerase I inhibitor, has shown strong anticancer activity but suffers from poor solubility, instability, and off-target toxicity. Here, we report the synthesis and in vitro mechanistic evaluation of a novel dendrimer-drug conjugate, PD-Campto, composed of a generation 4 hydroxyl-terminated PAMAM dendrimer (PD) covalently linked to Campto via biodegradable ester linkers using copper(I)-catalyzed alkyne-azide click (CuAAC) chemistry. PD-Campto demonstrated enhanced aqueous solubility, sustained release in tumor-relevant environments, and significant TNBC cellular uptake. In vitro studies showed significantly higher cytotoxicity, ROS generation, mitochondrial membrane depolarization, caspase-3/7 activation, and apoptosis compared to free Campto. PD-Campto modulated immune checkpoint and cancer stem-like cell markers and showed synergy with the PARP inhibitor Olaparib. These findings suggest PD-Campto is a promising nanotherapeutic for improving TNBC treatment.