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 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、预后差、耐药性、内脏转移和 早期疾病复发。TNBC在年轻女性中比老年女性和非洲女性中更常见- 美国和西班牙裔女性。铂类药物在TNBC中显示出比非TNBC更高的敏感性。 TNBC患者，最近对TNBC中的铂治疗重新产生了兴趣，特别是 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批准用于接受过化疗的TNBC患者。 至少两次化疗FDA批准了免疫治疗药物的加速批准 atezolizumab联合化疗（nab-紫杉醇）治疗TNBC（肿瘤阳性 对于PD-L1）。因此，化疗在TNBC的治疗管理中是重要的，即使在TNBC的出现中也是如此。 免疫治疗和靶向治疗的优势。然而，已知化疗会引起致命的外周血淋巴细胞减少。 除了反应差、转移、复发和多药耐药的发展之外，神经病变也是一个重要的因素。的 本申请的目标是开发能够实现更好的靶向纳米颗粒。 TNBC患者的结果：（a）将大剂量的多种药物靶向递送到癌细胞中（每一个单次给药）， 与单一免疫靶向药物（例如sacituzumab govitecan-hziy）相比， 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 其促进细胞内药物递送和释放，并可绕过多药耐药蛋白（p- 糖蛋白），其介导药物分子的外排;（c）能够长时间循环而不被隔离 进入肝脏EGFR在TNBC中过表达，文献中充满了使用西妥昔单抗的例子。 通过靶向EFGR进行治疗。我们假设生物可降解聚合物的发展 在核心中含有卡铂和紫杉醇并使用西妥昔单抗的纳米技术平台（标记在 纳米颗粒表面）作为靶向部分将改善TNBC患者的结果，不像重复的治疗。 化疗周期与高剂量的细胞毒性药物。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的小鼠异种移植模型中显示出体内功效 阳性肿瘤目的#1：制备聚合物染料负载的紫杉醇和卡铂负载的隐形 可水解的交联西妥昔单抗表面靶向聚乳酸（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-纳米颗粒在 核心目的#3：荷瘤小鼠中的生物分布和疗效研究。这项工作将带来承担 化学治疗剂、分子靶向治疗和纳米技术的联合力量， EGFR阳性TNBC抗性和改善疗效，毒性最小。