Multi-responsive nanofibers composite gel for local drug delivery to inhibit recurrence of glioma after operation

(2021) 19:198 Zhu et al. J Nanobiotechnol https://doi.org/10.1186/s12951-021-00943-z Journal of Nanobiotechnology Open Access RESEARCH Multi‑responsive nanofibers composite gel for local drug delivery to inhibit recurrence of glioma after operation Yufu Zhu1,2†, Jun Jia1†, Gang Zhao1†, Xuyang Huang1, Lansheng Wang1, Yongkang Zhang1, Long Zhang1, Naveena Konduru4, Jun Xie5, Rutong Yu1,2* and Hongmei Liu1,2,3* Abstract Background: The postoperative recurrence of malignant gliomas has presented a clinical conundrum currently. Worse, there is no standard treatment for these recurrent tumours. Therefore, novel promising methods of clinical treatment are urgently needed. Methods: In this study, we synthesized reactive oxygen species (ROS)-triggered poly(propylene sulfide)60 (PPS60) mixed with matrix metalloproteinases (MMPs)-responsive triglycerol monostearate (T) lipids and TMZ. The mixed solution could self-assemble at 50 ℃ to generate hydrogels with MMPs- and ROS-responsiveness. We explored whether the T/PPS + TMZ hydrogel could achieve the MMP- and ROS-responsive delivery of TMZ and exert anti-glioma regrowth effects in vitro and in vivo. These results demonstrated that the T/PPS + TMZ hydrogel significantly improved the curative effect of TMZ to inhibit postsurgical recurrent glioma. Results: The results confirmed the responsive release of TMZ encapsulated in the T/PPS + TMZ hydrogel, and the hydrogel showed excellent performance against glioma in an incomplete glioma operation model, which indicated that the T/PPS + TMZ hydrogel effectively inhibited the growth of recurrent glioma. Conclusion: In summary, we successfully developed injectable MMPs- and ROS-responsive hydrogels that could achieve the sustained release of TMZ in the surgical cavity to inhibit local recurrent glioma after surgery. Keywords: Local drug delivery, Glioma, Hydrogel, Operation, Recurrence Background Glioma is the most common type of primary tumour in the brain and is derived from the nerve epithelium [1, 2]. Although therapies against malignant gliomas, including surgery, radiotherapy and chemotherapy, have been widely used, the therapeutic effect remains poor [3–6]. The median survival of malignant glioma patients is less than 14.6 months [7, 8]. The hardest problem in treating *Correspondence: ; † Yufu Zhu, Jun Jia, and Gang Zhao contributed equally to this work 1 Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, China Full list of author information is available at the end of the article glioma is postoperative recurrence. Complete resection is deemed impossible in high-grade gliomas, and residual glioma cells contribute to postoperative glioma recurrence [9]. Clinical studies found that 80–90% of recurrent gliomas occur within 2 cm of the original region [8, 10, 11]. Decreasing glioma recurrence caused by residual tumour cells has become an important topic in clinical research and practice. Currently, there are no specific cures for recurrent gliomas. TMZ is still a first-line chemotherapeutic for the clinical treatment of recurrent gliomas [12–14]. However, the therapeutic efficacy of TMZ is often limited by several factors, including its short half-life in vivo, rapid © The Author(s) 2021. 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://creativeco mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhu et al. J Nanobiotechnol (2021) 19:198 decomposition, blood–brain barrier (BBB) permeability, and chemoresistance induced by O6-methylguanineDNA methyltransferase (MGMT) [13, 15–17]. To overcome the above problems, scholars have attempted to deliver TMZ directly to tumour regions in situ. Local TMZ delivery can avoid the systemic circulation of drugs, reduce the toxicity to normal tissues, provide localized sustained release of drugs, and thereby increase the amounts of drugs in the tumour site [18–20]. Injectable drug-loaded hydrogels, as a local drug delivery method, have attracted much attention in glioma therapies because they could bypass the BBB and act directly on the tumour regions to increase local drug concentrations while minimizing the adverse effects of systemic exposure to the drug [19, 21–25]. Hydrogels are polymer network systems with water as the dispersion medium that can be fabricated by UV irradiation, introducing irreversible covalent bonds, or by self-assembly through chemical reactions [26, 27]. The Page 2 of 14 mechanical properties of hydrogels can be continuously regulated by controlling the ratio of water. In addition, hydrogels possess the advantages of good biocompatibility, non-cytotoxicity, and low price, and they show broad prospects for application in the field of cancer treatment [28, 29]. Drug delivery systems based on hydrogels have been widely used in preclinical studies [25, 30–33]. However, due to the lack of balance among various considerations, this very promising strategy did not work as expected. To date, only Gliadel® has been approved by the FDA for clinical treatment, and has exhibited limited efficacy and many adverse effects compared to standard chemotherapy [34]. In this study, we developed a biodegradable, dualresponsive (ROS- and MMPs-) hydrogel to achieve local TMZ delivery (T/PPS + TMZ). T lipid-covered PPS60 hydrogels were prepared to load TMZ and implanted into the surgical cavity (Fig. 1). The T/PPS + TMZ hydrogel possessed the following features: (1) T lipids were Fig. 1 Structure and application of the MMPs- and ROS-responsive T/PPS + TMZ hydrogel for inhibiting recurrent glioma after surgery. A The structure of T and MMPs-responsive ability (a). The structure of PPS60 and ROS-responsive ability (b). B Schematic representation of the self-assembly of T, PPS60 and TMZ to form the T/PPS + TMZ hydrogel. C T/PPS + TMZ hydrogel injected into the surgical cavity (a). TMZ was released from the T/PPS + TMZ hydrogel in a postoperative environment (b). Released TMZ entered residual glioma cells to induce the apoptosis of glioma cells (c) Zhu et al. J Nanobiotechnol (2021) 19 (...truncated)