Development of functional dendrisomes based on a single molecule of polyesterbenzylether dendrimer and their application in cancer stem cell therapy

Abstract

The differentiation therapy of breast cancer stem cells (CSCs) represents a significant strategy to treat cancer, but inefficient delivery to CSCs hinders the efficacy of differentiation agents. In this work, we report a type of functional dendrisomes constructed by the synthesized amphiphilic dendrimers, which enhance cellular uptake by breast CSCs, differentiate breast CSCs by carrying all-trans retinoic acid (ATRA), and increase the anticancer efficacy by carrying ATRA and docetaxel (DTX) in vitro and in breast cancer-bearing mice. The study further reveals the mechanism of cellular uptake by breast CSCs and uncovers the differentiation mechanism by analyzing relevant signal molecules, transcription factors, and cell cycle-associated signaling pathways during differentiation therapy in breast CSCs. Hence, this study offers a novel type of functional dendrisomes for differentiation therapy of breast CSCs and has significant clinical implications. Vesicles formed from branched molecules, known as dendrisomes, can be used to reprogram cancer stem cells inside breast cancer tumors. Researchers are experimenting with all-trans retinoic acid (ATRA) that encourages cancer stem cells to differentiate into less malignant forms. Wan-Liang Lu from Peking University in Beijing, China, and colleagues has developed a protocol that improves cellular uptake of ATRA by encapsulating it in a biocompatible polymer. The team synthesized spherical vesicles with greater durability and drug delivery capability than typical lipid vesicles by using polyester-based chains with branched structures as membranes. The experiments on breast-cancer bearing mice demonstrated that dendrisomes containing a mixture of ATRA, cholesterol, lipids, and anticancer agent could successfully enter cancer stem cells and initiate differentiation over 48 h. The research represents a significant contribution to differentiation therapy of cancer stem cells. We report a kind of functional dendrisomes constructed by amphiphilic dendrimers, which enable to enhance cellular uptake by breast cancer stem cells (CSCs), to differentiate breast CSCs by carrying all-trans retinoic acid (ATRA), and to increase anticancer efficacy by carrying ATRA and docetaxel in vitro and in breast cancer-bearing mice. The study further reveals endocytosis mechanism, and uncovers differentiation mechanism by analyzing relevant signal molecules, transcription factors, and cell cycle associated signaling pathway. Hence, the present study offers a novel type of functional dendrisomes for differentiation therapy of breast CSCs, and has a significant clinical implication.