Novel drug delivery strategies for treatment of breast cancer brain metastases

随着越来越多的女性在军队服役，有必要有效地管理我们的 患乳腺癌的现役和退伍军人妇女。仅在美国，就有276,000名女性 被诊断为乳腺癌，预计今年将有约4.2万人死于这种疾病。病人 被诊断为三阴性乳腺癌(TNBC)和人类表皮生长因子受体2(HER2)- 与其他乳房相比，阳性乳腺癌在大脑中远处复发的可能性更大。 癌症亚型--超过35%的转移性乳腺癌患者。脑转移瘤(BMS)令人沮丧 预后，因为现有治疗方法的疗效非常有限；实际上，TNBC患者在治疗后的中位生存期 转移性疾病的检出时间为5个月。多种独特的障碍限制了乳腺癌的有效药物传递 BMS。这些屏障包括(I)正常脑实质内的血脑屏障(BBB)和血-脑屏障。 转移灶内的肿瘤屏障(BTB)；(Ii)肿瘤间质压力升高和密度增加 带静电的脑细胞外间隙(ECS)共同限制对流和扩散药物 穿透性；(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，降低肿瘤细胞内的药物水平；以及(Iv)脑胶质细胞系统(GLS)， 这是一种高效的毒品清关系统。因此，新的治疗提供策略旨在缓解 跨越这些障碍可能会为有效治疗BMS提供新的希望。 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 NPs)与MRI引导的聚焦超声(MRgFUS)治疗 乳腺癌的BMS治疗(BCBMS)。DART NPs将被设计成针对肿瘤坏死因子成员Fn14 受体超家族在乳腺癌和乳腺癌BMS中高表达，但在BMS中低表达 正常的乳房、大脑或其他器官。我们团队的研究成果与开发和 DART NPs和MRgFUS增强的药物传递的应用促进了拟议的研究，包括：(1) DART纳米粒子在体外迅速渗透到脑和乳腺肿瘤组织中，选择性靶向Fn14阳性肿瘤 在体外和体内的细胞，并显著提高药物在体内的颅内肿瘤内的滞留。(2) MRgFUS诱导的血脑屏障破坏(BBBD)可以安全地增加DART纳米颗粒进入正常大脑的输送 薄壁组织。(3)含有化疗紫杉醇的Fn14靶向DART纳米粒(PTX-DART纳米粒)是 在杀死过度表达mdr1外排泵的癌细胞方面，比游离PTX更有效。(4)PTX-DART NPs 更有效地抑制乳腺脂肪垫和颅内TNBC中的肿瘤生长并提高动物存活率 异种移植模型与FDA批准的目前用于治疗乳房的纳米疗法Abraxane的比较 癌症患者。拟议的工作将建立在这些发现的基础上，以检验临床级别的PTX- DART纳米粒与MRgFUS诱导的BBBD相结合将提供更好的递送、药物保留和 脑型脑膜瘤的疗效与临床标准药物治疗的比较。这项研究的结果 也有可能对患有其他Fn14+的男性和女性军人产生影响 经常转移到大脑的癌症类型；特别是肺癌和黑色素瘤。

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.