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

Fn14 靶向纳米颗粒对三阴性乳腺癌的影响

基本信息

批准号：
10772405
负责人：
Anthony J. Kim
金额：
$ 34.07万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10772405
关键词：
ABCB1 gene Abraxane Address Affinity Antineoplastic Agents Applications Grants Binding Biodistribution Blood Circulation Time Brain Breast Cancer Cell Breast Cancer Patient Cell Surface Receptors Clinical Couples Data Development Diameter Doxorubicin Drug Combinations Drug Delivery Systems Drug Formulations Drug Kinetics Drug usage Engineering Epidermal Growth Factor Receptor Equilibrium Estrogen Receptors Exhibits Extracellular Matrix Extravasation FDA approved Fibroblast Growth Factor Formulation Future Goals Human In Vitro Knowledge Lung MDA MB 231 Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Methods Modeling Multi-Drug Resistance Mus Neoplasm Metastasis Ovarian Paclitaxel Particle Size Patient-derived xenograft models of breast cancer Patients Penetration Pharmaceutical Preparations Polyethylene Glycols Primary Neoplasm Progesterone Receptors Prostate Pump Role Surface Plasmon Resonance Testing Therapeutic Tissues Toxic effect Translating Treatment Efficacy Tumor Necrosis Factor Receptor Tumor Tissue Vertebral column Work Xenograft procedure aggressive breast cancer cancer type chemotherapy cytotoxicity drug distribution drug resistance development effective therapy hormone therapy improved in vivo innovation insight malignant breast neoplasm member molecular drug target nanoparticle nanoparticle drug nanopolymer neoplastic cell novel orthotopic breast cancer particle receptor internalization surface coating targeted agent therapeutic nanoparticles trafficking treatment strategy triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor xenograft uptake

项目摘要

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).

项目摘要和摘要三阴性乳腺癌（TNBC） - 乳腺癌的侵略性亚型与增加有关转移性潜力和患者生存不良 - 的特征是缺乏雌激素受体的表达（ER），孕酮受体（PR）和人表皮生长因子受体2（HER2），约为15-- 20％的侵入性乳腺癌。 TNBC代表着重要的临床挑战，因为这些癌症对内分泌疗法或其他可用靶向剂的反应不佳；因此，化疗目前是标准疗法的骨干，中位生存期仅约13个月。当前FDA批准的纳米颗粒已经研究了阿霉素（Doxil）和紫杉醇（Abraxane）的药物制剂以治疗TNBC，但是，都没有证明可以显着改善肿瘤控制或患者的生存。这很可能是由于（i）受肿瘤脉管系统的渗出有限，（ii）乳腺肿瘤组织中的渗透不良，（iii）无法在肿瘤微环境中有效靶向肿瘤细胞药物的摄取，并且（iv）发展通过表达多药耐药性（MDR）泵（例如P-糖蛋白）的耐药性。解决这些治疗性障碍，我们最近有：（1）工程相对较大的聚合物纳米颗粒（63至63至之间 114 nm）迅速穿透具有肿瘤特异性成纤维细胞生长因子可诱导的乳腺肿瘤组织14 （FN14） - 靶向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）开发了一种新颖的高通量方法来定量表征各种纳米颗粒制剂的FN14特异性和非特异性结合（朝向肿瘤ECM）。因此，该赠款提案的中心假设是通过调节FN14特异性平衡结合亲和力（KD）。并最小化与肿瘤ECM的非特异性结合，FN14靶向的肿瘤穿透纳米颗粒将（1）提供充分分散的，持续的递送到含有TNBC细胞的肿瘤组织的肿瘤和区域（2）专门针对并有效地在FN14阳性TNBC细胞内进行交通，同时保留相邻的健康来自毒性作用的组织。该策略可能会导致功效的显着提高并降低毒性在TNBC原发性肿瘤和散布转移中，与临床纳米颗粒相比配方对应物，这将产生对限制速率障碍和机制的新见解纳米颗粒疗法的肿瘤特异性靶向。从此获得的信息的未来应用可以应用项目来提高分子靶向药物和药物的递送和治疗功效组合有可能最终转化为新颖，更有效的治疗策略。重要的是，有效开发有效的纳米颗粒治疗剂TNBC应该使我们能够将这些发现扩展到其他FN14阳性癌症类型（例如肺，前列腺，卵巢，大脑）的治疗。