Engineering oligo(ethylene glycol)-based thermosensitive microgels for drug delivery applications Ting Zhou, Weitai Wu, Shuiqin Zhou * Department of Chemistry of College of Staten Island, and The Graduate Center, The City University of New York, 2800 Victory Boulevard, Staten Island, New York 10314, USA article info Article history: Received 3 May 2010 Received in revised form 12 June 2010 Accepted 15 June 2010 Available online 22 June 2010 Keywords: PEG Microgel Drug delivery abstract Novel oligo(ethylene glycol)-based thermosensitive microgels with well engineered core-shell structures were developed for storage and delivery of chemotherapeutic agents. The core is consisted of hydro- phobic poly[2-(2-methoxyethoxy)ethyl methacrylate], while the shell is consisted of hydrophilic copolymer of 2-(2-methoxyethoxy)ethyl methacrylate with oligo(ethylene glycol) methyl ether meth- acrylates. These core-shell microgels exhibit tunable volume phase transition temperature and excellent colloidal stability across the physiologically important temperature range. The thickness of the hydro- philic shell can control the collapsing degree (or mesh size) of the hydrophobic core network, which can be utilized to significantly increase the loading capacity of the model hydrophobic drugs dipyridamole by tailoring the shell thickness of microgels. While the microgels are nontoxic, the drug molecules released from the microgels remain active to kill the cancer cells. The presented results provide important guidelines for the rational design of core-shell structured polymeric microgels for drug uptake and release applications. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Microgel particles as drug delivery carriers for biological and biomedical applications have received increasing attention during the last decade due to their unique chemical and physical versatility [1e6]. Microgels offer several advantages over other polymer based drug delivery systems: simple synthesis, tunable size from nano- meters to micrometers, large surface area for effective bio- conjugation to add target ligands for site-specific delivery, an interior network structure for the incorporation of drug molecules to protect the drug from hydrolysis and other type of chemical degradation, and potential biocompatibility. Among the various approaches used to enhance the efficacy of chemotherapy is the use of smart carrier systems that can release a drug in response to stimuli, such as changes in pH, temperature, light, or the presence of specific enzymes that are selectively encountered in relevant cell organelles [7e10]. So far, the thermo-responsive poly(N-isopropylacrylamide) (PNIPAM)-based microgels have been most extensively studied for applications in drug delivery [8e21], including the introduction of other environmental sensitivities such as pH, glucose, and light sensitive components into the PNIPAM microgels to control the drug release. However, the well studied PNIPAM-based microgels have not been translated into a biomedical breakthrough although a recent study on the microgels containing NIPAM and acrylic acid (AA) indicated no adverse effects [16]. To meet the general requirement in biocompatibility of the materials used for drug delivery systems, an important challenge is to develop biocom- patible polymers which have similar properties to PNIPAM [4]. Thermo-responsive polymers containing short oligo(ethylene glycol) side chains were recently proposed as an attractive alter- native to PNIPAM [22e28]. The lower critical solution temperature (LCST) of these graft polymers are tunable through the control in the compositions of the oligo(ethylene glycol) side chains. Lutz et al. have reported that the LCST of the copolymers composed of 2-(2-methoxyethoxy)ethyl methacrylate (MEO 2 MA) with oligo (ethylene glycol) methyl ether methacrylate (M n ¼ 475 g/mol, MEO 9 MA) can be adjusted by varying the comonomer ratios [22e24]. Ishizone et al. found that the LCST of the poly[oligo (ethylene glycol) alkyl ether methacrylates] is tunable by varying the oligo(ethylene glycol) side chain length [26,27]. The longer the oligo(ethylene glycol) side chain, the higher the LCST of the graft polymer. In addition, the star-block copolymers of these oligo (ethylene glycol) methyl ether methacrylate with star poly (ethylene glycol) (PEG) exhibit thermoreversible sol-gel transitions in physiological media [28]. Although the graft structure composed of a carbonecarbon backbone and multiple oligo(ethylene glycol) side chains is different from the standard linear PEG, these * Corresponding author. Tel.: þ1 718 982 3897; fax: þ1 718 982 3910. E-mail address: shuiqin.zhou@csi.cuny.edu (S. Zhou). Contents lists available at ScienceDirect Polymer journal homepage: www.elsevier.com/locate/polymer 0032-3861/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.polymer.2010.06.030 Polymer 51 (2010) 3926e3933