Thermosensitive hydrogels based on polypeptides for localized and sustained delivery of anticancer drugs Yilong Cheng a, b , Chaoliang He a , Jianxun Ding a , Chunsheng Xiao a , Xiuli Zhuang a , Xuesi Chen a, * a Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China b Graduate University of Chinese Academy of Sciences, Beijing 100039, PR China article info Article history: Received 20 August 2013 Accepted 17 September 2013 Available online 1 October 2013 Keywords: Thermosensitive hydrogels Polypeptide Paclitaxel Local chemotherapy Anticancer abstract Thermosensitive hydrogels based on poly(g-ethyl-L-glutamate)-poly(ethylene glycol)-poly(g-ethyl-L- glutamate) triblock copolymers (PELG-PEG-PELG) were prepared for localized and sustained delivery of anticancer drugs. The polypeptide-based hydrogels showed much lower critical gelation concentration than the traditional polyester-based hydrogels. In vivo biocompatibility studies revealed that the in situ formed gels in the subcutaneous layer last for w21 days, and H&E staining study suggested acceptable biocompatibility of our materials in vivo. Then the hydrogels were tried as injectable implants to encapsulate antitumor drug, paclitaxel (PTX), to assess the in situ anti-tumoral activity using liver cancer xenograft model. The results demonstrated that the PTX-incorporated hydrogels could efficiently sup- press the tumor growth, and did not result in obvious damage to normal organs. Therefore, the polypeptide-based thermosensitive hydrogels designed in the present study have great potential to serve as an effective platform for localized anti-cancer drug delivery. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Paclitaxel (PTX) is one of the most successful anti-neoplastic drugs found in the past decades, which has excellent therapeutic efficacy against a wide variety of cancers [1,2]. It interacts with tubulin dimers in the G2 phase of the mitotic cell cycle to promote microtubule polymerization and results in the formation of highly stable microtubules, which prevent cell division and account for the cytotoxic properties of PTX [3]. However, PTX has a low therapeutic index due to highly lipophilic and poor solubility in water. A current commercially available formulation for clinical use is Taxol, which consists of Cremophor Ò EL (polyethoxylated castor oil) and dehy- drated alcohol. The large quantity administration of Cremophor Ò EL to deliver the required doses of PTX causes serious side effects, particularly hypersensitivity reactions [4,5]. In order to eliminate the toxicity of Cremophor Ò EL and improve the drug efficacy, recent researches have been focused on devel- oping new drug delivery systems. A variety of approaches have been investigated including polymer-drug conjugates [6], lipo- somes [7], nanoparticles [8] and polymeric micelles [9]. Among various sorts of sustained release carriers, in-situ formed polymeric hydrogels have recently attracted considerable attention as depot drug delivery systems due to the advantages of easy formulation, high loading and low systemic toxicity [10e12]. In contrast to surgical implant systems, thermosensitive polymers that transform from sol to gel state at body temperature may be easily realized through a simple, minimally invasive injection of their aqueous solutions [13e15]. In a typical thermal gel system, drugs could be easily mixed with a polymer solution below room temperature or body temperature, and the drug-loaded hydrogel is formed in-situ after injection into body due to the increase in temperature, which may act as a depot system for localized and sustained drug release. This method can not only enhance the local drug concentrations and treatment efficiency, but also reduce systemic toxicity and improve patient compliance. Typical thermosensitive polymers are composed of a hydro- philic poly(ethylene glycol) (PEG) block and a hydrophobic, biodegradable block, such as poly(lactic acid) (PLA) [16], poly(lactic acid-co-glycolic acid) (PLGA) [17], poly(ε-caprolactone) (PCL) [18], poly((R)-3-hydroxybutyrate) (PHB) [19], poly(b-amino ester ure- thane) (PAEU) [20], etc. The PEG/polyester based hydrogels have been widely investigated for drug delivery, tissue engineering and prevention of postsurgical adhesion. In comparison with polyester- based thermo-gelling hydrogels, polypeptide-based systems have been shown to display relatively lower critical gelation concen- trations (CGC) and cause no acidic microenvironment after * Corresponding author. Tel.: þ86 431 85262112; fax: þ86 431 85262933. E-mail addresses: xschen@ciac.ac.cn, xschen@ciac.jl.cn (X. Chen). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.biomaterials.2013.09.064 Biomaterials 34 (2013) 10338e10347