Water-dispersible multifunctional hybrid nanogels for combined curcumin and photothermal therapy Weitai Wu a , Jing Shen a , Probal Banerjee a, b , Shuiqin Zhou a, * a Department of Chemistry, College of Staten Island, and The Graduate Center, The City University of New York, Staten Island, NY 10314, USA b CSI/IBR Center for Developmental Neuroscience, College of Staten Island, and The Graduate Center, The City University of New York, Staten Island, NY 10314, USA article info Article history: Received 11 August 2010 Accepted 31 August 2010 Available online 8 October 2010 Keywords: Curcumin Poly(ethylene oxide) Gold Drug delivery Chemotherapy Photothermal therapy abstract We design a class of water-dispersible hybrid nanogels for intracellular delivery of hydrophobic curcu- min. The core-shell structured hybrid nanogels were synthesized by coating the Ag/Au bimetallic nanoparticles (NPs) with a hydrophobic polystyrene (PS) gel layer as inner shell, and a subsequent thin hydrophilic nonlinear poly(ethylene glycol) (PEG)-based gel layer as outer shell. The uniqueness of these hybrid nanogels lies in the integration of the functional building blocks for combined curcumin and photothermal therapy to significantly improve the therapeutic efficacy. The Ag/Au core NPs cannot only emit strong fluorescence for imaging and monitoring at the cellular level, but also exhibit strong absorption in the near-infrared (NIR) region for photothermal conversion. While the inner PS gel layer is introduced to provide strong hydrophobic interactions with curcumin for high drug loading yields, the external nontoxic and thermo-responsive PEG analog gel layer is designed to trigger the release of the pre-loaded curcumin either by variation of surrounding temperature or exogenous irradiation with NIR light. Such designed multifunctional hybrid nanogels are well suited for in vivo studies and clinical trials, thereby likely to bring this promising natural medicine of curcumin to the forefront of therapeutic agents for cancers and other diseases. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Traditional medicine is known to be fertile ground for the source of modern medicines [1,2]. Curcumin, a yellow compound pre- sented in spice turmeric (Curcuma longa) that belongs to the ginger (Zingiberaceae) family, has antioxidant, antibacterial, antifungal, antiviral, anti-inflammatory, antiproliferative, and pro-apoptotic effects [2e5]. Chemopreventive and growth inhibitory activities of curcumin against many tumor cell lines have been reported [3,7], including cervical, prostate, breast, bladder, and colon cancers [8e12]. Our recent in vivo study reveals that curcumin can block brain tumor formation [13]. How a single agent could exhibit all these medical effects is an enigma under intensive scrutiny [5]. However, one of the most important limitations with curcumin is the hydrophobic nature of the molecule and consequently its poor bioavailability [2]. Even doses as high as 8 g of curcumin per day administered to human subjects only result in an average peak serum concentration of about 1.77 mM of curcumin [14]. The rapid metabolism of curcumin in vivo is another possible reason for the observation of very low plasma levels of the compound [15]. Numerous approaches have been undertaken to enhance the bioavailability. Some of the possible ways to overcome these problems involve the use of adjuvants such as piperine that inter- fere with glucuronidation [16,17]. The structural analogs of curcu- min have also been developed by ingenious organic synthesis [17e20]. Liposomes [21e23], micelles [24,25], phospholipid complexes [26,27], and other nanoparticle (NP)-based technologies [28e31] are other promising formulations, which appear to provide increased circulation time, improved permeability, and resistance to metabolic processes. On the other hand, a key attribute of drug delivery systems is their ability to regulate the drug release to improve therapeutic efficacy and reduce side effects [32]. Two approaches can be used to regulate the release of therapeutic payload from the carrier: endogenous and exogenous activation [33e39]. The endogenous activation strategies exploit specific physiochemical characteristics of the pathological microenvironment, e.g. local temperature increase (by 2e5  C) and/or pH decrease by 1e2.5 pH units (acidosis) that are found in many pathological processes in various tissues and organs such as cancer and cystic fibrosis [33,40,41], providing bio- logically controlled release. The exogenous activation provides a complementary approach, employing orthogonal external stimuli to affect drug release. Recently, monolayer functionalized gold (Au) * Corresponding author. Tel.: þ1 718 718 3897. E-mail address: shuiqin.zhou@csi.cuny.edu (S. Zhou). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2010.08.112 Biomaterials 32 (2011) 598e609