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.

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