基于调控肿瘤微环境的两亲性多肽自组装纳米药物载体的抗肿瘤机制研究

Extensive research activities over the past decade have been devoted to the design and fabrication of novel biomimetic nanobiomaterials through peptide self-assembly. Many synthetic peptides have recently been explored as useful nanobiomaterials in applications ranging from controlled drug release, gene delivery, skin care, nanofabrication, biomineralization, membrane protein stabilisation to 3D cell culture and tissue engineering, which is heavily linked to their unique nanostructures, remarkable simplicity, biocompatibility, biodegradability, excellent functions and bioactivity. Apart from sizes, the primary sequences of short peptides are very diverse as they can be either biomimetic or de novo designed. These attractive features are inherently related to their spontaneous formation of nano-assemblies. .To the best of our knowledge, tumor microenvironment provides a passive mechanism for targeting macromolecular or nanoparticle entrapment within the tumor through enhanced permeability and retention (EPR) effect, which may be exploited to improve the efficacy of drug delivery systems. As development of tumor-targeting nanomaterials expands, designed peptide amphiphiles have great potential as effective nanocarriers for therapeutic applications. .It is becoming increasingly clear that tumor growth is not just determined by malignant tumor cells themselves, but also by the tumor microenvironment. Tumor microenvironment has a prominent role in the tumor growth, progression and metastasis. Fibroblasts, a species of very important stromal cells in tumor microenvironment, are associated with tumor cells at all stages of tumor progression, and their structural and functional contributions to this process are beginning to emerge. Although our knowledge of the role of resting and activated fibroblasts in tumor is still evolving, and evidence is increasing that a subpopulation of fibroblasts, the cancer-associated fibroblasts (CAFs), are important promoters of tumor growth and progression. CAFs therefore represent a novel and important target for tumor therapy. CAFs-directed therapy can be envisioned as 'to ablate' CAFs..In this study, CAFs serve as therapeutic targets in tumor microenvironment. Amphiphilic peptide self-assembling nanomaterials as nanocarriers deliver hydrophobic drug and siRNA to selectively ablate CAFs. This study will also explore the mechanisms of peptide self-assembly, and deep investigate the processes of drug entrapment, targeting delivery, and release. Thus, based on the mechanisms by which the CAFs promote malignant progression of tumor, this study will indicate that further exploring tumor microenvironment, in particular, CAFs as potential therapeutic targets in patients is warranted, providing a strong rationale for clinical evaluation. It is expected that this study will provide proof of principle that targeting CAFs-mediated modifications of the tumor microenvironment may be an effective approach to treating tumors.

多肽自组装已经在众多领域，尤其在生物医学方面，展现出巨大的理论和应用价值。这主要是因为多肽分子具有良好的生物相容性、生物可降解性和多种生物活性。另外，多肽分子结构简单、种类繁多、易于改性、具有一定的稳定性，是自组装形成纳米结构的理想单体。本研究以调控肿瘤微环境的生物功能导向的两亲性多肽自组装纳米材料作为药物载体，并在载体表面修饰靶向配体，以肿瘤微环境中的肿瘤相关成纤维细胞为靶标，利用多肽纳米药物载体联合包载输运疏水性药物和siRNA，选择性清除肿瘤相关成纤维细胞。以期通过调控肿瘤微环境，抑制肿瘤的恶性生长，发挥抗肿瘤疗效。本项目将深入研究多肽分子的自组装原理，揭示外部环境因素和纳米载体的结构理化特性对药物的包载、输运、和释放的影响，阐明多肽自组装纳米药物载体与其生物医学功能的构效关系，为在调控肿瘤微环境的基础上实现肿瘤治疗的关键科学目标奠定基础。

多肽自组装纳米材料，具有良好的生物相容性；多肽分子的设计精确可控；其自组装及解聚过程的环境响应速度较快；此外，多肽的生物功能性也是构建生物纳米材料的关键；因此，多肽自组装材料非常适合纳米医学领域的应用。目前，在纳米载药体系的抗肿瘤研究方面，瘤内疏运仍然是一大瓶颈问题。如果能打破肿瘤组织中的生物屏障，就有望大幅提高利用纳米技术诊断和治疗肿瘤的效果。. 肿瘤相关成纤维细胞（CAFs）是肿瘤微环境中一类主要的间质细胞，它自身及其分泌的一些细胞外基质构成肿瘤组织中的重要生物屏障，而CAFs的生物学特性使其非常适合作为治疗靶点。随着肿瘤的快速生长，CAFs参与塑造的致密生物屏障极大的限制纳米药物以及很多药物分子在实体瘤中的渗透，导致不能实现预期疗效。因此，如果我们能够靶向消除CAFs，将有望提高实体瘤中的药物输运效率。为验证这种猜想，我们设计并构建了双功能的多肽自组装纳米药物载体，集靶向CAFs和有效穿透细胞为一体，实现肿瘤的靶向输运以及消除CAFs和肿瘤细胞；同时打破肿瘤组织的屏障作用，增加抗肿瘤药物在肿瘤组织中的高效渗透，有效提高对富含CAFs的实体瘤的抗肿瘤疗效，并降低化疗药物对正常器官的毒副作用。此外，此载体可载带多种化疗药物，对多种肿瘤都能取得治疗效果，具有较好的普适性。此药物载体的成功设计是第一次利用纳米技术靶向CAFs，并取得良好的治疗效果，为纳米材料抗肿瘤的研究提供一种新思路。另一方面，我们还通过对多肽分子的巧妙设计，详尽的研究其自组装动力学过程及相关原理，实现对多肽组装体形貌转变的控制。我们还第一次实时观察到多肽自组装、多肽-药物共组装及自组装体重组的形貌变化过程，总结一系列组装规律，这也为精确调控多肽分子自组装过程的研究提供新的视角。