Doxorubicin–polyphosphazene conjugate hydrogels for locally controlled delivery of cancer therapeutics

• Published in: Biomaterials Vol. 30; no. 27; pp. 4752 - 4762
• Main Authors: Chun, ChangJu, Lee, Sun M, Kim, Chang W, Hong, Ki-Yun, Kim, Sang Y, Yang, Han K, Song, Soo-Chang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-09-2009
• Subjects: Advanced Basic Science; Animals; Antitumor efficacy; Biodegradable; Cell Line, Tumor; Dentistry; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Delivery Systems; Fluorodeoxyglucose F18 - pharmacokinetics; Humans; Hydrogel; Hydrogels - chemistry; Hydrolysis - drug effects; Localization; Magnetic Resonance Spectroscopy; Mice; Mice, Nude; Neoplasms - drug therapy; Organophosphorus Compounds - chemistry; Phase Transition - drug effects; Polymers - chemistry; Polymer–doxorubicin conjugate; Positron-Emission Tomography; Spectrophotometry, Ultraviolet; Temperature; Thermosensitive; Xenograft Model Antitumor Assays; Polymer–doxorubicin conjugate; Thermosensitive; Biodegradable; Hydrogel; Localization; Antitumor efficacy
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2009.05.031

Abstract Poly(organophosphazene)–doxorubicin (DOX) conjugate bearing hydrophobic l -isoleucine ethyl ester (IleOEt) and hydrophilic α-amino-ω-methoxy-poly(ethylene glycol) with molecular weight of 550 Da (AMPEG 550) along with carboxylic acid as a functional group was synthesized to create a drug delivery system, which is based on locally injectable, biodegradable, and thermosensitive hydrogels. In addition to the evaluation of the in vitro and in vivo antitumor activities, the physicochemical properties, hydrolytic degradation, and DOX release profile of the poly(organophosphazene)–DOX conjugate were determined. The aqueous solution of the polymer–DOX conjugate showed a sol–gel transition behavior depending on temperature changes. Based on the in vivo antitumor activities of the locally injected poly(organophosphazene)–DOX conjugate into the tumor-induced nude mice, the conjugate hydrogel after the local injection at the tumor site was shown to inhibit tumor growth more effectively with less toxicity and much longer than doxorubicin and saline as controls, indicating that tumor active DOX from the conjugate hydrogel is released slowly over a longer period of time and effectively accumulated locally in the tumor sites. These results suggest that the poly(organophosphazene)–doxorubicin conjugates hold great potential for use in preclinical and clinical studies as single and/or combination therapies.