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

• 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
• 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

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).

项目概要和摘要 三阴性乳腺癌 (TNBC) - 乳腺癌的一种侵袭性亚型，与乳腺癌的增加相关 转移潜力和患者生存率低 - 其特点是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 (HER2)，约占 15- 20% 的浸润性乳腺癌。 TNBC 是一项重要的临床挑战，因为这些癌症 对内分泌治疗或其他可用的靶向药物反应不佳；因此，目前化疗是 标准治疗的支柱，中位生存期仅为约 13 个月。目前FDA批准的纳米粒子- 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，两者都没有被证明可以显着改善肿瘤控制或患者生存率。这最有可能 由于（i）肿瘤脉管系统的外渗有限，（ii）乳腺肿瘤组织内的渗透性差，（iii） 无法有效地靶向肿瘤微环境中的肿瘤细胞药物摄取，以及（iv）开发 通过表达多药耐药性 (MDR) 泵（例如 P-糖蛋白）而产生耐药性。为了解决这些 治疗障碍，我们最近：（1）设计了相对较大的聚合物纳米粒子（63 至 114 nm），通过肿瘤特异性成纤维细胞生长因子诱导剂快速渗透乳腺肿瘤组织 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定量表征方法 各种纳米颗粒制剂的 Fn14 特异性和非特异性结合（针对肿瘤 ECM）。因此， 该拨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) 并最大限度地减少与肿瘤 ECM 的非特异性结合，Fn14 靶向肿瘤穿透纳米颗粒将 (1) 提供良好分散、持续的递送至肿瘤和含有 TNBC 细胞的肿瘤组织区域 (2) 专门针对 Fn14 阳性 TNBC 细胞并在其内有效运输，同时不伤害邻近的健康细胞 组织免受毒性作用。该策略可能会显着提高疗效并降低毒性 与游离药物及其临床纳米颗粒相比，在 TNBC 原发性肿瘤和播散性转移瘤中 制剂对应物，这将对速率限制障碍和机制产生新的见解 纳米颗粒治疗的肿瘤特异性靶向。从此获得的信息的未来应用 项目可用于改善分子靶向药物和药物的递送和治疗效果 组合，有可能最终转化为新颖、更有效的治疗策略。 重要的是，成功开发针对 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 Fn14 阳性癌症类型（例如肺癌、前列腺癌、卵巢癌、脑癌）的治疗。