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

• 批准号: 10672982
• 负责人: JOHN A MARTIGNETTI
• 金额: $ 32.4万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 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/10672982
• 关键词: Acids; 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 Adduction; 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; Investigation; 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; 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; bevacizumab; bioluminescence imaging; cancer cell; cancer therapy; chemotherapy; clinical investigation; combination cancer therapy; 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; nanopolymer; nanotherapy; nephrotoxicity; non-invasive imaging; non-invasive optical imaging; novel; novel therapeutic intervention; pharmacologic; pre-clinical; rational design; receptor mediated endocytosis; reproductive outcome; systemic toxicity; targeted agent; targeted delivery; targeted treatment; theranostics; therapeutic nanoparticles; therapy outcome; tumor; tumor growth; uptake

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）是女性生殖系统所有癌症中死亡率最高的癌症 过去四十年来，结果没有改变。今年，将有超过 20,000 名女性被诊断出患有此病。 在美国超过 14,000 名 OC 女性将死于这种疾病。 OC 患者的主要治疗选择，最终，全身毒性限制了给药剂量，这在 为了克服这一治疗障碍，有替代的给药途径。 一直在寻求并包括实际上困难的腹膜内（IP）注射，以及最近出现的新兴技术 Pt（II）化疗与肿瘤血管靶向药物相结合的策略。 本研究旨在开发一种基于纳米颗粒 (NP) 的疗法，用于靶向递送高剂量 Pt (II) 和 血管破坏剂直接作用于癌细胞和内皮，以增强治疗效果。 原则上，我们选择考布他汀 CA4 作为血管靶向剂，我们的建议探索了一种。 第二代缓释聚合物纳米颗粒平台，具有聚乳酸-乙醇酸 (PLGA) 酸核心 封装 Pt (II) 和 CA4 的涂层由 RGDFFF 肽组成，可稳定 NP 和 同时通过其 RGD 部分作为 αvβ3 整合素的靶向配体 PLGA 已获得 FDA 批准。 且该肽的氨基酸具有完全公认安全 (GRAS) 状态。 Pt (II) 和 CA4 的封装将降低全身毒性，使我们能够探索其用途。 当 NP 在肿瘤间质中积累时，可以使用比目前可行的更高的有效剂量。 增强渗透性和保留（EPR）效应，细胞对纳米粒子的吸收将通过受体增强 Pt (II) 和 CA4 对癌细胞和细胞的细胞毒活性的影响。 肿瘤的脉管系统，将通过一小部分近红外的治疗结果来测量。 荧光团 (NIRF) 将被纳入 NP 的涂层中，以实现非侵入性光学成像。 治疗和诊断功能的结合将把 NP 转变为一个“体外治疗诊断”平台。 研究将包括评估针对癌细胞的纳米颗粒、其生物活性以及与 免疫系统的体内研究将侧重于纳米颗粒药理参数、肿瘤的评估。 靶向性、耐受性以及最终的治疗效果将采用体外和体内联合研究。 显微镜、免疫化学和组织学，以确定最佳的基于 NP 的治疗方案，从而 治疗结果可与目前临床上使用的免费药物常规相媲美，因此，提出了具体目标。 是： 目标 1：合成并表征 RGDFFF 涂层的 NP 平台，用于靶向、可视化和治疗 目标 2：体外测试 CA4-NP 和 Pt-NP 的靶向功效和治疗潜力。 目标 3： 通过体内成像研究临床前 OC 小鼠模型中 NP 的生物分布和靶向“捕获”。 目标 4：进行一项治疗研究，将 CA4-NP 和 Pt-NP 应用于临床前 OC 小鼠模型。

项目成果

Engineering and Validation of a Peptide-Stabilized Poly(lactic-co-glycolic) Acid Nanoparticle for Targeted Delivery of a Vascular Disruptive Agent in Cancer Therapy.

• DOI: 10.1021/acs.bioconjchem.2c00418
• 发表时间: 2022-12-21
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: Dragulska SA;Poursharifi M;Chen Y;Wlodarczyk MT;Acosta Santiago M;Dottino P;Martignetti JA;Mieszawska AJ
• 通讯作者: Mieszawska AJ

Pt(II)-PLGA Hybrid in a pH-Responsive Nanoparticle System Targeting Ovarian Cancer.

• DOI: 10.3390/pharmaceutics15020607
• 发表时间: 2023-02-10
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Wlodarczyk MT;Dragulska SA;Chen Y;Poursharifi M;Acosta Santiago M;Martignetti JA;Mieszawska AJ
• 通讯作者: Mieszawska AJ