Preparation of Injectable Hydrogel with Near-Infrared Light Response And

Zhao et al. Bioresour. Bioprocess. (2020) 7:1 https://doi.org/10.1186/s40643-019-0289-x RESEARCH Open Access Preparation of injectable hydrogel with near-infrared light response and photo-controlled drug release Jianbo Zhao1,2, Xingxing Liang1, Hui Cao1* and Tianwei Tan1 Abstract Photo-controlled release hydrogel provides a new strategy for treating tumours. Under the stimulation of external light sources, the ability to release the entrapped drug on time and space on demand has outstanding advantages in improving drug utilisation, optimising treatment, and reducing toxicity and side efects. In this study, a photo- controlled drug delivery system for disulphide cross-linked polyaspartic acid (PASP-SS) hydrogels encapsulating proteinase K (ProK) adsorbed with platinum nanoparticles (PtNPs) was designed. The injectable cysteamine-modifed polyaspartic acid (PASP-SH) sol and PtNPs adsorbed by ProK (ProK-PtNPs) as regulatory factors were prepared. Then, ProK-PtNPs and lentinan were dissolved in the sol, and the oxidant was added to the matrix to form the gel in situ quickly after injection. Finally, the degradation of PASP-SS hydrogel by ProK and the controllability of drug release under near-infrared (NIR) light irradiation were elucidated. In vitro degradation of hydrogels and drug release experi- ments showed that the degradation rate of PASP-SS hydrogel signifcantly increased and the drug release rate increased signifcantly under near-infrared radiation. The results of cytotoxicity test showed that PASP-SS, ProK-PtNPs, and lentinan all had more than 90% cell survival rate on NIH3T3, and the lentinan released from the carrier obviously inhibited the proliferation of MCF7. PASP hydrogel has the potential to respond to on-demand light control. Keywords: Polyaspartic acid hydrogel, Near-infrared light, On-demand degradation, Drug delivery, Photo-controlled release Introduction which can maintain local high concentrations of drugs for Injectable hydrogels have been developed over the past a long time to reduce the risk of side efects and patient decades. Teir high water content, biocompatibility, bio- discomfort (Singh and Lee 2014; Dong et al. 2016; Xing degradability, and in situ gel-sol conversion capabilities et al. 2016). Terefore, a great deal of research focuses on make them attractive in a variety of biomedical applica- its potential application in targeted drug delivery; how- tions (Li et al. 2012, 2014; Huynh and Wylie 2019; Yang ever, drug difusion is generally passive or reliant on the et al. 2019). Due to the injectable hydrogel delivery sys- natural degradation of hydrogels to release drugs: such tem, the drug and sol can be fxed at the target point by drug release is not controllable and on-demand release injection (Yesilyurt et al. 2016; Liu et al. 2017). After the is thus impossible. Currently, a common strategy is to gel is formed in situ, small molecules or macromolecular give the drug delivery system the ability to receive signals drugs are released through difusion of the gel network, spontaneously and rationally release the drug in response to environmental changes. Stimuli-responsive hydrogels, also known as smart *Correspondence: [email protected] 1 Beijing Key Laboratory of Biochemical Engineering, Beijing University hydrogels, undergo signifcant changes in their swelling of Chemical Technology, No. 15 Beisanhuan East Road, Chaoyang District, behaviour, network structure, permeability, or mechani- Beijing 100029, People’s Republic of China cal strength under external stimulation (Aimetti et al. Full list of author information is available at the end of the article 2009; Hu et al. 2011; Qiu et al. 2014), such as temperature © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. Zhao et al. Bioresour. Bioprocess. (2020) 7:1 Page 2 of 13 (Tuncaboylu et al. 2011; Zheng et al. 2016), pH (Gharaie release the drug. Nevertheless, the uncontrollability of et al. 2018; Qu et al. 2018), light (Hu et al. 2017a, b; Liu drug release limits the application of PASP hydrogel in and Liu 2019; Zhang et al. 2019), and electromagnetic injectable hydrogel delivery systems. As a consequence, felds (Shi et al. 2014). Terefore, when stimuli-respon- cysteamine-modifed polyaspartic acid (PASP-SH) sol sive hydrogels are applied to a drug delivery system, the and PtNPs could be prepared, and then, PtNPs were embedded drug can be released in a controlled manner. adsorbed and immobilised on the surface of proteinase Light-responsive hydrogels