Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy

用于卵巢癌治疗的抗血管和细胞毒性纳米颗粒制剂

基本信息

批准号：
10524135
负责人：
JOHN A MARTIGNETTI
金额：
$ 11.9万
依托单位：
BROOKLYN COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524135
关键词：
Adverse effects Amino Acids Angiogenesis Inhibitors Antineoplastic Agents Biodistribution Biological Biological Assay Blood Blood Vessels Cancer Patient Cancer Relapse Cancer cell line Cell Proliferation Cell Survival Cells Clinic Clinical Combretastatin Confocal Microscopy Coupled DNA Adducts DNA Damage DNA Repair Data Diagnosis Diagnostic Disease Dose Dose-Limiting Drug resistance Effectiveness Encapsulated Endothelial Cells Endothelium Ensure Evaluation Exhibits FDA approved Fluorescence Formulation Generations Glycolates Goals Half-Life Histologic Histology Immune system Immunochemistry In Vitro Integrin alphaVbeta3 Intraperitoneal Injections Kinetics Ligands Liposomes Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Measures Microscopic Microscopy Minor Modification Molecular Monoclonal Antibodies Near-infrared optical imaging Ovarian Patients Peptides Peripheral Nervous System Permeability Pharmaceutical Preparations Pharmacology Platinum Polymers Progression-Free Survivals Property Resistance Route Surface System Techniques Testing Therapeutic Tissue imaging Toxic effect Treatment Efficacy Treatment Protocols Treatment outcome United States Visualization Woman Work base bevacizumab bioluminescence imaging cancer cell cancer therapy chemotherapy clinical investigation cytotoxic dosage drug efficacy drug release profile female reproductive system flexibility fluorophore imaging modality improved in vitro testing in vivo in vivo imaging mortality mouse model nanoparticle nanoparticle delivery nanotherapy nephrotoxicity non-invasive imaging non-invasive optical imaging novel pre-clinical rational design receptor mediated endocytosis reproductive outcome systemic toxicity targeted agent targeted delivery targeted treatment theranostics therapy outcome treatment strategy tumor tumor growth uptake

项目摘要

Ovarian cancer (OC) has the highest mortality rate of all cancers of the female reproductive system and outcomes have not changed over the past four decades. This year, over 20,000 women will be diagnosed with OC in the United States more than 14,000 women will die from this disease. Platinum-based therapy is the main therapeutic option for OC patients and ultimately, systemic toxicity limits the dosage given and this, in part, limits its effectiveness. To overcome this therapeutic roadblock, alternative routes of administration have been sought and include the practically difficult intraperitoneal (IP) injection, and more recently, the emerging strategy of combining Pt (II) chemotherapy with tumor vasculature-targeting agents. The overarching goal of this study is to develop a nanoparticle (NP)-based therapy for targeted delivery of high dose Pt (II) and a vascular disrupting agent directly to cancer cells and endothelium, to enhance treatment outcomes. As proof- of-principle, we have chosen combretastatin CA4 as the vascular targeting agent. Our proposal explores a second generation, slow releasing polymer NP platform, with poly(lactic-co-glycolic) (PLGA) acid core encapsulating Pt (II) and CA4. The NP’s coating is comprised of a RGDFFF peptide that stabilizes the NP and simultaneously serves as a targeting ligand to αvβ3 integrin via its RGD moiety. The PLGA is FDA-approved and amino acids of the peptide have Generally Regarded As Safe (GRAS) status. The NP is completely biodegradable. Encapsulation of Pt (II) and CA4 will reduce systemic toxicity and allow us to explore the use of effectively higher dosages than currently feasible. Upon the NP’s accumulation in the tumor interstitium, via enhanced permeability and retention (EPR) effects, the cellular NPs uptake will be enhanced via receptor- mediated endocytosis. The effect of the cytotoxic activity of Pt (II) and CA4 towards cancer cells and the tumor’s vasculature, will be measured through therapeutic outcomes. A small percentage of near infrared fluorophore (NIRF) will be incorporated into the NP’s coating to enable noninvasive optical imaging. The combination of therapeutic and diagnostic features will transform the NP into a “theranostic” platform. In vitro studies will include evaluation of NPs targeting to cancer cells, their biological activity, and compatibility with the immune system. In vivo studies will focus on the assessment of NPs pharmacologic parameters, tumor targeting, tolerability, and, finally, therapeutic efficacy. Combined in vitro and in vivo studies will employ microscopy, immunochemistry, and histology, to define the best NP-based treatment regimen resulting in therapeutic outcomes rivaling free drug routines currently used in the clinic. Thus, the proposed specific aims are: Aim 1: Synthesize and characterize an RGDFFF-coated NP platform for targeting, visualizing and treating ovarian cancer. Aim 2: Test targeting efficacy and therapeutic potential of CA4-NPs and Pt-NPs in vitro. Aim 3: Study the biodistribution and targeted ‘trapping’ of NPs in a preclinical OC mouse model via in vivo imaging. Aim 4: Conduct a therapy study wherein CA4-NPs and Pt-NPs, are applied to a preclinical OC mouse model.

