肿瘤表面靶向矿化沉积无机矿物层及其抗肿瘤增殖、转移活性构效关系研究

As a serious life- and health-threatening disease, the incidence and mortality rates of the malignant tumor remain high throughout the world. Tumor metastasis is the major cause of the patient death. Therefore, the inhibition of the tumor metastasis is very important for the efficient tumor treatment. The current anti-metastatic studies focus on the treatment of the metastatic tumor and cannot inhibit the further metastasis from the start, resulting in the unsatisfactory performance. In principle, the in situ deposition of the inorganic mineral layer onto the tumor surface will affect the substance transport and biological functions of the cell membrane. This might inhibit the proliferation, invasion and metastasis of the tumor. Based on this principle, this project focuses on the proliferation and local invasion of tumor cells. In this project, using targeting molecules as mineralization regulating agents, inorganic mineral layers with good biocompatibility will be in situ controllable targeted deposited onto the tumor surface to prevent the proliferation and local invasion of tumor cells and subsequently prevent the metastasis of tumor efficiently. The studies will be performed from three aspects. Firstly, the regulation effects of the deposition methods, deposition conditions, and molecular structures of targeting agents on the physico-chemical properties of the inorganic mineral layers will be systematically studied. Secondly, the structure-performance relationship between the physico-chemical properties of the inorganic mineral layers and the corresponding anti-proliferative and anti-metastatic activities of the inorganic mineral layers will be systematically explored. Thirdly, the pathways and molecular mechanisms of the anti-proliferative and anti-metastatic activities of the inorganic mineral layers will be discovered. The results can develop the strong theoretical and experimental bases for the design and preparation of the targeted inorganic anti-proliferative and anti-metastatic materials with ideal biocompatibility and the potential applications for efficient metastasis prevention and tumor treatment.

作为主要的致命性疾病，肿瘤的发病率和死亡率居高不下，其中肿瘤的转移是患者死亡的主要原因，因而抑制肿瘤转移至关重要。目前的抗肿瘤转移手段主要是杀伤转移病灶，难以从源头上抑制进一步转移，疗效不佳。本项目基于对肿瘤表面进行包覆以影响细胞内外的物质进出和细胞膜的生物功能，从而抑制肿瘤细胞增殖、侵袭的基本原理，针对肿瘤细胞的增殖、侵袭，以靶向分子为矿化调控剂，以生物相容性良好的难溶无机物为抑制剂，通过在肿瘤表面原位靶向矿化沉积无机矿物层以抑制肿瘤细胞的增殖、侵袭、转移。系统研究沉积方法、沉积条件和靶向分子结构对无机矿物层理化性质的调控规律；探索无机矿物层理化性质和靶向分子结构等因素与其抗肿瘤增殖、转移活性之间的构效关系；研究无机矿物层抗肿瘤增殖、转移的分子机制。本项目的研究可为设计合成具有良好生物相容性的靶向抗肿瘤增殖、转移材料，并将其应用于抗肿瘤增殖、转移以有效治疗肿瘤提供坚实的理论和实验依据。

肿瘤是人类主要的致命性疾病，尽管近年来在肿瘤的预防、诊断和治疗方面投入的资源不断攀升，但恶性肿瘤的发病率和死亡率仍居高不下。目前临床上治疗肿瘤的手段主要有外科手术、放疗、化疗和免疫疗法，但这些治疗手段均存在明显不足，严重影响了治疗效果。本项目基于化学、材料学、细胞生物学、分子生物学等学科的基本原理，主要开展了以下三方面的研究。一是系统研究了良好生物相容性的碳酸钙、磷酸钙、二氧化硅等无机矿物层在肿瘤细胞和肿瘤病灶表面进行原位靶向矿化沉积的方法和条件，探索了沉积机理，研究沉积条件、靶向分子的官能团、空间结构等因素对无机矿物层理化性质的调控规律。二是系统研究了上述无机矿物层的抗增殖活性和抗肿瘤转移活性。探索了靶向分子结构、无机矿物层的理化性质等因素与其抗肿瘤增殖和转移活性之间的构效关系，认识了影响无机矿物层抗肿瘤增殖和转移活性的关键因素，揭示相关调控机理。三是综合运用多种细胞生物学、分子生物学和生物信息学手段，系统深入研究了系列无机矿物层与肿瘤细胞和肿瘤病灶之间的相互作用、尤其是与肿瘤细胞增殖和侵袭过程中的关键生物分子之间的相互作用，揭示了其抑制肿瘤增殖和转移的相关分子机制。研究结果不仅对认识无机纳米材料抑制肿瘤增殖和转移的分子机制具有重要的理论意义，而且为设计无机生物医用纳米材料并提高其在肿瘤治疗领域的应用安全性、目的性和有效性提供了新的理念和坚实的理论及实验依据。