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Reactive and Functional Polymers Volume 72, Issue 10, October 2012, Pages 729–735
Inês N. Peça, Krasimira T. Petrova,M. Margarida Cardoso, M. Teresa Barros
REQUIMTE, CQFB, Departamento de Quimica, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Caparica, Portugal
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One of the biggest issues with current cancer therapies is to increase local drug concentration at the tumour while lowering the systemic dose, coupled with the ability to kill only cancer cells while affecting as few healthy cells as possible. Targeted delivery of drugs to defined cells can improve the efficacy of treatment and minimize side-effects of drugs, and can be achieved via specific recognition processes. For this purpose, galactose-containing conjugates as targeting agents for asialoglycoprotein receptors (ASGPR) abundant on hepatocytes have been a useful tool for specific therapy of liver diseases.
We have designed a simple synthetic strategy for direct esterification of the carboxylic end-groups of the biopolymer PLGA with galactose. This way, the use of organic reagents has been minimized with a view to low-cost and greener synthetic procedures. We are reporting the synthesis of galactose-poly(DL-lactide-co-glycolide) conjugate and galactose-poly (DL-lactide-co-glycolide)-co-poly(ethylene glycol) 10 % Triblock conjugate by esterification of the end carboxyl groups. Six different methods of esterification were evaluated, as well as the effect of microwave irradiation on the reactions. The procedure was a conventional esterification, which can be performed in three main ways: in basic conditions in the presence of triethylamine; in acidic conditions catalyzed by methane sulfonic acid; or in the presence of activated zeolite as dehydrating agent. The three methods were experimented using conventional heating in an oil bath and under microwave irradiation. As a result, the highest yield and incorporation of galactose were obtained using acidic catalization and mild conditions (60°C, 24h).
The obtained polymer conjugates were used to prepare nanoparticles by the solvent extraction/evaporation method. The binding of galactose moiety to the polymer was proved by NMR, and the elevated glucose content on the surface of the nanoparticles was evidenced by the XPS experiments. Particles shapes and surface morphology were examined by SEM; their size, size distribution and zeta potential were measured by DLS; and the crystallinity properties and phase transitions characterized by DSC.
The nanoparticles carrying galactose are expected to be useful in targetable liver-specific drug delivery, as they have an amphiphilic structure which, during the nanoparticles process formation, allows to entrap an active principle in the hydrophobic inner core and show a hydrophilic outer shell with pending galactose moieties available for ASGPR recognition. This higher hydrophilicity is believed to play a key role in avoiding uptake by the reticuloendothelial system (RES).