卵巢癌（OC）的死亡率是女性复制系统所有癌症的最高死亡率，在过去的四十年中，结果没有改变。今年，将有20,000多名妇女被诊断出患有美国的OC在美国将死于这种疾病。基于铂的治疗是 OC患者的主要理论选择，最终，全身毒性限制了给药的剂量，这是部分，限制其有效性。为了克服这种治疗性障碍，替代行政途径被感知并包括实际上困难的腹膜内注射（IP）注射，最近是新兴的将PT（II）化学疗法与肿瘤脉管系统靶向剂相结合的策略。总体目标这项研究是开发基于纳米颗粒（NP）的疗法，用于针对性递送高剂量PT（II）和A 直接对癌细胞和内皮的血管破坏剂，以增强治疗结果。作为证明 - 原则上，我们选择了COMBRETASTANT CA4作为血管靶向剂。我们的建议探讨了第二代，缓慢释放聚合物NP平台，带有聚（乳酸 - 糖）（PLGA）酸内核封装Pt（II）和CA4。 NP的涂层完成了稳定NP和的RGDFFF胡椒类似地，通过其RGD部分用作对αVβ3整合素的靶向配体。 PLGA是FDA批准的胡椒的氨基酸通常被认为是安全的（GRA）状态。 NP完全可生物降解。 PT（II）和CA4的封装将降低全身毒性，并允许我们探索使用有效地比目前可行的剂量更高。在NP积聚在肿瘤间质中，增强的渗透性和保留效应（EPR）效应，细胞NP的摄取将通过受体增强介导的内吞作用。 Pt（II）和CA4对癌细胞和CA4的细胞毒性活性的影响肿瘤的脉管系统将通过治疗结果来测量。一小部分近红外荧光团（NIRF）将纳入NP的涂层，以实现非侵入性光学成像。这理论和诊断特征的组合将将NP转变为“ heranostic”平台。体外研究将包括评估针对癌细胞的NPS，其生物学活性以及与免疫系统。体内研究将重点介绍NPS药物参数，肿瘤的评估靶向，耐受性，最后是治疗效率。体外和体内研究将采用显微镜，免疫化学和组织学，以定义最佳的基于NP的治疗方案，导致治疗结果是诊所目前使用的自由无药物例程。这是拟议的特定目标是： AIM 1：合成并表征用于靶向，可视化和治疗的RGDFFF涂层的NP平台卵巢癌。 AIM 2：在体外测试CA4-NP和PT-NP的靶向靶向效率和治疗潜力。目标3：通过体内成像研究生物分布和靶向NP的“捕获”。 AIM 4：进行一项治疗研究，其中CA4-NP和PT-NP被应用于临床前OC小鼠模型。