Novel drug delivery strategies for treatment of breast cancer brain metastases

治疗乳腺癌脑转移的新型药物递送策略

• 批准号: 10367645
• 负责人: Anthony J. Kim
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367645
• 关键词: ABCB1 gene; Abraxane; Adhesives; Affinity; Animals; Antineoplastic Agents; Binding; Biodistribution; Biological; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Capillary Endothelial Cell; Cell Surface Receptors; Charge; Clinical; Clinical Trials; Convection; Detection; Development; Diagnosis; Diffuse; Disease; Distant; Drug Combinations; Drug Delivery Systems; Drug Efflux; Drug Kinetics; Electrostatics; Engineering; Epidermal Growth Factor Receptor; Extracellular Space; FDA approved; Face; Fatty acid glycerol esters; Female; Focused Ultrasound; Focused Ultrasound Therapy; Formulation; Goals; Human; Human Resources; Immunocompetent; In Vitro; Intracranial Neoplasms; Kinetics; MDA MB 231; Magnetic Resonance Imaging; Malignant neoplasm of lung; Mammary Neoplasms; Maximum Tolerated Dose; Mediating; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Microfluidics; Military Personnel; Modeling; Monoclonal Antibodies; Multi-Drug Resistance; Mus; Neoplasm Metastasis; Neuroglia; Neurons; Organ; Paclitaxel; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Process; Production; Prognosis; Property; Pump; Recurrence; Regimen; Research; Safety; Screening for cancer; Specimen; Surface Properties; System; Systemic Therapy; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Necrosis Factor Receptor; Tumor Tissue; United States; Veterans; Woman; Work; Xenograft Model; active duty; blood-brain barrier disruption; blood-brain tumor barrier; brain parenchyma; cancer cell; cancer subtypes; cancer type; cell killing; cerebral capillary; clinical development; clinical translation; cytotoxicity; design; drug clearance; drug standard; efflux pump; glymphatic system; improved; in vivo; innovation; instrument; interstitial; intravenous administration; male; malignant breast neoplasm; mammary; melanoma; member; military service; nanoparticle; nanoparticle delivery; nanotherapeutic; neoplastic cell; new therapeutic target; novel therapeutics; overexpression; pressure; programmed cell death ligand 1; receptor; standard care; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth

With an increasing number of women serving in the military, there is a significant need to effectively manage our active duty and Veteran women who develop breast cancer. In the United States alone, ~276,000 women will be diagnosed with breast cancer, of whom ~42,000 are predicted to die from this disease this year. Patients diagnosed with triple negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)- positive breast cancer have an increased likelihood of distant recurrence in the brain compared to other breast cancer subtypes – exceeding 35% of metastatic breast cancer patients. Brain metastases (BMs) confer dismal prognosis, as existing treatments have very limited efficacy; indeed, median survival for TNBC patients after detection of metastatic disease is ~5 months. Multiple unique barriers limit effective drug delivery to breast cancer BMs. These barriers include (i) the blood-brain barrier (BBB) within the normal brain parenchyma and the blood- tumor barrier (BTB) within metastatic lesions; (ii) elevated tumor interstitial pressure and the dense electrostatically charged brain extracellular spaces (ECS) which together limit convective and diffusive drug penetration; (iii) the activity of multidrug resistance (MDR) pumps expressed by both brain capillary endothelial cells and tumor cells, which reduce drug levels within tumor cells; and (iv) the brain glialymphatic system (GLS), which acts as an efficient drug clearance system. Thus, new therapeutic delivery strategies designed to mitigate and surmount these barriers will likely offer new promise towards effectively treating BMs. Accordingly, we propose to couple an emerging therapeutic delivery technology, decreased nonspecific adhesivity, receptor-targeted nanoparticles (DART NPs) with MRI-guided focused ultrasound (MRgFUS) for treatment of breast cancer BMs (BCBMs). DART NPs will be engineered to target Fn14, a member of the TNF receptor superfamily that is highly expressed in primary breast cancer and breast cancer BMs; but minimally in normal breast, brain, or other organs. Research findings from our team related to the development and application of DART NPs and MRgFUS-enhanced drug delivery that motivate the proposed studies include: (1) DART NPs rapidly penetrate in brain and breast tumor tissues ex vivo, selectively targeting Fn14-positive tumor cells both in vitro and in vivo, and significantly enhancing drug retention within intracranial tumors in vivo. (2) MRgFUS-induced BBB disruption (BBBD) can safely increase DART nanoparticle delivery into the normal brain parenchyma. (3) Fn14-targeted DART NPs containing the chemotherapeutic paclitaxel (PTX-DART NPs) are more effective than free PTX in killing cancer cells that overexpress the MDR1 efflux pump. (4) PTX-DART NPs more effectively reduce tumor growth and improve animal survival in mammary fat pad and intracranial TNBC xenograft models compared to Abraxane, an FDA-approved nanotherapeutic currently used to treat breast cancer patients. The proposed work will build on these findings to test the hypothesis that clinical-grade PTX- DART NPs in combination with MRgFUS-induced BBBD will provide superior delivery, drug retention, and therapeutic efficacy in BCBMs compared to the clinical standard drug treatments. The results from this study also have the potential to make an impact on both male and female military service personnel with other Fn14+ cancer types that frequently metastasize to the brain; specifically, lung cancer and melanoma.

