Curcumin-loaded biocompatible thermoresponsive polymeric nanoparticles for cancer drug delivery N. Sanoj Rejinold a , M. Muthunarayanan a , V.V. Divyarani a , P.R. Sreerekha a , K.P. Chennazhi a , S.V. Nair a , H. Tamura b , R. Jayakumar a,⇑ a Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham University, Kochi 682 041, India b Faculty of Chemistry, Materials and Bioengineering, Kansai University, Osaka-564-8680, Japan article info Article history: Received 14 December 2010 Accepted 2 April 2011 Available online 14 April 2011 Keywords: Chitosan Thermoresponsive nanoparticles LCST Curcumin Specific toxicity Cancer drug delivery abstract This study aims at the formulation of curcumin with biodegradable thermoresponsive chitosan-g-poly (N-vinylcaprolactam) nanoparticles (TRC-NPs) for cancer drug delivery. The spherical curcumin-loaded nanoparticles of size 220 nm were characterized, and the biological properties were studied using flow cytometry and cytotoxicity by MTT assay. The in vitro drug release was higher at above LCST compared to that at below LCST. TRC-NPs in the concentration range of 100–1000 lg/mL were non-toxic to an array of cell lines. The cellular localization of the curcumin-loaded TRC-NPs was confirmed from green fluores- cence inside the cells. The time-dependent curcumin uptake by the cells was quantified by UV spectro- photometer. Curcumin-loaded TRC-NPs showed specific toxicity to cancer cells at above their LCST. Flow cytometric analysis showed increased apoptosis on PC3 compared to L929 by curcumin-loaded TRC-NPs. These results indicate that novel curcumin-loaded TRC-NPs could be a promising candidate for cancer drug delivery. Ó 2011 Elsevier Inc. All rights reserved. 1. Introduction The limitations of current therapy provide a compelling ratio- nale for the development of alternative modalities for the targeted delivery of therapeutics for the treatment of solid tumors [1]. An exciting potential solution in cancer treatments is to encapsulate the drug in a biocompatible material that can be injected into the blood stream with the intention of delivering drug to a tumor site in response to an external thermal source like radio frequency (RF) generator, which is the source that provides radio waves to heat and kill cancer cells [2]. Chitosan is a well-known biopolymer having many applications in tissue engineering [3–6], wound heal- ing [7], drug delivery [8–11], and also in gene delivery [12,13]. In recent years, much interest has been given on stimuli-sensitive polymeric systems that show a phase transition in response to external stimulus such as temperature, pH, specific ion, and elec- tric field [14]. Among all intelligent polymers studied, tempera- ture- and pH-responsive polymeric systems have drawn much more attention, because these are the important environmental factors in the body, and some disease states manifest themselves by a change in temperature and/ or pH. In recent years, several re- search groups have reported the preparation of pH- and tempera- ture-sensitive polymers based on the poly (N-isopropylacrylamide) (PNIPAAm) for biomedical applications [15]. Poly (N-vinyl capro- lactam) (PNVCL) is another well-studied polymer that shows a good response toward temperature. The actual interest in PNVCL is connected with its thermoresponsive nature, complexation abil- ity, and biocompatibility. The utility of these polymers as micro drug delivery carriers has been well explored. Presently, there are no studies concerning the nanoformulation of chitosan-g- PNVCL with curcumin loading for cancer therapy. Curcumin, a naturally occurring polyphenolic phytoconstituent, possesses anticancer, antioxidant, anti-inflammatory, hyperlipi- demic, antibacterial, wound healing, and hepatoprotective activi- ties [16–18]. The therapeutic efficacy of curcumin is limited due to its poor oral bioavailability [19] , which has been attributed to its poor aqueous solubility and extensive first-pass metabolism. Various attempts have been made through encapsulation in poly- meric nanoparticles, but no work has been reported in thermore- sponsive polymeric nanomaterials. Highly stable formulations are required to take full advantage of the EPR effect in treating solid tu- mors [20], in maximizing the duration of exposure, and for thermal targeting using hyperthermia to direct the drug-encapsulated TRC- NPs to target cancer cells where the drug can then be released locally. Since curcumin is specific to treat cancer cells, more effica- cies would be achieved by utilizing the LCST of carrier system. Nanoscale drug delivery vehicles formulated from biocompatible chitosan and biodegradable thermoresponsive polymers constitute 0021-9797/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jcis.2011.04.006 ⇑ Corresponding author. Fax: +91 484 2802020. E-mail addresses: jayakumar77@yahoo.com, rjayakumar@aims.amrita.edu (R. Jayakumar). Journal of Colloid and Interface Science 360 (2011) 39–51 Contents lists available at ScienceDirect Journal of Colloid and Interface Science www.elsevier.com/locate/jcis