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

项目摘要 目前，大多数纳米技术治疗癌症的重点是治疗原发肿瘤，但这一点很重要 利用纳米药物的潜力在转移过程的每个阶段对抗癌症扩散。 肺转移是一种高度侵袭性、复杂性和异质性的疾病。没有有效的治疗方法 对于转移性肺肿瘤，化疗是延长患者临床预后的唯一选择。备择 已经提出了包括靶向治疗和免疫治疗在内的策略，但未能成功 治疗转移灶。 迫切需要加快治疗肺转移瘤和 降低患者死亡率。我们的目标是开发一种新的治疗方法，将更多的药物带到 并保留肺转移瘤，现场释放广谱抗肿瘤药物。在这个项目中，我们 建议使用具有优先肺靶向特性的多肽基纳米纤维(PNFP6)来克服 转移的选择性药物输送障碍。PNFP6是创新的，因为多个纳米纤维可以重新排列 形成较大的纤维间网络，延长局部滞留时间，提供长期治疗。纳米纤维 该技术将与电离放射治疗相结合，以增强药物交付后的抗肿瘤效果。 我们的中心假设是，联合疗法将协同和协同地抑制这种疾病。 进展导致对肺转移的有效治疗。对于原则证明研究，我们将使用 PNFP6携带和传递多柔比星(Dox)，一种标准的细胞毒剂和放射增敏剂。纳米纤维 将有利于药物在现场的蓄积和滞留，而放射治疗将促进整体抗癌效果 通过直接杀伤肿瘤细胞和辐射介导的免疫原性。时空受控的药物 释放将是确保治疗成功的关键。为了确定这种抗肿瘤转移的潜力 通过多种方式，将追求两个具体目标：(1)评估当地药物释放及其对 治疗效果；以及(2)确定Dox-pNFP6联合应用时的治疗和生存益处 放射疗法。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pNFP6类似物 对肿瘤微环境刺激敏感的可切割连接物释放药物。我们将研究体内药物 使用光片荧光显微镜和MALDI成像的传递、释放和肿瘤摄取。和 确定对转移性肺肿瘤的最佳释放机制。为了完成目标2，我们将 评估Dox-pNFP6联合化疗的疗效(抑瘤和生存期)和毒性 在几个带有转移性肺肿瘤的动物模型上进行放射治疗。治疗结果将是 与FREE Dox和Doxil相比，FDA批准的Dox脂质体配方。我们还将调查 这一新的治疗策略激活了分子和免疫途径，以更好地了解其机制 负责增强抗癌活性。该项目的成功完成将提供一个有效的 对肺转移瘤的治疗和管理有临床影响的治疗方案。

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.