随着越来越多的女性在军队服役，迫切需要有效管理我们的军队 患有乳腺癌的现役女性和退伍军人。仅在美国，就有约 276,000 名女性将 被诊断患有乳腺癌，预计今年约有 42,000 人死于这种疾病。患者 诊断患有三阴性乳腺癌 (TNBC) 和人类表皮生长因子受体 2 (HER2)- 与其他乳腺癌相比，阳性乳腺癌在大脑中远处复发的可能性更高 癌症亚型——超过 35% 的转移性乳腺癌患者。脑转移（BM）带来惨淡的结果 预后，因为现有治疗方法的疗效非常有限；事实上，TNBC 患者的中位生存期 转移性疾病的检测时间约为 5 个月。多种独特的障碍限制了乳腺癌的有效药物输送 BM。这些屏障包括（i）正常脑实质内的血脑屏障（BBB）和血脑屏障。 转移病灶内的肿瘤屏障（BTB）； (ii) 肿瘤间质压力升高和致密 带静电的脑细胞外空间 (ECS) 共同限制药物的对流和扩散 渗透; (iii) 脑毛细血管内皮细胞表达的多药耐药性 (MDR) 泵的活性 细胞和肿瘤细胞，降低肿瘤细胞内的药物水平； (iv) 大脑胶质淋巴系统 (GLS)， 它充当有效的药物清除系统。因此，新的治疗递送策略旨在减轻 并克服这些障碍可能会给有效治疗脑转移带来新的希望。 因此，我们建议结合一种新兴的治疗递送技术，减少非特异性 粘附性、受体靶向纳米颗粒 (DART NP) 和 MRI 引导聚焦超声 (MRgFUS) 乳腺癌 BM（BCBM）的治疗。 DART NP 将被设计用于靶向 TNF 成员 Fn14 在原发性乳腺癌和乳腺癌骨髓中高表达的受体超家族；但至少在 正常的乳房、大脑或其他器官。我们团队的研究成果涉及开发和 DART NP 和 MRgFUS 增强药物输送的应用推动了拟议的研究，包括：(1) DART NP 离体快速渗透到脑和乳腺肿瘤组织中，选择性靶向 Fn14 阳性肿瘤 体外和体内细胞，并显着增强体内颅内肿瘤内的药物保留。 (2) MRgFUS 诱导的 BBB 破坏 (BBBD) 可以安全地增加 DART 纳米颗粒进入正常大脑的递送 薄壁组织。 (3) 含有化疗紫杉醇的 Fn14 靶向 DART NP (PTX-DART NP) 比游离 PTX 更有效地杀死过度表达 MDR1 外排泵的癌细胞。 (4) PTX-DART 纳米颗粒 更有效地减少乳腺脂肪垫和颅内TNBC的肿瘤生长并提高动物存活率 异种移植模型与 Abraxane 的比较，Abraxane 是 FDA 批准的目前用于治疗乳腺癌的纳米疗法 癌症患者。拟议的工作将建立在这些发现的基础上，以检验临床级 PTX- DART NP 与 MRgFUS 诱导的 BBBD 相结合将提供卓越的递送、药物保留和 与临床标准药物治疗相比，BCBM 的治疗效果。这项研究的结果 也有可能对其他 Fn14+ 的男性和女性军人产生影响 经常转移至大脑的癌症类型；具体来说，是肺癌和黑色素瘤。