Thermoresponsive nanocomposite gel for local drug delivery to suppress the growth of glioma by inducing autophagy

Although the treatments of malignant glioma include surgery, radiotherapy and chemotherapy by oral drug administration, the prognosis of patients with glioma remains very poor. We developed a polyethylene glycol-dipalmitoylphosphatidyle- thanoiamine (mPEG-DPPE) calcium phosphate nanoparticles (NPs) injectable thermoresponsive hydrogel (nanocomposite gel) that could provide a sustained and local delivery of paclitaxel (PTX) and temozolomide (TMZ). In addition, the proportion of PTX and TMZ for the optimal synergistic antiglioma effect on C6 cells was determined to be 1:100 (w/w) by the Chou and Talalay method. Our results clearly indicated that the autophagy induced by PTX:TMZ NPs plays an important role in regulating tumor cell death, while autophagy inhibition dramatically reverses the antitumor effect of PTX:TMZ NPs, suggesting that antiproliferative autophagy occurs in response to PTX:TMZ NPs treatment. The antitumor efficacy of the PTX:TMZ NP-loaded gel was evaluated in situ using C6 tumor-bearing rats, and the PTX:TMZ NP-loaded gel exhibited superior antitumor performance. The antitumor effects of the nanocomposite gel in vivo were shown to correlate with autophagic cell death in this study. The in vivo results further confirmed the advantages of such a strategy. The present study may provide evidence supporting the development of nanomedicine for potential clinical application.

尽管恶性胶质瘤的治疗手段涵盖手术、放疗与口服药物化疗，但胶质瘤患者的预后仍极差。本研究开发了一种聚乙二醇-二棕榈酰磷脂酰乙醇胺（polyethylene glycol-dipalmitoylphosphatidylethanolamine, mPEG-DPPE）基磷酸钙纳米粒（nanoparticles, NPs）负载的可注射温敏水凝胶（纳米复合凝胶），可实现紫杉醇（paclitaxel, PTX）与替莫唑胺（temozolomide, TMZ）的持续局部递送。此外，通过Chou-Talalay法筛选得到对C6细胞具有最优协同抗胶质瘤效应的PTX与TMZ质量比为1:100（w/w）。本研究结果明确显示，PTX:TMZ纳米粒诱导的自噬在调控肿瘤细胞死亡过程中发挥重要作用；而自噬抑制可显著逆转PTX:TMZ纳米粒的抗肿瘤效应，提示PTX:TMZ纳米粒处理可引发抗增殖性自噬。采用C6胶质瘤荷瘤大鼠对PTX:TMZ纳米粒负载凝胶的体内抗肿瘤功效进行了原位评价，结果显示该凝胶展现出优异的抗肿瘤性能。本研究证实，该纳米复合凝胶的体内抗肿瘤效应与自噬性细胞死亡密切相关。体内实验结果进一步验证了该给药策略的优势。本研究可为纳米药物的开发及其潜在临床应用提供理论依据。