Administrative Supplements for Equipment Purchases for Select NIGMS_Akala

特定 NIGMS_Akala 设备采购的行政补充

• 批准号: 10793724
• 负责人: EMMANUEL O AKALA
• 金额: $ 9.65万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793724
• 关键词: ABCB1 gene; Acceleration; Administrative Supplement; African American; Antibodies; Applications Grants; Award; Biodistribution; Brain; Breast Cancer Patient; Breast Cancer Treatment; Bypass; Carboplatin; Cetuximab; Circulation; Code; Cytotoxic agent; Development; Dose; Drug Delivery Systems; Drug Efflux; Dyes; Epidermal Growth Factor Receptor; Equipment; Event; Fluorescent Dyes; Gifts; Goals; Grant; Hispanic; Immunotherapy; In Vitro; Interruption; Link; Literature; Liver; Mediating; Monoclonal Antibodies; Multi-Drug Resistance; Mus; Nanotechnology; National Institute of General Medical Sciences; Neoplasm Metastasis; Outcome; Paclitaxel; Patient-Focused Outcomes; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Platinum; Polymers; Positioning Attribute; Postdoctoral Fellow; Prior Chemotherapy; Prognosis; Recurrent disease; Relapse; Research Support; Resistance; SN-38; Surface; System; Technology; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Tumor Biology; Visceral metastasis; Woman; Work; Xenograft Model; biodegradable polymer; cancer cell; chemotherapeutic agent; chemotherapy; crosslink; discount; efficacy study; equipment acquisition; fabrication; improved; in vivo; interest; malignant breast neoplasm; molecular targeted therapies; nanoparticle; nanotechnology platform; older women; overexpression; parent grant; poly(lactide); programmed cell death ligand 1; programs; receptor; response; student training; systemic toxicity; targeted delivery; targeted treatment; triple-negative invasive breast carcinoma; tumor; young woman

Abstract of the Parent Grant Award Project Summary: Triple-negative breast cancer (TNBC) accounts for approximately 15% of invasive breast cancers and is associated with aggressive tumor biology, poor prognosis, resistance, visceral metastases and earlier disease recurrence. TNBC is more common in younger women than in older women and in African- American and Hispanic women. Platinum-based drugs showed higher sensitivity in TNBC compared to non- TNBC patients and recently there has been a renewed interest for platinum therapy in TNBC, especially combination of carboplatin with paclitaxel (PTX). Sacituzumab govitecan is made up of an anti–Trop-2 antibody linked to the chemotherapy drug (SN-38) and was cleared by the FDA for TNBC patients who have undergone at least two prior chemotherapies. The FDA granted an accelerated approval for the immunotherapy drug atezolizumab in combination with chemotherapy (nab-paclitaxel) for the treatment of TNBC (for tumors positive for PD-L1). Thus chemotherapy is important in the therapeutic management of TNBC even in the advent of immunotherapy and targeted therapy. However, chemotherapies are known to cause fatal peripheral neuropathy in addition to poor response, metastasis, relapse and development of multidrug resistance. The goal of this application is the development of multifunctional targeted nanoparticles capable of achieving better outcomes for TNBC patients: (a) targeted delivery of large doses of multiple drugs into cancer cells (per a single biorecognition event compared to a single immunotargeted drug (e.g. sacituzumab govitecan-hziy)) to maximize therapeutic effects while reducing systemic toxicity (off target toxicity); (b) EGFR-receptor targeted nanoparticles that promote intracellular drug delivery and release and which can bypass multidrug resistant protein (p- glycoprotein) which mediates efflux of drug molecules; (c) capable of long circulation without being sequestered into the liver. EGFR is overexpressed by TNBC and literature is replete with examples of the use of cetuximab in therapy by targeting EFGR. We hypothesize that the development of biodegradable polymeric nanotechnology platform containing carboplatin and paclitaxel in the core and using cetuximab (tagged on nanoparticle surface) as a targeting moiety will improve TNBC patients’ outcomes, unlike repeated chemotherapy cycles with high doses of cytotoxic drugs. We hypothesize that the dual-loaded multifunctional targeted nanoparticles will be active in vitro and show in vivo efficacy in mouse xenograft models of TNBC positive tumors. Aim #1: Fabrication of polymeric dye-loaded and-paclitaxel and carboplatin-loaded stealth hydrolysable crosslinked cetuximab surface-targeted polylactide (PLL) nanoparticles. Aim #2: Characterization of anti-EGFR mAb (cetuximab) surface-targeted-PLL-nanoparticles containing carboplatin and paclitaxel in the core. Aim #3: Biodistribution and efficacy studies in tumor-bearing mice. This work will bring to bear the combined power of chemotherapeutic agents, molecular targeted therapy and nanotechnology to overcome EGFR positive TNBC resistance and improve efficacy with minimal toxicity.

