Novel drug delivery strategies for treatment of breast cancer brain metastases

随着越来越多的妇女在军队服役，非常需要有效地管理我们的 患乳腺癌的现役军人和退伍军人。仅在美国，就有约276，000名女性 被诊断出患有乳腺癌，其中约42，000人预计今年将死于这种疾病。患者 诊断为三阴性乳腺癌（TNBC）和人表皮生长因子受体2（HER 2）- 与其他乳腺癌相比，阳性乳腺癌在脑中远处复发的可能性增加。 癌症亚型-超过35%的转移性乳腺癌患者。脑转移瘤（BM）带来令人沮丧的 预后，因为现有的治疗方法具有非常有限的疗效;事实上，TNBC患者的中位生存期 转移性疾病的检测约为5个月。多种独特的屏障限制了乳腺癌的有效药物递送 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（BBB）。 转移病灶内的肿瘤屏障（BTB）;（ii）升高的肿瘤间质压和致密的 带静电的脑细胞外间隙（ECS）共同限制了药物的对流和扩散 （iii）脑毛细血管内皮细胞表达的多药耐药（MDR）泵的活性， 细胞和肿瘤细胞，其降低肿瘤细胞内的药物水平;和（iv）脑胶质淋巴系统（GLS）， 其充当有效的药物清除系统。因此，新的治疗递送策略被设计为减轻 并克服这些障碍将可能为有效治疗BM提供新的希望。 因此，我们建议将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 NPs）与MRI引导的聚焦超声（MRgFUS）， 治疗乳腺癌BM（BCBMs）。DART NPs将被工程化以靶向Fn 14，Fn 14是TNF-α的成员。 受体超家族在原发性乳腺癌和乳腺癌BM中高度表达;但在乳腺癌BM中表达最低。 正常的乳房大脑或其他器官我们团队的研究结果与开发和 DART NP和MRgFUS增强的药物递送的应用激发了所提出的研究，包括：（1） DART NPs在离体脑和乳腺肿瘤组织中快速渗透，选择性靶向Fn 14阳性肿瘤 细胞，并显著增强体内颅内肿瘤内的药物滞留。（二） MRgFUS诱导的BBB破坏（BBBD）可以安全地增加DART纳米颗粒递送到正常大脑中 薄壁组织(3)含有化疗紫杉醇的Fn 14靶向DART NP（PTX-DART NP）是 在杀死过表达MDR 1外排泵的癌细胞方面比游离PTX更有效。(4)PTX-DART纳米粒 在乳腺脂肪垫和颅内TNBC中更有效地减少肿瘤生长并提高动物存活率 与Abraxane（FDA批准的目前用于治疗乳腺癌的纳米药物）相比， 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的组合将提供上级递送、药物保留和生物相容性。 与临床标准药物治疗相比，BCBM的治疗效果。本研究的结果 也有可能对男性和女性军事服务人员产生影响， 经常转移到大脑的癌症类型;特别是肺癌和黑素瘤。

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.