基于聚吡咯/树状大分子的多功能纳米平台在恶性肿瘤诊疗中的基础研究

Effective diagnostic and therapy of malignant tumors is a major challenge in the current biomedical field. Development of tumor-targeting theranostic nanoplatforms is urgently needed to tackle this challenge. This project plan to employ polypyrrole nanoparticles (NPs) as core, which could be used as photoacoustic (PA) agent and photothermal (PT) agent. Generation 5 poly(amidoamine) dendrimers will be loaded onto the core surfaces, which could entrap computed tomography (CT) contrast agents gold NPs and load vascular disrupting agents combretastatin A-4 (CA4) in the interior of dendrimers, and be further modified with tumor neovasculature targeting ligand, RGD peptide, and biocompatible polyethylene glycol (PEG) chains on their surfaces. This theranostic nanoplatform could be applied in the PA and CT imaging and PT therapy (PTT) combined with drug-based chemotherapy against malignant tumors. Compared to other existing theranostic nanoplatforms reported in the literature, this nanoplatform takes advantage of the unique properties of polydopamine to integrate the targeting ligands, dendrimer/gold NPs and polypyrrole NPs, which could finally realize PA/CT dual-modality imaging of tumors. The loaded vascular disrupting agents CA4 could show remote attacking ability against tumors. Combined with the short-range therapeutic effect of PTT, the proposed multimodal therapy is expected to achieve more efficient tumor eradication. This project could provide critical insight on the interaction between this new class of polypyrrole/dendrimer-based nanoplatforms and the biological systems, which may lead to an “all-in-one” and efficient theranostic tool against malignant tumors.

实现恶性肿瘤的有效诊断与治疗是当前医学领域面临的巨大挑战。开发针对恶性肿瘤的诊疗一体化纳米平台有望应对并解决此挑战。本项目拟以具有光声、光热效应的聚吡咯纳米颗粒为内核，外围装载第五代聚酰胺胺树状大分子，随后利用其内部空腔包裹CT造影剂金纳米颗粒和肿瘤血管阻断剂CA4，表面修饰肿瘤新血管靶向分子RGD多肽和具有良好生物相容性的聚乙二醇链。将所开发的多功能纳米诊疗平台用于恶性肿瘤的PA/CT双模态诊断和光热/药物联合治疗。与文献报道的纳米诊疗平台相比，本项目拟利用聚多巴胺有效地将功能化修饰的树状大分子和聚吡咯纳米颗粒结合起来，实现肿瘤组织靶向PA/CT双模态造影。所负载的肿瘤血管阻断剂CA4可实现对肿瘤组织内部细胞的“远程攻击”，亦可有效地配合光热治疗的“近程攻击”，实现肿瘤杀伤效果的最大化。本项目将为面向恶性肿瘤的诊疗一体化纳米平台的开发提供新的思路和研究基础。

近年来恶性肿瘤呈逐渐高发的态势，成为影响人类健康的重要杀手。目前，临床措施所采用的传统癌症诊断和治疗手段存在突出的问题，面临着日益严峻的挑战。光热治疗是近年来新兴的一种癌症治疗手段，有助于发展针对肿瘤的精准化医疗手段。开发具有优良特性的光热转化剂是取得有效光热治疗的关键。聚吡咯和聚多巴胺都具有良好的生物相容性和近红外光响应能力，且易于制备和多功能修饰。在本项目的资助下，首先制备了一种具有增强近红外光响应能力的功能化聚吡咯纳米颗粒，用于癌症的诊断和治疗。利用聚多巴胺涂层的多功能特性，可以将聚吡咯纳米颗粒、聚乙二醇链、吲哚菁绿有机的结合为一个整体。负载的吲哚菁绿可以显著地增强聚吡咯纳米颗粒的近红外光响应能力，同时增强光声成像能力和光热转化性能。体内实验表明，该纳米颗粒可以有效富集于肿瘤部位，在光声成像的指导下，对肿瘤进行有效的光热治疗。其次，成功制备了一种“核-卫星”结构的载药聚多巴胺/树状大分子-金复合纳米颗粒。所得复合纳米颗粒在肿瘤部位可响应偏酸的微环境释放小尺寸的“卫星”纳米颗粒，实现肿瘤深处药物递送。同时金纳米颗粒表现类过氧化氢酶活性，原位催化过氧化氢分解产生氧气，降低乏氧环境产生的耐药性。复合纳米颗粒负载的抗癌药物阿霉素可在内部（酸和过氧化氢）和外部（近红外光）刺激下定点释放，具有良好的肿瘤特异性。除此之外，所得复合纳米颗粒能响应近红外光，对肿瘤部位实现光声诊断和光热治疗；而且具有良好的生物安全性，可以对肿瘤生长实现显著的抑制作用。本项目的实施为新型有效的肿瘤诊疗剂的开发奠定了基础，并提供了一定的指导意义。