Department of Pharmaceutics, Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of pharmacy, Nanjing Medical University, Nanjing 211166, China; National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China.
Department of Pharmaceutics, Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of pharmacy, Nanjing Medical University, Nanjing 211166, China.
J Control Release. 2022 May;345:786-797. doi: 10.1016/j.jconrel.2022.03.050. Epub 2022 Mar 31.
It is well known that glioma is currently the most malignant brain tumor. Because of the existence of blood-brain barrier (BBB) and tumor cell heterogeneity, systemic chemotherapy exerts unsatisfied therapeutic effect for the treatment of glioma after surgical resection and may even damage the body's immune system. Here, we developed an in situ sustained-release hydrogel delivery system for combined chemo-immunotherapy of glioma by combined chemotherapy drug and immunoadjuvant through the resection cavity local delivery. Briefly, glioma homing peptide modified paclitaxel targeting nanoparticles (PNP) and mannitolated immunoadjuvant CpG targeting nanoparticles (MNP) were embedded into PLGA-PEG-PLGA thermosensitive hydrogel framework (PNP&MNP@Gel). The in vitro and in vivo results showed that the targeting nanoparticles-hydrogel hybrid system could cross-link into a gel drug reservoir when injected into the resection cavity of glioma. And then, the sustained-release PNP could target the residual infiltration glioma cells and produce tumor antigens. Meanwhile, MNP targeted and activated the antigen-presenting cells, which enhanced the tumor antigen presentation ability and activated CD8T and NK cells to reverse immunosuppression of glioma microenvironment. This study indicated that the PNP&MNP@Gel system could enhance the therapeutic effect of glioma by chemo-immunotherapy.
众所周知，脑胶质瘤是目前最恶性的脑肿瘤。由于血脑屏障（BBB）的存在和肿瘤细胞异质性，系统化疗在脑胶质瘤切除术后的治疗效果并不令人满意，甚至可能损害机体的免疫系统。在这里，我们通过切除腔局部给药，开发了一种用于脑胶质瘤联合化免疫治疗的原位持续释放水凝胶递药系统，将化疗药物和免疫佐剂联合递送至肿瘤部位。简而言之，将脑胶质瘤归巢肽修饰的紫杉醇靶向纳米粒（PNP）和甘露糖化免疫佐剂 CpG 靶向纳米粒（MNP）嵌入 PLGA-PEG-PLGA 温敏水凝胶骨架中（PNP&MNP@Gel）。体外和体内实验结果表明，该靶向纳米粒-水凝胶杂化系统在注入脑胶质瘤切除腔后可以交联成凝胶药物库。然后，持续释放的 PNP 可以靶向残留浸润的胶质瘤细胞并产生肿瘤抗原。同时，MNP 靶向并激活了抗原呈递细胞，增强了肿瘤抗原呈递能力，激活了 CD8T 和 NK 细胞，逆转了脑胶质瘤微环境的免疫抑制。这项研究表明，PNP&MNP@Gel 系统可以通过化疗免疫治疗增强脑胶质瘤的治疗效果。
