Hierarchical self-assembly of heparin-PEG end-capped porous silica as a redox sensitive nanocarrier for doxorubicin delivery Thu Thao Nguyen Thi a,b , Tuong Vi Tran a,b , Ngoc Quyen Tran a,b , Cuu Khoa Nguyen b , Dai Hai Nguyen b, ⁎ a Institute of Research and Development, Duy Tan University, Da Nang City 550000, Vietnam b Institute of Applied Materials Science, Vietnam Academy of Science and Technology, Ho Chi Minh City 70000, Vietnam abstract article info Article history: Received 1 February 2016 Received in revised form 28 March 2016 Accepted 24 April 2016 Available online xxxx Porous nanosilica (PNS) has been attracting a great attention in fabrication carriers for drug delivery system (DDS). However, unmodified PNS-based carriers exhibited the initial burst release of loaded bioactive molecules, which may limit their potential clinical application. In this study, the surface of PNS was conjugated with adamantylamine (A) via disulfide bonds (PNS-SS-A) which was functionalized with cyclodextrin-heparin-poly- ethylene glycol (CD-HPEG) for redox triggered doxorubicin (DOX) delivery. The modified PNS was successfully formed with spherical shape and diameter around 50 nm determined by transmission electron microscopy (TEM). DOX was efficiently trapped in the PNS-SS-A@CD-HPEG and slowly released in phosphate buffered saline (PBS) without any initial burst effect. Importantly, the release of DOX was triggered due to the cleavage of the disulfide bonds in the presence of dithiothreitol (DTT). In addition, the MTT assay data showed that PNS-SS- A@CD-HPEG was a biocompatible nanocarrier and reduced the toxicity of DOX. These results demonstrated that PNS-SS-A@CD-HPEG has great potential as a novel nanocarrier for anticancer drug in cancer therapy. © 2016 Elsevier B.V. All rights reserved. Keywords: Porous nanosilica Heparin Polyethylene glycol Cyclodextrin Self-assembly Host-guest complex Disulfide bond Doxorubicin Redox sensitive 1. Introduction Porous nanosilica (PNS) is received as a promising and broadly ap- plicable of drug delivery system (DDS) due to their unique properties including high area and large pore volume, high chemical and thermal stability as well as excellent biocompatibility and biodegradability [1, 2]. Moreover, the guest molecules are effectively entrapped and protected by silica matrix which is capable of preventing enzymatic degradation, induced by pH and temperature changes of the surround- ing medium [3]. Despite PNS's adequate impact on the drug loading ca- pacity of PNS, the loading bioactive molecules would burst release, and be poorly dispersible from the unmodified PNS, leading to the loss of drug that actually reach cancer cells. These disadvantages limit the pos- sible uses of unmodified PNS as novel drug delivery carriers. In order to overcome these challenges, surface modification of PNS by polymer grafting for DDS is receiving much attention, both the interfacial fea- tures of the modified nanoparticles can be engineered and the mechan- ical and thermal properties of the polymers can be enhanced at the same time. However, this preparation can precisely alter the release rate of drug for controlled release system, instead of deciding when or where to release drug [4]. In recent years, stimuli-responsive PNS as programmable drug deliv- ery systems have attracted rapidly growing interest and drug release from PNS can be triggered by using appropriate stimuli. Enormous ef- forts have been devoted to formulate advanced PNS that are sensitive to either external stimuli (light, magnetic fields, and ultrasound) or in- ternal stimuli (pH, temperature, and redox potential). Among these dif- ferent types of stimuli, the redox stimulus is one the most effective strategies because the concentration of reducing agent, such as glutathi- one (GSH) in abnormal cells (2–10 mM) is 100 to 1000-fold higher than that in normal healthy cells (1–2 μM). In order words, the difference in concentration of antioxidants could offer a significant opportunity for redox sensitive system to deliver chemotherapeutic agents at the targeted tumor sites. For instance, Liang et al. reported the association of N-deacetylated heparin (HP) with PNS via disulfide bonds which would facilitate for the release of drug based on intracellular GSH- triggered [5–7]. By coating with heparin agents, PNS was proved to be able to elicit various promising characteristics such as to prevent or at least delay the process of phagocytosis, to stop the formation of blood clots as a part of inflammation as well as to inhibit angiogenesis and me- tastasis [8]. Additionally, this also has been shown to enhance the in vitro apoptosis and in vivo suppression of tumor growth and expan- sion considering for the efficient DOX delivery. Therefore, the redox- responsive DOX-loaded PNS utilizing heparin (HP) as end-capping agent could possibly be functioned as a promised candidate for cancer target delivery system [9]. In addition, Zhao et al. developed a redox- Materials Science and Engineering C xxx (2016) xxx–xxx ⁎ Corresponding author. E-mail address: nguyendaihai0511@gmail.com (D.H. Nguyen). MSC-06465; No of Pages 8 http://dx.doi.org/10.1016/j.msec.2016.04.085 0928-4931/© 2016 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec Please cite this article as: T.T. Nguyen Thi, et al., Hierarchical self-assembly of heparin-PEG end-capped porous silica as a redox sensitive nanocarrier for doxorubicin delivery, Mater. Sci. Eng., C (2016), http://dx.doi.org/10.1016/j.msec.2016.04.085