Impact of Fn14-targeted Nanoparticles for Triple-Negative Breast Cancer

项目摘要和摘要 三阴性乳腺癌(TNBC)--乳腺癌的一种侵袭性亚型，与 转移潜能和患者生存不良--以雌激素受体缺乏表达为特征 (ER)、孕激素受体(PR)和人表皮生长因子受体-2(HER2)，占~15- 20%的浸润性乳腺癌。TNBC代表着一个重要的临床挑战，因为这些癌症 对内分泌治疗或其他可用的靶向药物反应差；因此，化疗目前是 标准治疗的骨干，中位生存期仅为13个月。目前FDA批准的纳米颗粒- 阿霉素(Doxil)和紫杉醇(Abraxane)的药物制剂已被研究用于治疗TNBC， 然而，这两种药物都没有显着改善肿瘤控制或患者生存。这很可能是 由于(I)从肿瘤血管中渗出有限，(Ii)在乳腺肿瘤组织中穿透性差，(Iii) 不能有效地靶向肿瘤细胞在肿瘤微环境中的药物摄取，以及(Iv)发展 通过表达P-糖蛋白等多药耐药(MDR)泵产生耐药性。要解决这些问题 治疗障碍，我们最近有：(1)设计了相对较大的聚合物纳米颗粒(在63到63之间 114 nm)，通过肿瘤特异性成纤维细胞生长因子诱导的14在乳腺肿瘤组织中快速渗透 (Fn14)-靶向，以进一步改善粒子分散、药物分布和肿瘤特异性细胞摄取 肿瘤微环境和(2)发展了一种新的高通量定量表征方法 各种纳米颗粒配方的Fn14特异性和非特异性结合(对肿瘤细胞外基质)。因此， 这一赠款提案的中心假设是，通过调节Fn14特定的平衡结合亲和力(Kd)。 Fn14靶向肿瘤穿透纳米粒将使与肿瘤ECM的非特异性结合最小化(1) 向肿瘤和肿瘤组织中含有TNBC细胞的区域提供分散良好的持续递送 和(2)专门针对并有效地在Fn14阳性的TNBC细胞内传输，同时保留邻近的健康 来自有毒影响的组织。这一策略可能会显著提高疗效并降低毒性。 在TNBC原发肿瘤和转移性转移中，与游离药物及其临床纳米粒的比较 制定对应物，这将产生对速率限制障碍和机制的新见解 纳米粒子疗法的肿瘤特异性靶向。从本报告中获得的信息的未来应用 该项目可用于改善分子靶向药物和药物的传递和治疗效果 这可能最终转化为新的、更有效的治疗策略。 重要的是，针对TNBC的有效纳米颗粒疗法的成功开发应该使我们能够 将这些发现扩展到其他Fn14阳性癌症类型的治疗(例如，肺癌、前列腺癌、卵巢癌、脑癌)。

Project Summary and Abstract Triple-negative breast cancer (TNBC) - an aggressive subtype of breast cancer that is associated with increased metastatic potential and poor patient survival - is characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) and accounts for ~15- 20% of invasive breast cancers. TNBC represents an important clinical challenge because these cancers respond poorly to endocrine therapy or other available targeted agents; thus, chemotherapy is currently the backbone of standard therapy with a median survival of only ~13 months. Current FDA-approved nanoparticle- drug formulations of doxorubicin (Doxil) and paclitaxel (Abraxane) have been studied for the treatment of TNBC, however neither have been shown to significantly improve tumor control or patient survival. This is most likely due to (i) limited extravasation from the tumor vasculature, (ii) poor penetration within breast tumor tissue, (iii) inability to efficiently target tumor cell drug uptake within the tumor microenvironment, and (iv) development of drug resistance via expression of multidrug resistance (MDR) pumps such as P-glycoprotein. To address these therapeutic barriers, we have recently: (1) engineered relatively large polymeric nanoparticles (between 63 to 114 nm) that rapidly penetrate in breast tumor tissue with tumor-specific fibroblast growth factor-inducible 14 (Fn14)-targeting to further improve particle dispersion, drug distribution, and tumor-specific cellular uptake within the tumor microenvironment and (2) developed a novel high-throughput method for quantitative characterization of Fn14-specific and nonspecific binding (towards tumor ECM) of various nanoparticle formulations. Thus, the central hypothesis of this grant proposal is that by modulating the Fn14-specific equilibrium binding affinities (KD) and minimizing the nonspecific binding to tumor ECM, Fn14-targeted tumor penetrating nanoparticles will (1) provide well-dispersed, sustained delivery into the tumor and regions of the tumor tissue that contain TNBC cells and (2) specifically target to and efficiently traffic within Fn14-positive TNBC cells while sparing adjacent healthy tissues from toxic effects. This strategy is likely to result in significant improvements in efficacy and reduce toxicity in TNBC primary tumors and disseminated metastases, compared to free drugs and their clinical nanoparticle formulation counterparts, which will generate new insights into the rate-limiting barriers and mechanisms of tumor-specific targeting for nanoparticle therapeutics. Future applications of the information obtained from this project may be applied to improve the delivery and therapeutic efficacy of molecularly targeted drugs and drug combinations, which has the potential to eventually translate into novel, more effective treatment strategies. Importantly, the successful development of effective nanoparticle therapeutics for TNBC should allow us to extend these findings to the treatment of other Fn14-positive cancer types (e.g., lung, prostate, ovarian, brain).