Hou Yong, Liu Tonghe, Sun Zhonghao, Xu Xudong, Sun Zhaocui, Li Zongyang, Liu Jianzhou, Tian Sichao, Li Yihang, Zhu Nailiang, Liu Haitao, Ma Guoxu
Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education; Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100193, China.
Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518035, China.
Mater Today Bio. 2025 Mar 20;32:101689. doi: 10.1016/j.mtbio.2025.101689. eCollection 2025 Jun.
Pancreatic cancer is one of the most devastating solid tumors and lacks ideal therapeutic options. The efficiency of using classic chemotherapeutic agents like gemcitabine (GEM) solely has been limited immensely owing to severe resistance and systemic toxicity, thus necessitating alternative multi-pronged strategies. Multicomponent supramolecular co-assembly leveraging natural small molecules (NSMs) cannot only produce carrier-free hydrogel materials having superior mechanical properties for convenient administration, but also achieve optimal synergies in combinational drugs therapy. Herein, a natural structural analog of GEM with favorable pro-apoptotic effect, adenosine (Ado), was found firstly to self-assemble spontaneously into a hydrogel (Ado-gel). Sequentially, we constructed a novel two-component hydrogel (DA-gel) via co-assembling Ado with another NSM evidenced here as new autophagy inhibitor, gentisic acid (2,5-dihydroxybenzoic acid, DHB). Addition of DHB had reinforced the thermal-responsiveness and viscoelasticity evidently in DA-gel, which ascribed to the heightened intermolecular hydrogen bonding and π-π stacking interactions. Together with its good injectability and biosafety, the local injection can be conducted smoothly so as to improve the compliableness of patients in clinical settings. More intriguingly, DA-gel was proven to exhibit the best anti-tumor efficiency in pancreatic carcinoma comparing with corresponding single-component and mixture and , possibly due to its unique supramolecular structure amplifying two-component synergistic effects on inhibition of autophagy and mitochondrial injury, thus lead to more obvious apoptosis. Overall, the presented co-assembling strategy exhibits admirable synergistic effects, thereby may provide a new perspective for functional application of multiple NSMs and a promising alternative to current chemotherapy for the treatment of pancreatic cancer.
胰腺癌是最具毁灭性的实体瘤之一，且缺乏理想的治疗方案。由于严重的耐药性和全身毒性，单纯使用吉西他滨（GEM）等经典化疗药物的效率受到极大限制，因此需要采用多管齐下的替代策略。利用天然小分子（NSMs）的多组分超分子共组装不仅可以制备出具有优异机械性能、便于给药的无载体水凝胶材料，还能在联合药物治疗中实现最佳协同效应。在此，首先发现具有良好促凋亡作用的GEM天然结构类似物腺苷（Ado）能自发自组装成水凝胶（Ado-凝胶）。随后，我们通过将Ado与另一种NSM（在此证明为新型自噬抑制剂龙胆酸（2,5-二羟基苯甲酸，DHB））共组装，构建了一种新型双组分水凝胶（DA-凝胶）。添加DHB明显增强了DA-凝胶的热响应性和粘弹性，这归因于分子间氢键和π-π堆积相互作用的增强。其良好的可注射性和生物安全性使其能够顺利进行局部注射，从而提高临床患者的顺应性。更有趣的是，与相应的单组分和混合物相比，DA-凝胶在胰腺癌中表现出最佳的抗肿瘤效率，这可能是由于其独特的超分子结构放大了双组分对自噬抑制和线粒体损伤的协同作用，从而导致更明显的细胞凋亡。总体而言，所提出的共组装策略展现出令人钦佩的协同效应，从而可能为多种NSMs的功能应用提供新的视角，并为当前胰腺癌化疗提供一种有前景的替代方案。
