双模态纳米造影剂Au@MnO-Tf通过自噬介导的光、化疗协同增敏靶向诊疗前列腺癌的效应与机制研究

探索前列腺癌(PCa)的无创、灵敏诊断方法及激素抵抗性前列腺癌(HRPC)的新疗法是当今该领域研究的重点与难点。申请人已发表论文显示纳米氧化锰(MnO)具有增强MRI对比度同时诱导自噬增强化疗杀伤的能力。同时，我们的前期研究揭示金纳米棒(AuNRs)可通过诱导自噬增强近红外光热对前列腺癌的杀伤。因此，本项目拟将MnO与Au复合并偶联靶向分子转铁蛋白(Tf)合成出纳米Au@MnO-Tf，在显著增强MRI/CT双模态成像对比度的同时，利用MnO和Au协同诱导自噬并交互增强的特性，有效实现对HRPC基于化疗、光疗的靶向协同增敏杀伤。最后，通过多种抑制剂及siRNA的使用，初步揭示自噬在其中扮演的重要角色及分子调控机制。综上，本项目拟综合运用涵盖了多个学科的癌症纳米技术，通过一系列体内外实验阐明Au@MnO-Tf实现PCa靶向协同诊疗一体化的效应与机制，有望为临床PCa诊疗及相关研究提供新的思路。

It is of great importance and also quite an effort to explore the noninvasive and sensitive prostate cancer (PCa) diagnostic methods, as well as the novel approaches to achieving effective hormone refractory prostate cancer (HRPC) therapy. Based on our previous publications, we have found that manganese oxide nanocrystals (MnO NCs) can efficiently to serve as an excellent T1 magnetic.resonance imaging (MRI) contrast agent and elicit autophagy-mediated chemotherapeutic cancer killing effect. Meanwhile, our latest study has originally revealed that gold nanorods (Au NRs) can also induce genuine autophagy and enhance the near-infrared light-based tumoricidal activity in prostate cancer cells. Thus, in the present project, we intend to integrate MnO NCs with Au NRs and also conjugate the active targeting motif transferrin (Tf) to them and eventually obtain the multifunctional nano-sized Au@MnO-Tf, which nanomaterials can obviously enhance the MRI and X-ray computed tomography (CT) dual-modal imaging contrast to diagnose prostate cancer. Simultaneously, Au@MnO-Tf can effectively achieve the targeted synergistic chemotherapeutic and photothermal sensitization effect to killing HRPC, based on the synergistic and reciprocally-enhanced autophagy induction elicited by MnO NCs and Au NRs. Furthermore, via the inhibitors administration and siRNA knockdown, we expect to elucidate the role of autophagy and molecular mechanism underlying modulation of the synergistic destruction of prostate cancer. In summary, the current proposal is designed to utilize cancer nanotechnology which integrates cancer imaging, cellular and molecular biology to illuminate the effects and correlated mechanisms of the targeted theragnosis to prostate cancer elicited by multifunctional nanomaterials Au@MnO-Tf in vitro and in vivo, which could shed light on some valuable ideas and feasible approaches for clinical theragnosis of prostate cancer and follow-up investigations.