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

具有优先肺部靶向特性的定制纳米纤维可用于治疗转移性肺肿瘤

基本信息

批准号：
10623913
负责人：
Vanessa Bellat
金额：
$ 51.16万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-10 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623913
关键词：
3-Dimensional Acceleration Adverse effects Animal Model Animals Architecture Biodistribution Brain Breast Cancer Patient Cessation of life Charge Clinical Complex Cytotoxic agent Detection Disease Disease Progression Disseminated Malignant Neoplasm Doxorubicin Doxorubicin Hydrochloride Liposome Drug Delivery Systems Engineering Ensure FDA approved Fluorescence Microscopy Genomics Goals Histologic Hydrophobicity Hypoxia Image Immune Immunotherapy Injections Ionizing radiation Kidney Lesion Light Liver Lung Lung Neoplasms Lung retention Malignant Neoplasms Maps Mediating Metabolism Metastatic Neoplasm to the Lung Modeling Molecular Monitor Mus Nanotechnology Nature Neoplasm Metastasis Organ Outcome Pathologic Pathway interactions Patients Penetration Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacotherapy Phenotype Primary Neoplasm Property Radiation Radiation therapy Radiation-Sensitizing Agents Shapes Site Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Stimulus Surface Techniques Technology Therapeutic Time Tissues Toxic effect Translating Treatment Efficacy Treatment Failure Treatment outcome Treatment-related toxicity Variant Vascular blood supply acute toxicity analog anti-cancer anticancer activity antitumor effect cancer therapy cancer type cell killing chemotherapy clinical prognosis combat combinatorial comparative design drug distribution effective therapy flexibility immunogenicity improved in vivo innovation liposomal formulation lung lesion metastatic process mortality multiple omics nanocarrier nanofiber nanomedicine nanotechnology platform neoplastic cell novel strategies novel therapeutic intervention novel therapeutics response spatiotemporal success synergism targeted treatment therapeutically effective triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor xenograft uptake

项目摘要

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.

项目概要目前，大多数纳米技术癌症疗法侧重于治疗原发性肿瘤，但重要的是利用纳米医学的潜力来对抗转移过程每个阶段的癌症扩散。肺转移是一种高度侵袭性、复杂性和异质性的疾病，目前尚无有效的治疗方法。对于转移性肺肿瘤，化疗是延长患者临床预后的唯一选择。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性病变。迫切需要加快治愈肺转移瘤的进展我们的目标是开发一种新的治疗方法，将更多的药物运送到患者体内。在这个项目中，我们保留了转移性肺部肿瘤并在现场释放广谱抗肿瘤药物。建议使用具有优先肺部靶向特性的肽基纳米纤维（pNFP6）来克服 pNFP6 具有创新性，因为多个纳米纤维可以重新排列。进入一个大的原纤维间网络，以延长局部保留并提供长期治疗。技术将与电离放射治疗相结合，以增强药物递送后的抗肿瘤功效。我们的中心假设是组合疗法将协同地抑制疾病对于原理验证研究，我们将使用它来有效治疗肺部进展转移。 pNFP6 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。有利于药物在现场的积累和保留，放疗则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的时空控制药物。释放对于确保治疗成功至关重要。要确定这种抗转移的潜力。多重方法，将追求两个具体目标：（1）评估局部药物释放及其对治疗效果；(2) 确定与 Dox-pNFP6 联合使用时的治疗和生存益处为了实现目标 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。使用光片荧光显微镜和 MALDI 成像进行递送、释放和肿瘤摄取。为了完成目标 2，我们将确定针对转移性肺肿瘤的最佳释放机制。评估 Dox-pNFP6 组合的治疗效果（肿瘤抑制和生存获益）和毒性特征在几种患有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，FDA 批准的 Dox 脂质体制剂的性能也将进行研究。这种新的治疗策略激活的分子和免疫途径，以更好地了解其机制负责加强抗癌活动，该项目的成功完成将提供有效的支持。对肺转移的治疗和管理具有临床影响的治疗解决方案。