Synthesis and Characterization of Biodegradable and Thermosensitive Polymeric Micelles with Covalently Bound Doxorubicin-Glucuronide Prodrug via Click Chemistry
- 3 November 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Bioconjugate Chemistry
- Vol. 22 (12), 2519-2530
- https://doi.org/10.1021/bc2003499
Abstract
Doxorubicin is an anthracycline anticancer agent that is commonly used in the treatment of a variety of cancers, but its application is associated with severe side effects. Biodegradable and thermosensitive polymeric micelles based on poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAmLac(n))) have been studied as drug delivery systems for therapeutic and imaging agents and have shown promising in vitro and in vivo results. The purpose of this study was to investigate the covalent coupling of a doxorubicin-glucuronide prodrug (DOX-propGA3) to the core of mPEG-b-p(HPMAmLac(2)) micelles. This prodrug is specifically activated by human beta-glucuronidase, an enzyme that is overexpressed in necrotic tumor areas. To this end, an azide modified block copolymer (mPEG(5000)-b-p(HPMAmLac(2)-r-AzEMA)) was synthesized and characterized, and DOX-propGA3 was coupled to the polymer via click chemistry with a high (95%) coupling efficiency. Micelles formed by this DOX containing polymer were small (50 nm) and monodisperse and released 40% of the drug payload after 5 days incubation at 37 degrees C in the presence of beta-glucuronidase, but less than 5% in the absence of the enzyme. In vitro cytotoxicity experiments demonstrated that DOX micelles incubated with 14C cells showed the same cytotoxicity as free DOX only in the presence of beta-glucuronidase, indicating full conversion of the polymer-bound DOX into the parent drug. Overall, this novel system is very promising for enzymatically responsive anticancer therapy.Keywords
This publication has 45 references indexed in Scilit:
- Improving the efficacy of combined modality anticancer therapy using HPMA copolymer-based nanomedicine formulationsAdvanced Drug Delivery Reviews, 2010
- Structural and chemical aspects of HPMA copolymers as drug carriersAdvanced Drug Delivery Reviews, 2010
- HPMA copolymers: Origins, early developments, present, and futureAdvanced Drug Delivery Reviews, 2010
- Preclinical Evaluation of Linear HPMA-Doxorubicin Conjugates with pH-Sensitive Drug Release: Efficacy, Safety, and Immunomodulating Activity in Murine ModelPharmaceutical Research, 2009
- Doxorubicin: The Good, the Bad and the Ugly EffectCurrent Medicinal Chemistry, 2009
- Preclinical and clinical studies of anticancer agent‐incorporating polymer micellesCancer Science, 2009
- Doxorubicin, Cardiac Risk Factors, and Cardiac Toxicity in Elderly Patients With Diffuse B-Cell Non-Hodgkin's LymphomaJournal of Clinical Oncology, 2008
- Engineered Nanocarriers of Doxorubicin: A Current UpdateCritical Reviews in Therapeutic Drug Carrier Systems, 2008
- Targeted pharmaceutical nanocarriers for cancer therapy and imagingThe AAPS Journal, 2007
- Preclinical evaluation of polymer-bound doxorubicinJournal of Controlled Release, 1992