Co-delivery of 10-Hydroxycamptothecin with Doxorubicin Conjugated Prodrugs for Enhanced Anticancer Efficacy

• Published in: Macromolecular bioscience Vol. 13; no. 5; pp. 584 - 594
• Main Authors: Zhang, Yu, Xiao, Chunsheng, Li, Mingqiang, Chen, Jie, Ding, Jianxun, He, Chaoliang, Zhuang, Xiuli, Chen, Xuesi
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.05.2013; WILEY‐VCH Verlag
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cell Survival - drug effects; Cellular; Chemical compounds; Dendrimers - chemistry; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Drug Delivery Systems; Drugs; Endocytosis - drug effects; Flow Cytometry; Hep G2 Cells; Humans; Hydrazones; In vitro testing; Intracellular Space - metabolism; Magnetic Resonance Spectroscopy; MCF-7 Cells; Microscopy, Confocal; Nanoparticles; Nanoparticles - chemistry; Polyethylene Glycols - chemistry; Prodrugs - administration & dosage; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; self-assembly; stimuli-sensitive polymers
• ISSN: 1616-5187; 1616-5195
• DOI: 10.1002/mabi.201200441

Well‐defined amphiphilic linear‐dendritic prodrugs (MPEG‐b‐PAMAM‐DOX) are synthesized by conjugating doxorubicin (DOX), to MPEG‐b‐PAMAM through the acid‐labile hydrazone bond. The amphiphilic prodrugs form self‐assembled nanoparticles in deionized water and encapsulate the hydrophobic anticancer drug 10‐hydroxycamptothecin (HCPT) with a high drug loading efficiency. Studies on drug release and cellular uptake of the co‐delivery system reveal that both drugs are released in a pH‐dependent manner and effectively taken up by MCF‐7 cells. In vitro methyl thiazolyl tetrazolium (MTT) assays and drug‐induced apoptosis tests demonstrate the HCPT‐loaded nanoparticles suppress cancer cell growth more efficiently than the MPEG‐b‐PAMAM‐DOX prodrugs, free HCPT, and physical mixtures of MPEG‐b‐PAMAM‐DOX and HCPT at equivalent DOX or HCPT doses. A co‐delivery system is prepared by loading 10‐hydroxycamptothecin in self‐assembled nanoparticles of acid‐liable MPEG‐b‐PAMAM‐DOX prodrugs. The use of inert carrier materials is reduced remarkably and the drug loading content is greatly increased. Moreover, enhanced anticancer efficiency is achieved, benefitting from the synergistic anticancer effects of the two drugs released from the co‐delivery system.