Colloids and Surfaces B: Biointerfaces 122 (2014) 674–683 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces jo ur nal ho me p ag e: www.elsevier.com/locate/colsurfb Targeted delivery of doxorubicin into tumor cells via MMP-sensitive PEG hydrogel-coated magnetic iron oxide nanoparticles (MIONPs) Caner Nazli a , Gozde S. Demirer b , Yasemin Yar a , H. Yagci Acar a,c , Seda Kizilel a,b,∗ a Koc ¸ University, Material Science and Engineering, Istanbul 34450, Turkey b Koc ¸ University, Chemical and Biological Engineering, Istanbul 34450, Turkey c Koc ¸ University, Chemistry Department, Istanbul 34450, Turkey a r t i c l e i n f o Article history: Received 4 February 2014 Received in revised form 29 July 2014 Accepted 31 July 2014 Available online 10 August 2014 Keywords: Integrin targeting Protease responsive PEG hydrogel coating Controlled release Doxorubicin Magnetic iron oxide nanoparticles Targeted nanocarrier a b s t r a c t Targeting tumors with nano-scale delivery systems shows promise to improve the therapeutic effects of chemotherapeutic drugs. However, the limited specificity of current nano-scale systems for cancer tissues prevents realization of their full clinical potential. Here, we demonstrate an effective approach to creating as targeted nanocarriers for drug delivery: MIONPs coated with integrin-targeted and matrix- metalloproteinase (MMP)—sensitive PEG hydrogel scaffolds. The functional PEG hydrogel coating has been designed for active loading as well as triggered intra-cellular release of the cancer therapeutic agent doxorubicin (DOX). Our study demonstrated that coated nanocarriers could be taken into cancer cells 11 times more efficiently than uncoated ones. Furthermore, confocal laser scanning microscopy images revealed that these targeted nanocarriers could efficiently deliver and release DOX into the nuclei of HeLa cells within 2 h. Coating MIONPs with multifunctional PEG hydrogel could be a promising alternative to existing vehicles for targeted delivery of DOX into tumor tissue. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Chemotherapy is commonly employed to treat cancer patients [1]. However, non-specificity of chemotherapeutic agents and resistance of cancer cells to drugs compromise the efficiency of chemotherapy [1–4]. Previous studies have used various types of drug-loaded nanoparticles, and a few of such systems are commercially available [5]. For clinical use, nanoparticles should demonstrate a couple of important properties including excellent in vivo stability, high drug-loading capacity, and long circulation time in the bloodstream [4,6]. Responsiveness to local stimulus such as pH, temperature, or protease would add additional ben- efits for drug delivery vehicle design. These properties can be used to achieve specific accumulation of nanoparticles at the cancer sites and/or to deliver therapeutic drug in the cancerous tissue in response to a stimulus [4]. MIONPs, which are superparamag- netic, have demonstrated great potential for simultaneous imaging and targeted delivery of therapeutic agents into tumor sites [7–9]. MIONPs may be coated with various materials. When polymers ∗ Corresponding author at: Koc ¸ University, Chemical and Biological Engineering, Istanbul 34450, Turkey. Tel.: +90 212 338 1836; fax: +90 212 338 1548. E-mail address: skizilel@ku.edu.tr (S. Kizilel). are considered for coatings, end-grafting, direct adsorption, or self- assembly of linear polymers via hydrophobic interactions can be utilized [10–16]. Dextran has been widely used as a coating material due to its biocompatability and high affinity to iron oxide surfaces [17–20]. For example, a contrast agent based on MIONP was coated with carboxydextran to prevent aggregation of particles.[21–24] This agent, commercialized as Resovist ® (Bayer Schering Pharma, Berlin-Wedding, Germany), was used for imaging liver lesions dur- ing the 1990s. However, the product did not meet all expectations of magnetic particle imaging and was withdrawn by the company at the end of 2008. PEG, a well-studied polymer due to its biocompatible and non- toxic nature, has been conjugated to MIONPs to increase circulation time in blood and to prevent agglomeration and degradation by macrophages in blood [4,25]. Despite a PEG coating, previously developed MIONPs may still have low colloidal stability and lack stimuli responsiveness for enhanced drug release at the specific site [26,27]. Responsive design of the MIONP coating is also beneficial to accomplish high contrast in medical imaging [28]. Hence, advanced strategies are needed both to enhance therapeutic efficacy and minimize side effects of cancer drugs. The on-demand delivery of chemotherapeutics at a targeted site to improve therapeutic efficacy is crucial for translating research into clinical application [29–32]. To achieve this end goal, many studies have developed http://dx.doi.org/10.1016/j.colsurfb.2014.07.049 0927-7765/© 2014 Elsevier B.V. All rights reserved.