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

  • Biomacromolecules. 2025 Sep 8;26(9):5979-6000. doi: 10.1021/acs.biomac.5c00917.
Anunay James Pulukuri  1 ,  Anubhav Dhull  1 ,  Aqib Iqbal Dar  1 ,  Anu Rani  1 ,  Rishi Sharma  1 ,  Clifford E Berkman  1 ,  Anjali Sharma  1
Affiliations
  • 1. Department of Chemistry, College of Arts and Sciences, Washington State University, 1470 NE College Avenue, Pullman, Washington 99164, United States.
PMID: 40792696 DOI: 10.1021/acs.biomac.5c00917
Abstract

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.

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