铈基材料通过催化疗法调控肿瘤内乳酸代谢及机制研究

Lactate, largely produced and accumulated in tumors through anaerobic glycolytic pathway (also called Warburg metabolism), has been recognized as the characteristic signaling molecule for their tumorigenesis and subsequent progression. Hypoxia inducible factor-1α (HIF-1α), which is closely related to tumor hypoxia tolerance, has a mutually reinforcing effect with the intratumoral level of lactate. Generally, lactate increases the expression of HIF-1α. Meanwhile, HIF-1α also enhances glycolysis to produce more lactic acid, which greatly increases the difficulty of tumor treatments. To date, the modulations of both the intratumoral levels of lactate and the expression of HIF-1α haven’t been achieved yet. Inspired by the catalytic chemotherapy of tumors, the catalytic conversion of lactate into the very harmful reactive oxygen species (ROS) through a cascade intratumoral catalytic reaction suggests the high possibility to realize to this synergistic control of intratumoral lactic acid metabolism and HIF-1α. In this proposal, the hybrids integrating the cerium-base catalysts and lactate oxidase (LOx) have been designed to modulate the intratumoral levels of lactate and the expression of HIF-1α at the same time through a cascade reaction. LOx catalytically converts intratumoral lactate into H2O2 and pyruvic acid. Subsequently, the generation of toxic ROS from H2O2 is realized by cerium-base catalysts with peroxidase-like activity, reaching the catalytic tumor chemotherapy. Benefiting from the long-circulation property of the heterogeneous hybrid catalysts, the nanocomposites can gradually accumulate in tumor sites through the enhanced permeability and retention effect. In this strategy, the cascade reaction consumes intratumoral lactate molecules and decreases the intratumoral glycolysis as well as the expression HIF-1α. The defect modulations on cerium-based catalysts are the keys to optimize the cascade catalytic performance of the hybrids. This proposal combines the catalytic therapy and tumor metabolic therapy, and delivers beneficial explorations for the new methodology of tumor therapy.

乳酸作为肿瘤细胞糖酵解代谢产物在肿瘤内大量堆积，是肿瘤发生和发展的关键分子。调控糖酵解代谢将有助于肿瘤治疗研究。缺氧诱导因子-1α(HIF-1α)增强肿瘤糖酵解作用生成更多乳酸的同时，HIF-1α的表达也受瘤内乳酸的影响，两者存在互相促进的关系。因此肿瘤内乳酸和HIF-1α协同控制是一种非常有希望的糖酵解调控策略。但相关研究目前尚无报道。本项目拟通过催化疗法利用铈基催化剂负载乳酸氧化酶实现瘤内乳酸和HIF-1α的协同调控。乳酸氧化酶消耗瘤内乳酸形成丙酮酸和过氧化氢，而后具有类过氧化物酶活性的铈基催化剂将过氧化氢转化为活性氧，实现肿瘤催化治疗。催化过程导致肿瘤内乳酸水平下降，进而下调肿瘤细胞HIF-1α的表达。通过催化疗法进行瘤内乳酸和HIF-1α的协同控制，有望实现调控糖酵解代谢的目的。在缺陷调控铈基催化剂的机制研究基础上，本项目融合催化治疗和肿瘤代谢为开拓肿瘤治疗新方法提出了有益的探索。

乳酸作为肿瘤细胞异常代谢产物在肿瘤微环境内大量积累，会促进肿瘤生长与转移，也是造成肿瘤免疫抑制导致肿瘤治疗失败的关键因素。通过催化治疗策略调控肿瘤乳酸代谢将有助于肿瘤治疗研究。. 制备高活性和良好选择性的纳米酶催化剂是构建高效安全的肿瘤催化治疗体系的前提。生物安全性良好并具有多种可调催化活性的纳米二氧化铈在实现低毒副作用和选择性催化治疗方面具有独特的优势。在类酶催化反应过程中，纳米二氧化铈表面大量的氧缺陷可以作为催化反应中的底物结合位点和反应场所，是实现高效催化治疗的关键。本项目中，我们利用钆掺杂和表面修饰的方式有效调节了二氧化铈纳米酶的表面性质，并验证了钆离子浓度对氧缺陷水平以及类酶催化性能的影响，确认了氧缺陷水平与类酶活性的关系。同时，材料表界面修饰对二氧化铈的类酶活性至关重要。纳米二氧化铈的类氧化酶活性在经过聚苯乙烯磺酸钠修饰后得到明显改善，其活性与聚苯乙烯磺酸钠的分子量密切相关。在上述类酶催化性能研究的基础上，进一步开展了肿瘤催化治疗和动脉粥样硬化治疗的相关研究。. 在催化肿瘤乳酸的相关工作中，我们利用乳酸氧化酶、乳酸外排抑制剂（Syrosingopine）和钆掺杂CeO2共同构建了一个乳酸生物催化肿瘤免疫调控策略，在实现肿瘤治疗的基础上深入分析铈基纳米酶-乳酸氧化酶治疗体系对肿瘤细胞乳酸代谢的影响以及作用关系。该策略在级联催化分解瘤内乳酸生成大量羟基自由基用于肿瘤催化治疗的同时，有效抑制糖酵解和三羧酸循环，实现了酶催化诱导代谢重编程的目的。并以此为基础，通过激活巨噬细胞M1极化和CD8+ T细胞来激发局部和全身的抗肿瘤免疫，从而诱导高效的抗肿瘤免疫，促使肿瘤免疫重构，提高免疫系统的抗肿瘤治疗活性。上述分子作用机制的研究，为通过催化乳酸清除调控肿瘤糖酵解代谢以及免疫治疗里的相关研究提供坚实的理论支持。