瘦素信号通路在Gd@C82(OH)22调控乳腺癌肿瘤微环境中的作用研究

Gd@C82(OH)22, dicovered by Chinese scientists, is a first reported nanoparticle which displays anti-cancer effects independently (in the absence of conventional chemotherapeutic drugs) with low toxicity and high efficiency, yet its molecular mechanism is not well elucidated. According to the potential relevence between the pharmacological properties of Gd@C82(OH)22 and physiological functions of leptin signaling pathway in regulating breast tumor microenvironment, as well as the lack of investigation by applying nanotechnology to modulate endocrinological metabolism and then attenuate breast cancer progress, the current study aims to explore the connection linking the unique structural and physical-chemical characters of Gd@C82(OH)22 to leptin signaling pathway through a combination of molecular and cellular biology, animal experiments and theoretical calculation approaches. The goal of this project is to define the possible target of Gd@C82(OH)22 and identify novel Gd@C82(OH)22 analogs which are capable of inhibiting breast cancer development. This work will be helpful for the further understanding of the basic molecular mechanism underlying Gd@C82(OH)22 and could lead to novel therapeutic interventions of breast cancer.

Gd@C82(OH)22是中国科学家首次发现、也是首个单独(勿须载带传统药物)具有高效抑制肿瘤生长和转移活性的低毒纳米颗粒，其作用机制广受关注却仍不清楚。鉴于leptin信号通路在乳腺癌肿瘤微环境调控中的作用与Gd@C82(OH)22已知的药理效应具有潜在的相关性，同时应用纳米技术调控内分泌代谢来抑制乳腺癌发病和生长也研究甚少，本课题因此提出通过分子细胞生物学、动物实验，结合分子动力学理论模拟等手段探讨Gd@C82(OH)22纳米颗粒的特殊结构特征和理化性质与leptin信号通路之间的关系，寻找Gd@C82(OH)22可能的作用靶点，并探索具有抗肿瘤活性的新型Gd@C82(OH)22结构的潜在类似物，揭示中国科学家提出的第一个抗肿瘤创新纳米药物Gd@C82(OH)22的作用机制，为乳腺癌的临床治疗提供新的思路。

本课题原计划研究金属富勒醇Gd@C82(OH)22这一低毒高效抗肿瘤的纳米药物通过调控leptin信号通路在乳腺癌肿瘤微环境中的药理作用，但由于后续项目进展过程中Gd@C82(OH)22产能的限制，项目计划进行了调整。我们先后证明：1. Gd@C82(OH)22能够显著抑制leptin诱导的JAK2、STAT3磷酸化；2. 两种多钨酸钆材料Na9[Gd(W5O18)2]•35H2O与K12(GdP5W30O110)•54H2O对leptin诱导的STAT3磷酸化具有一定的刺激作用，初步观察到多钨酸钆对高脂饮食诱导的肥胖具有一定的抑制作用，其他代谢指标也有显著改善；3. 氧化石墨烯能够显著抑制Erk1/2以及Akt的磷酸化，即抑制BDNF/TrkB信号通路的激活；4. 为期3个月的长期毒性试验，通过12个周期间断性静脉注射低、中、高三个剂量的富勒醇C60(OH)x，来评价药物对大鼠的潜在毒性。上述这一系列有意义的尝试将为纳米材料在上述生物研究领域的应用提供了更多的选择。