家长资助奖摘要 项目摘要：三阴性乳腺癌 (TNBC) 约占浸润性乳腺癌的 15% 癌症，并与侵袭性肿瘤生物学、不良预后、耐药性、内脏转移和 较早的疾病复发。 TNBC 在年轻女性中比在年长女性中更常见，而且在非洲 美国和西班牙裔女性。与非铂类药物相比，铂类药物在 TNBC 中表现出更高的敏感性 TNBC 患者最近对 TNBC 铂类治疗重新产生了兴趣，尤其是 卡铂与紫杉醇 (PTX) 的组合。 Sacituzumab govitecan 由抗 Trop-2 抗体组成 与化疗药物 (SN-38) 相关，并已被 FDA 批准用于接受过 TNBC 治疗的患者 之前至少接受过两次化疗。 FDA 加速批准该免疫治疗药物 atezolizumab 联合化疗（白蛋白结合型紫杉醇）治疗 TNBC（肿瘤阳性） 对于 PD-L1）。因此，即使在 TNBC 出现之初，化疗对于 TNBC 的治疗管理也很重要。 免疫治疗和靶向治疗。然而，已知化疗会导致致命的外周病变 神经病除了反应差、转移、复发和产生多重耐药性之外。这 该应用的目标是开发能够实现更好效果的多功能靶向纳米粒子 TNBC 患者的结果：(a) 将大剂量的多种药物靶向输送到癌细胞中（每一个 与单一免疫靶向药物（例如 sacituzumab govitecan-hziy）相比，生物识别事件可最大化 治疗效果同时降低全身毒性（脱靶毒性）； (b) EGFR 受体靶向纳米颗粒 促进细胞内药物递送和释放，并且可以绕过多重耐药蛋白（p- 糖蛋白）介导药物分子的流出； (c) 能够长期流通而不被隔离 进入肝脏。 TNBC 过度表达 EGFR，文献中充满了西妥昔单抗的使用示例 通过针对 EFGR 进行治疗。我们假设可生物降解聚合物的发展 以卡铂和紫杉醇为核心并使用西妥昔单抗的纳米技术平台（标记为 纳米颗粒表面）作为靶向部分将改善 TNBC 患者的预后，与重复治疗不同 高剂量细胞毒药物的化疗周期。我们假设双负载多功能 靶向纳米颗粒将在体外具有活性，并在 TNBC 小鼠异种移植模型中显示出体内功效 阳性肿瘤。目标#1：制造载有聚合物染料的紫杉醇和载有卡铂的隐形材料 可水解交联西妥昔单抗表面靶向聚丙交酯 (PLL) 纳米颗粒。目标#2：表征 含有卡铂和紫杉醇的抗 EGFR mAb（西妥昔单抗）表面靶向 PLL 纳米颗粒的制备 核。目标#3：荷瘤小鼠的生物分布和功效研究。这项工作将带来 化疗药物、分子靶向治疗和纳米技术的综合力量克服了 EGFR 阳性 TNBC 耐药并以最小的毒性提高疗效。