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% 癌症与侵袭性肿瘤生物学、预后不良、耐药、内脏转移和 早期疾病复发。TNBC在年轻女性中比在老年女性和非洲人中更常见- 美国和西班牙裔妇女。与非铂类药物相比，铂类药物对TNBC的敏感性更高。 最近，铂类药物在TNBC中的治疗重新引起了人们的兴趣，尤其是 卡铂联合紫杉醇(PTX)。Sacituzumab gov.itecan是由一种抗trop-2抗体组成的 与化疗药物(SN-38)有关，FDA批准了接受过TNBC治疗的患者 之前至少接受过两次化疗。FDA批准了这种免疫疗法药物的加速批准 阿替唑单抗联合化疗(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，即使在出现的时候 免疫治疗和靶向治疗。然而，众所周知，化疗会导致致命的外周血管疾病。 神经病除了反应差、转移、复发和发展多药耐药外。这个 这一应用的目标是开发多功能靶向纳米颗粒，能够实现更好的 对TNBC患者的结果：(A)有针对性地将大剂量多种药物输送到癌细胞中(每次 生物识别事件与单一免疫靶向药物(例如，saituzumab goitecan-hziy)相比)，以最大限度地提高 治疗效果，同时降低全身毒性(脱靶毒性)；(B)EGFR受体靶向纳米粒 促进细胞内药物传递和释放，并可绕过多药耐药蛋白(p- 糖蛋白)介导药物分子外流；(C)能够长循环而不被隔离 进入肝脏。EGFR被TNBC过度表达，文献中充斥着使用西妥昔单抗的例子 通过靶向EFGR进行治疗。我们假设可生物降解聚合物的发展 纳米技术平台，核心含有卡铂和紫杉醇，使用西妥昔单抗(标记在 纳米颗粒表面)作为靶向部分将改善TNBC患者的预后，不同于重复 化疗周期中使用大剂量的细胞毒药物。我们假设双负荷多功能 靶向纳米粒在体外具有活性，在小鼠TNBC异种移植模型中显示出体内疗效 阳性肿瘤。目的1：制备载聚合物染料和紫杉醇、卡铂的隐身材料 可水解性交联西妥昔单抗表面靶向聚乳酸(PLL)纳米粒。目标2：角色塑造 含卡铂和紫杉醇的抗EGFR单抗(西妥昔单抗)表面靶向PLL纳米粒在小鼠体内的研究 核心。目的#3：荷瘤小鼠体内的生物分布和疗效研究。这项工作将带来 化疗药物、分子靶向治疗和纳米技术的结合力量 EGFR阳性对TNBC耐药，并以最小的毒性提高疗效。