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

项目概要和摘要 三阴性乳腺癌（TNBC）-乳腺癌的一种侵袭性亚型， 转移潜力和患者生存率差-特征在于缺乏雌激素受体表达 (ER)孕激素受体（PR）和人表皮生长因子受体-2（HER 2），占约15- 20%的浸润性乳腺癌。TNBC代表了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较差;因此，化疗目前是 标准治疗的骨干，中位生存期仅约13个月。目前FDA批准的纳米颗粒- 已经研究了多柔比星（Doxil）和紫杉醇（Abraxane）的药物制剂用于治疗TNBC， 然而，两者都没有显示出显著改善肿瘤控制或患者存活。这很可能是 由于（i）从肿瘤脉管系统的外渗有限，（ii）在乳腺肿瘤组织内的渗透性差，（iii） 不能有效地靶向肿瘤微环境内的肿瘤细胞药物摄取，和（iv） 通过表达多药耐药（MDR）泵如P-糖蛋白而产生的耐药性。解决这些 （1）设计了相对大的聚合物纳米颗粒（63至100 μ m）， 114 nm），其与肿瘤特异性成纤维细胞生长因子诱导的14 （Fn 14）-靶向，以进一步改善颗粒分散、药物分布和肿瘤特异性细胞摄取。 肿瘤微环境和（2）开发了一种新的高通量定量表征方法 各种纳米颗粒制剂的Fn 14特异性和非特异性结合（针对肿瘤ECM）。因此 这项拨款提案的中心假设是，通过调节Fn 14特异性平衡结合亲和力（KD）， 和最小化与肿瘤ECM的非特异性结合，Fn 14靶向肿瘤穿透纳米颗粒将（1） 提供良好分散的持续递送到肿瘤和含有TNBC细胞的肿瘤组织区域中 和（2）特异性靶向Fn 14阳性TNBC细胞并在其中有效运输，同时保留相邻的健康TNBC细胞， 组织免受毒性影响。这一策略很可能会导致疗效的显著改善并降低毒性 与游离药物及其临床纳米颗粒相比， 这将产生新的见解的限速障碍和机制， 肿瘤特异性靶向纳米颗粒治疗。未来的应用所获得的信息，从这个 该项目可用于改善分子靶向药物和药物的递送和治疗效果 联合用药，这有可能最终转化为新的，更有效的治疗策略。 重要的是，成功开发用于TNBC的有效纳米颗粒疗法应该使我们能够 将这些发现扩展到其他Fn 14阳性癌症类型的治疗（例如，肺、前列腺、卵巢、脑）。

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).