are a type of stimuli-respon- K (ProK) to form regulatory elements. Ten, the regu- sive hydrogel that is currently of widespread interest, latory elements and drugs were encapsulated in the sol, with limited side efects because illumination is noninva- and the injectable properties of the sol were used to gel sive and allows remote manipulation without additional in situ around the tumour under non-surgical conditions. reagents (Hu et al. 2017a, b; Lei et al. 2017). By adjust- Finally, the enzyme activity was tailored by local warming ing the irradiation parameters, such as the illumination under NIR radiation to control the degradation of PASP power density and the illumination time, the irradiation hydrogel, so as to achieve the goal of controlling drug dose can be accurately controlled, so that the light reac- release. tion can be precisely controlled. Near-infrared (NIR) light has good tissue penetration and no phototoxicity Materials and methods to cells (Hu et al. 2017a, b; Raia et al. 2017). Terefore, Materials NIR-responsive hydrogels are important in biomedi- Polysuccinimide (PSI) was prepared by the Luoyang cal applications. For instance, the method of adjusting Cairun Environmental Protection Materials Co., Ltd enzyme activity by NIR illumination is facile and feasible. (China): its purity was greater than 99%. Phosphate It has been reported that platinum nanoparticles (PtNPs) bufer solution (PBS), dimethylformamide (DMF) (A.R.), within an enzyme allow local heating through the pho- sodium borohydride (A.R.), and cysteamine hydro- tothermal efect of the PtNPs upon NIR irradiation and chloride (A.R.) were obtained from Beijing Chemical consequently tailoring the enzyme activity (Wang et al. Industry Group (China). Imidazole (A.R.) and polyvi- 2017). nylpyrrolidone (PVP) (A.R.) from J & K Scientifc (China) Polyaspartic acid (PASP) hydrogel has excellent water were used. Dibutylamine (DBA) (TCI, A.R.) and DL-dith- absorption and water retention, biocompatibility and iothreitol (DTT) (Fluka, purum) were bought from Alad- biodegradability, and can be applied in biosensors, drug din. Chloroplatinic acid (A.R.) and proteinase K (ProK) delivery systems, and tissue engineering scafolds (Zhao (A.R., average diameter 12.7 nm) were purchased from et al. 2005; Fujita et al. 2009; Liu et al. 2012; Quan et al. Sigma-Aldrich (USA). All reagents and solvents were 2019). Tiol-modifed PASP can achieve sol–gel revers- used without further purifcation. ible phase transitions as reported in the literature, with potential as a carrier for injectable hydrogel drug delivery Synthesis of disulphide cross‑linked PASP (PASP‑SS) gel systems (Zrinyi et al. 2013; Gyarmati et al. 2013, 2014). and cysteamine‑modifed PASP (PASP‑SH) sol Moreover, the PASP backbone is destroyed by protease PASP-SS gel and PASP-SH sol were synthesised accord- cleavage of the amide bond (Wang et al. 2016a, b; Han ing to a previously reported procedure (Scheme 1) et al. 2018), causing the gel network to collapse and (Gyarmati et al. 2013). In a typical synthesis, 0.97 g PSI O O O O NH NH NH N O O O HN xyO HN x OH y O O O O O Reduction + - Oxidation NH3 Cl Hydrolysis S (DTT) HS NH (air) S NH NH N N O S O O DMF S Imidazolebuffer solution, pH=8 Oxidation O n HN xyO (NaBrO3) HN x OH y HN OH HN O SH SH O O O N NH NH NH a b O abO O O Polysuccinimide cysteamine-modified PSI Disilfidecross-linked PSI Disilfidecross-linkedPASP cysteamine-modifiedPASP (PSI) (PASP-SS) (PASP-SH) Scheme 1 Schematic illustration of the synthetic route to PASP-SS gel and PASP-SH sol preparation Zhao et al. Bioresour. Bioprocess. (2020) 7:1 Page 3 of 13 (containing 10 mmol of succinimide repeating units) to monitor the gel storage modulus G´ and loss modu- and 0.228 g (2 mmol) cysteamine hydrochloride were lus G´´ during the redox process. After the PASP-SS gel dissolved in DMF under a nitrogen atmosphere. 340 μL was reduced by DTT, 1 M NaBrO3 solution was added deprotonating agent DBA was added dropwise. After 3 h for oxidation to monitor the storage modulus G´ and loss of reaction, the solution was transferred to a watch glass modulus G´´ of the secondary redox process. A constant −1 and the thiol side chain of the cysteamine-modifed PSI angular frequency (ω = 10 s ) and constant strain (1%) was oxidised in air for 2 days to form disulphide bonds. were used. Te disulphide cross-linked PSI specimens were then subjected to ring-opening hydrolysis in imidazole bufer Microscopy solution (at pH = 8) for 3 days to obtain PASP-SS gels.

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