Colloids and Surfaces B: Biointerfaces 126 (2015) 288–296 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces jo ur nal ho me p ag e: www.elsevier.com/locate/colsurfb Green-step assembly of low density lipoprotein/sodium carboxymethyl cellulose nanogels for facile loading and pH-dependent release of doxorubicin Lei He a,b , Hongshan Liang a,b , Liufeng Lin a,b , Bakht Ramin Shah a,b , Yan Li a,b , Yijie Chen a,b , Bin Li a,b,∗ a College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China b Key Laboratory of Environment Correlative Dietology, Huazhong Agricultural University, Ministry of Education, China a r t i c l e i n f o Article history: Received 12 August 2014 Received in revised form 9 December 2014 Accepted 12 December 2014 Available online 31 December 2014 Keywords: Low density lipoprotein Sodium carboxymethyl cellulose Nanogels Doxorubicin Drug delivery a b s t r a c t In this study, a simple and green approach was developed to produce a novel nanogel via self-assembly of low density lipoproteins (LDL) and sodium carboxymethyl cellulose (CMC), to efficiently deliver doxo- rubicin (DOX) to cancer cells. Under optimal conditions, the stable nanogels were of spherical shape with an average diameter of about 90 nm, PDI < 0.3 and a zeta potential -35 mV. Furthermore, the cationic anticancer drug, doxorubicin (DOX) was effectively encapsulated into LDL/CMC nanogels with an excep- tionally high encapsulation efficiency of ∼98%. The release of DOX from DOX-LDL/CMC nanogels was pH-dependent, and DOX was released at a quicker rate at pH 6.2 than at pH 7.4. Importantly, the DOX- LDL/CMC nanogels were shown to effectively kill cancer cells in vitro. The IC 50 of the DOX-LDL/CMC nanogels in HeLa and HepG2 cells was approximately 2.45 and 1.72 times higher than that of free DOX. The slightly reduced antitumor efficacy was primarily due to the less cellular uptake of the DOX-LDL/CMC nanogels, which was confirmed by confocal laser scanning microscope (CLSM) and flow cytometry anal- ysis. The high DOX payload and pH-dependent drug release rendered LDL/CMC nanogels as an efficient carrier for doxorubicin and possibly be used for other cationic drugs in different biomedical applications. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Nanoparticle drug delivery systems have outstanding advan- tages as follows: (1) passing through the smallest capillary vessels because of their ultratiny volume and avoiding rapid clearance by phagocytes; (2) penetrating cells and tissue gap to arrive at target organs; (3) showing controlled release properties due to the pH, ion and/or temperature sensibility of materials, and (4) improving the utility of drugs with the reduce of toxic side effects [1]. In recent years, there has been a considerable interest in the development of novel drug delivery systems using nanotechnology [2]. Obviously, there is growing interest in developing biopoly- mer nanoparticles (e.g. polysaccharides-based nanoparticles and protein-based nanocarriers) as GRAS (generally regarded as safe) ∗ Corresponding author at: College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. Tel.: +86 27 6373 0040; fax: +86 27 8728 8636. E-mail address: libinfood@mail.hzau.edu.cn (B. Li). drug delivery devices due to their exceptional characteristics, namely biodegradability, high nutritional value, abundant renew- able sources and extraordinary binding capacity to various drugs [3–5]. However, compared to conventional biopolymer nanopar- ticles, hydrogel nanoparticles (nanogels) formed by self-assembly of natural protein and polysaccharide have been expected to be suitable drug delivery vehicles due to their good biocompatibility, high aqueous dispersibility and stability, well-defined structure, and multifunctional possibility [6]. Up to now, a lot of self-assembly experiments between proteins and polysaccharides have been performed such as chitosan–ovalbumin nanogels [7], lysozyme–dextran nanogels [8], bovine serum albumin (BSA)–dextran–chitosan nanoparticles [9], zein/chitosan nanoparticles [10], -lactoglobulin/pectin nanogels [11], doxorubicin–BSA–dextran nanoparticles [12] and so on. These studies showed that the size, charge, and stability of the biopolymer particles formed depend on the pH, ionic strength, ratio of protein to polysaccharide, biopolymer type, heating time and temperature. However, currently, very few protein/polysaccharide nanogels have been reported as carriers for encapsulation, protection, http://dx.doi.org/10.1016/j.colsurfb.2014.12.024 0927-7765/© 2014 Elsevier B.V. All rights reserved.