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

• 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
• 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

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.

项目摘要 目前，大多数纳米技术癌症疗法都集中在原发性肿瘤的治疗上，但这很重要 利用纳米医学在转移过程的每个阶段打击癌症扩散的潜力。 肺转移是一种高度侵略性，复杂和异质性疾病。没有有效的治疗 对于转移性肺部肿瘤和化疗是延长患者临床预后的唯一选择。选择 已经提出了包括针对性疗法和免疫疗法在内的策略，但他们未能成功 治疗转移性病变。 迫切需要加速进步，以治愈肺转移和 降低患者的死亡率。我们的目标是开发一种新的治疗方法，该方法将更多的药物带到 转移性肺部肿瘤并保留现场以释放广谱抗肿瘤药物。在这个项目中，我们 使用基于胡椒的纳米纤维（PNFP6）具有优先肺靶向特性的提议来克服 选择性药物递送到转移酶的障碍。 PNFP6具有创新性，因为多个纳米纤维可以重新排列 进入一个大型的成纤维网络，以延长局部保留率并提供长期治疗。纳米纤维 技术将与电离放射疗法结合使用，以增强药物后保存后抗肿瘤效率。 我们的核心假设是组合疗法将在协同上抑制该疾病 进展导致对肺转移的有效治疗。为了证明原则研究，我们将使用 PNFP6携带和传递毒bucin（Dox），这是一种标准的细胞毒性剂和放射性敏感剂。纳米纤维 将有利于药物积累和现场保留，而放疗将促进总体抗癌作用 通过直接的肿瘤细胞杀伤和辐射介导的免疫原性。时空控制的药物 释放对于确保疗法成功至关重要。建立这种抗转移性的潜力 多路复用方法，将追求两个具体目标：（1）评估当地药物释放及其对 治疗效率； （2）与DOX-PNFP6的治疗和生存优势定义 放射治疗。为了实现AIM 1，我们将使用不同 可裂解的接头对肿瘤微环境刺激敏感以释放该药物。我们将研究体内药物 使用轻板荧光显微镜和MALDIMIGAGES的递送，释放和肿瘤摄取。和 确定响应转移性肺肿瘤的最佳释放机制。要完成AIM 2，我们将 评估治疗效率（肿瘤抑制和生存益处）和DOX-PNFP6合并的毒性特征 在几种带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 与自由DOX和DOXIL相比，DOX的FDA批准的脂质体配方。我们还将调查 这种新理论策略激活了分子和免疫途径，以更好地了解机制 负责增强的抗癌活性。成功完成该项目将有效 具有临床影响对肺转移治疗和管理的治疗溶液。