骨肿瘤靶向纳米粒子抑制“恶性循环”治疗恶性骨肿瘤

There is a "vicious circle" between malignant bone tumors and bone microenvironment: tumor cells release cytokines to increase bone resorption, while growth factors released from bone resorption process feed back to promote tumor growth. Therefore, inhibiting the "vicious circle" is the key to improve the therapeutic effect of malignant bone tumors. Photothermal therapy is a new method in the field of bone tumors treatment. However, bone microenvironment provides a barrier against clinical radiotherapy and chemotherapy for malignant bone tumors, the "barrier effect" leads to the failure of tumor- targeting molecules to target bone tumors. Bone tumors targeting is still a difficult problem in the field of bone tumors photothermal therapy. In this study, we intend to design and synthesize bone tumor targeting peptides, targeting bone tumors through: targeting at the interface of bone damage, secondly shearing off by tumor metalloproteinases, and then introducing cell penetrating peptide into bone tumor cells. The metal organic framework @ polydopamine nanoparticles loaded with chloroquine, an autophagy inhibitor, for photothermal-autophagy inhibition combined therapy of malignant bone tumors. Chloroquine can inhibit autophagy induced by photothermal therapy and sensitize photothermal therapy to kill tumors, and inhibit the differentiation and activation of osteoclasts, thus successfully inhibiting the "vicious circle" between malignant bone tumors and bone microenvironment. The implementation of this project will provide a new idea for the clinical treatment of bone tumors, which has important scientific significance and clinical application value.

恶性骨肿瘤与骨微环境之间存在“恶性循环”：即肿瘤细胞释放细胞因子增加骨吸收，而骨吸收过程释放出的生长因子又反馈促进肿瘤生长。因此，抑制“恶性循环”是提高恶性骨肿瘤治疗效果的关键。光热治疗是骨肿瘤治疗领域的新方法，但由于骨微环境为恶性骨肿瘤提供了一个抵抗临床放、化疗的“壁垒”，这种“壁垒效应”导致肿瘤靶向分子无法靶向骨肿瘤，骨肿瘤靶向仍是骨肿瘤光热治疗领域的难题。本研究拟设计合成骨肿瘤靶向肽，通过①先靶向到骨破损界面，②再由肿瘤金属蛋白酶剪切脱落，③最后由细胞穿膜肽导入骨肿瘤细胞，将装载自噬抑制剂氯喹的金属有机框架@聚多巴胺纳米颗粒靶向到骨肿瘤，用于光热-自噬抑制协同治疗恶性骨肿瘤。氯喹通过抑制光热治疗诱导的细胞自噬，增敏光热杀伤肿瘤；并能抑制破骨细胞分化与活化，从而成功地抑制恶性骨肿瘤与骨微环境之间的“恶性循环”。该项目的实施将为临床骨肿瘤治疗提供新思路，具有重要的科学意义和临床应用价值。

恶性骨肿瘤的治疗仍然是主要的临床挑战。纳米系统介导的光热-化疗协同治疗和光热-自噬抑制协同疗法有望解决此问题。但是，骨微环境为骨肿瘤提供了抵抗临床放射疗法和化学疗法的“屏障”。骨肿瘤的“屏障”效应导致仅靶向肿瘤细胞的分子无法有效地靶向骨肿瘤细胞，骨肿瘤细胞靶向仍然是纳米系统介导治疗骨肿瘤领域的瓶颈，在这里我们设计了新型的骨靶向系统和骨肿瘤细胞靶向的纳米系统各一种。.1. 骨靶向光热纳米材料装载自噬抑制剂用于针对骨髓微环境中的破骨细胞分化与成熟。我们证明了在骨肿瘤的光热治疗中引入自噬抑制剂不仅可以增加光热治疗效果，还可以抑制骨肿瘤区域破骨细胞分化，从两个方面共同降低了骨肿瘤对骨的破坏。此外，PPA/CQ生物相容性光热纳米颗粒由光热纳米颗粒和自噬抑制剂组成，进行了系统给药和体内骨肿瘤的治疗。结果表明，抑制肿瘤细胞自噬可以增强光热治疗效果，从而在温和的温度下完全抑制肿瘤生长。与此同时，无论在体内还是体外，CQ都能抑制破骨细胞前体分化成破骨细胞，抑制骨肿瘤区域内破骨细胞活性，降低了骨肿瘤区域的骨损伤。.2.骨肿瘤细胞靶向肽（BTTP），将其共价连接在Mn-Co金属有机框架与聚多巴胺杂化形成的纳米粒子（M@P）的表面得到TM@P。然后将抗癌药物阿霉素（Doxorubicin (DOX)）负载在TM@P表面得到TM@P/DOX。该纳米系统首先可以通过BTTP的骨靶向肽八聚天冬氨酸（D8）将TM@P/DOX纳米系统靶向至骨损伤界面，然后KCQGWIGQPGCK多肽可以通过骨肿瘤分泌的基质金属蛋白酶（MMP）切断BTTP的片段，并最终通过BTTP的细胞穿透肽（R8）将纳米系统引入骨肿瘤细胞，该纳米系统对骨肿瘤细胞具有良好的靶向性在体内，不仅可以增强骨肿瘤MRI的对比度，还可以通过释放抗癌药DOX来实现光热-化疗协同治疗（Chemo-photothermal combined therapy , CPT）。最后，TM@P/DOX纳米系统介导的CPT有效抑制了骨肿瘤的生长以及伴随的骨溶解。.该研究为恶性骨肿瘤治疗提供了有效的新思路。