Customized nanofibers with preferential lung-targeting properties for treating metastatic pulmonary tumors

项目摘要 目前，大多数纳米技术癌症疗法集中在治疗原发性肿瘤，但重要的是， 利用纳米医学的潜力来对抗转移过程中每个阶段的癌症扩散。 肺转移瘤是一种高度侵袭性、复杂性和异质性的疾病。尚无有效的治疗方法 而化疗是延长患者临床预后的唯一选择。替代 已经提出了包括靶向治疗和免疫治疗在内的策略，但他们未能成功 治疗转移性病变。 迫切需要加快治疗肺转移癌的进展， 降低患者死亡率。我们的目标是开发一种新的治疗方法， 转移性肺肿瘤，并保留在现场释放广谱抗肿瘤药物。本课题 我建议使用具有优先肺靶向特性的肽基重组质粒（pNFP 6）来克服 选择性给药转移的屏障。pNFP 6是创新的，因为多个纳米纤维可以重新排列 形成一个大型的原纤维间网络，以延长局部保留并提供长期治疗。纳米纤维 技术将与电离辐射治疗相结合，以提高药物输送后的抗肿瘤疗效。 我们的中心假设是，联合治疗将合作和协同抑制疾病 导致肺转移的有效治疗的进展。对于原理验证研究，我们将使用 pNFP 6携带和递送阿霉素（Dox），一种标准的细胞毒性剂和放射增敏剂。纳米纤维 有利于药物在体内的蓄积和滞留，而放射治疗可促进整体抗癌效果 通过直接的肿瘤细胞杀伤和辐射介导的免疫原性。时空控制药物 释放将是确保治疗成功所必需的。为了确定这种抗转移的潜力， 多重方法，两个具体目标将追求：（1）评价局部药物释放及其对 治疗功效;和（2）定义Dox-pNFP 6在与以下组合时的治疗和存活益处： 放射治疗为了实现目标1，我们将使用不同的方法合成一组负载Dox的pNFP 6类似物。 对肿瘤微环境刺激敏感的可裂解接头释放药物。我们将研究体内药物 使用光片荧光显微术和MALDI成像，观察递送、释放和肿瘤摄取。和 确定对转移性肺肿瘤的最佳释放机制。为了实现目标2，我们将 评估Dox-pNFP 6组合的治疗功效（肿瘤抑制和存活益处）和毒性概况 在几种携带转移性肺肿瘤的动物模型中进行放射治疗。治疗结果将是 与游离Dox和Doxil相比，Dox是FDA批准的Dox脂质体制剂。我们还将调查 通过这种新的治疗策略激活的分子和免疫途径，以更好地了解机制 负责增强抗癌活性。该项目的成功完成将提供有效的 对肺转移瘤的治疗和管理具有临床影响的治疗解决方案。

Project Summary Currently, most nanotechnology cancer therapies focus on the treatment of primary tumors, but it is important to leverage the potential of nanomedicine to combat cancer spread at each stage of the metastatic process. Lung metastasis is a highly aggressive, complex, and heterogeneous disease. There is no effective treatment for metastatic lung tumors and chemotherapy is the only option to prolong patients’ clinical prognosis. Alternative strategies, including targeted therapy and immunotherapy have been proposed, but they failed to successfully treat metastatic lesions. There is an urgent need to accelerate progress toward curing lung metastases and reduce patients’ mortality. Our goal is to develop a new therapeutic approach that carries more drugs to the metastatic lung tumors and retains on-site to release a broad-spectrum antitumor medication. In this project, we propose to use peptide-based nanofiber (pNFP6) with preferential lung-targeting properties to overcome the barrier of selective drug delivery to metastases. The pNFP6 is innovative as multiple nanofibers can rearrange into a large interfibril network to prolong the local retention and offer a long-term treatment. The nanofiber technology will be combined with ionizing radiation therapy to enhance the drug post-delivery antitumor efficacy. Our central hypothesis is that the combinatorial therapy will cooperatively and synergistically inhibit the disease progression leading to an effective treatment of lung metastases. For proof-of-principle studies, we will use pNFP6 to carry and deliver doxorobucin (Dox), a standard cytotoxic agent and radiosensitizer. The nanofibers will favor the drug accumulation and retention on-site while radiotherapy will promote the overall anticancer effect through direct tumor cell killing and radiation-mediated immunogenicity. The spatiotemporal-controlled drug release will be essential to ensure the therapeutic success. To establish the potential of this antimetastatic multiplexed approach, two specific aims will be pursued: (1) evaluate the local drug release and its impact on the therapeutic efficacy; and (2) define the therapeutic and survival benefit of Dox-pNFP6 when combined with radiation therapy. To achieve Aim 1, we will synthesize a panel of Dox-loaded pNFP6 analogues using different cleavable linkers sensitive to tumor microenvironment stimuli to release the drug. We will study the in vivo drug delivery, release, and tumoral uptake using Light Sheet Fluorescence Microscopy and MALDI-imaging. and identify the optimal release mechanisms in response to metastatic lung tumors. To complete Aim 2, we will assess the therapeutic efficacy (tumor inhibition and survival benefit) and toxicity profile of Dox-pNFP6 combined with radiation therapy in several animal models bearing metastatic lung tumors. The treatment outcomes will be compared to free Dox and Doxil, the FDA-approved liposomal formulation of Dox. We will also investigate the molecular and immune pathways activated by this new therapeutic strategy to better understand the mechanisms responsible for the enhanced anticancer activity. Successful completion of this project will provide an effective therapeutic solution with clinical impacts on the treatment and management of lung metastases.