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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.

项目总结