1. Introduction Recently, polymeric nanogels have emerged as an interesting candidate in many areas of research, es- pecially in material science and pharmacy, due to their diverse and suitable drug carrier properties [1– 6]. Their outstanding properties include a high drug loading capacity, prolonged circulation period in the blood stream, and enhanced permeability, allowing efficient delivery of drug molecules to tumor site [7, 8]. Two approaches are commonly used for prepara- tion of polymeric nanogels including physical and chemical crosslinking of preformed polymers [9– 11]. Physical self-assembly in nanogel formation oc- curs via non-covalent attractive forces such as hy- drophilic-hydrophilic, hydrophobic-hydrophobic, and ionic interactions, whereas chemical crosslinking can prevent dissolution of the hydrophilic polymer chains in aqueous media by covalent bonds [12]. Drug mol- ecules can be efficiently loaded in nanogels before or after crosslinking process [13–15]. Cleavable cross- links (e.g., ester, acetal, ketal, disulfide, hydrazine, amide, and anhydride bonds) are inserted either in cross-linkers or polymeric chains for allowing degra- dation of the nanogels network [16–18]. Recently, the Diels-Alder (DA) click reaction between maleimide and furan has attracted much attention for the design of crosslinked nanogels, since they can be efficiently carried out in water at low temperature without any catalyst and side-products [19–22]. On the other hand, the enhanced targeting of tumors by nanomedicines considerably depends on their size. The nanogels de- signed for anticancer drug delivery require a strict control of nanogel size in the range 10–200 nm to avoid fast excretion through kidney and target tumor 688 Facile approach to prepare pH and redox-responsive nanogels via Diels-Alder click reaction C. M. Q. Le 1 , X. T. Cao 2 , T. T. K. Tu 1 , Y-S. Gal 3 , K. T. Lim 1* 1 Department of Display Engineering, Pukyong National University, Busan, South Korea 2 Faculty of Chemical Engineering, Industrial University of Ho Chi Minh City, Vietnam 3 Department of Fire Safety, Kyungil Univeristy, Gyeongsan City, Gyeongsangbuk-Do, South Korea Received 8 January 2018; accepted in revised form 6 March 2018 Abstract. A novel pH and redox responsive system of sub-100 nm nanogels was prepared by arm-first approach via Diels- Alder click reaction. First, well-defined poly(ethylene glycol)-block-poly(styrene-alt-maleic anhydride) (PEG-b-PSM) was synthesized and subsequently functionalized with furfuryl amine, leading to the formation of the dual-functional block copolymer of PEG-b-PSMf. The furfuryl groups in the PSMf block were employed to incorporate a redox-responsive linkage and the carboxylic acid moieties generated through functionalization acted as a pH-responsive part. The Diels-Alder click reaction between a bismaleimide crosslinker and PEG-b-PSMf was conducted at 60 °C, affording star-like nanogel structures. Doxorubicin, a model anticancer drug, was loaded into to the core of the nanogels primarily by the ionic interaction with carboxylates of core blocks and a highest drug loading capacity of 38.1% was obtained. Furthermore, the in vitro profile showed a low release percentage (11.2%) of DOX at PBS pH 7.4, whereas a burst release (62%) at pH 5.0 in the presence of 10 mM glutathione, indicating the effective pH and redox responsive characteristic of the PEG-b-PSMf nanogels. Keywords: smart polymers, nanomaterials, nanogels, Diels-Alder click, drug delivery eXPRESS Polymer Letters Vol.12, No.8 (2018) 688–698 Available online at www.expresspolymlett.com https://doi.org/10.3144/expresspolymlett.2018.59 * Corresponding author, e-mail: ktlim@pknu.ac.kr © BME-PT