Active Delivery of Platinum Nanoimmunoconjugates to Improve Breast Cancer Therapy

主动递送铂纳米免疫缀合物以改善乳腺癌治疗

• 批准号: 10249060
• 负责人: Bogdan Olenyuk
• 金额: $ 43.23万
• 依托单位: PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-10 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249060
• 关键词: Address; Annexin A1; Antibodies; Antibody-drug conjugates; Applications Grants; Attenuated; Binding; Biological; Blood; Blood Cells; Blood Vessels; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer therapy; Carboplatin; Caveolae; Cell Death; Cell Wall; Cell surface; Chemicals; Cisplatin; Cleaved cell; Complex; DNA; DNA Binding; DNA lesion; Data; Dextrans; Dose; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Drug resistance; ERBB2 gene; Endothelial Cells; Endothelium; Fluorescence; Fluorescence Microscopy; Fostering; Goals; Half-Life; Health; Human; Immunoconjugates; Infection; Injections; Intravenous; Maximum Tolerated Dose; Membrane; Microfilaments; Mission; Modeling; Monitor; Mus; Myelosuppression; Neoplasm Metastasis; Normal tissue morphology; Organ; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Phospholipids; Platinum; Property; Proteins; Publishing; Pump; RNA; Renal clearance function; Research; Risk; Shapes; Side; Solid Neoplasm; Specificity; Speed; System; Testing; Therapeutic; Time; Toxic effect; Translating; Treatment Efficacy; United States National Institutes of Health; Vascular Endothelial Cell; animal imaging; anti-cancer therapeutic; antitumor drug; base; cancer therapy; carcinogenicity; chemotherapy; clinical efficacy; design; drug candidate; drug development; improved; in vivo; innovation; intravital microscopy; iterative design; malignant breast neoplasm; nanoparticle; neoplastic cell; nephrotoxicity; novel; oxaliplatin; pre-clinical; self assembly; side effect; single photon emission computed tomography; systemic toxicity; targeted delivery; targeted treatment; therapeutic effectiveness; treatment response; tumor; uptake; vascular endothelium permeability

The overall objective of the proposed research is to utilize a newly discovered, active transendothelial transport pathway, the caveolae pumping system, in order to provide an effective solution to the delivery and toxicity problem of Pt(II)-based chemotherapeutics in breast cancer. Systemic chemotherapy is one of the common forms of breast cancer treatments, however clinical efficacy of Pt(II) antitumor drugs is limited by the significant in vivo barriers inhibit delivery of these drugs into solid tumors, requiring the use of high doses, producing serious side effects and facilitating development of drug resistance. In order to address these problems and significantly improve treatment of breast cancer we propose two novel paradigms: 1) our newly discovered endothelial cell (EC) caveolae targeting system to sidestep passive delivery and dramatically enhance speed and efficiency of tumor penetration, and 2) to design and develop novel platinum(II) supramolecular coordination complexes (Pt(II)-SCCs), the nanoparticles (NPs) that have shown remarkable efficacy in tumor destruction in preclinical breast cancer models while being monodisperse, stable and well-characterized. Our main hypothesis is that immunoconjugates that fully utilize the advantages of caveolae-targeting antibodies will increase Pt(II)-SCCs delivery into tumors for enhanced efficacy and reduced toxicity, potentially resulting in a fundamentally new class of anticancer therapeutics. This hypothesis will be tested by the following specific aims: In Aim 1, we plan to design and synthesize Pt(II)-SCC immunoconjugates. In this Aim will also design, synthesize and characterize the chemical identity, purity and physicochemical properties of our Pt(II)-SCCs immunoconjugates. We will use caveolae-targeted antibody which we have shown can move the attached cargo from the blood across the EC barrier into solid tumor with unprecedented speed and specificity. In Aim 2 we will characterize in vivo delivery of Pt(II)-SCC immunoconjugates targeting the EC caveolae in tumors. We will perform dynamic monitoring of antibody-Pt(II)-SCC targeting in real time in live mice with intravital microscopy (IVM) using fluorescence emission of the assembled SCCs. In Aim 3 we will assess the therapeutic efficacy of the EC-targeting Pt(II)-SCC immunoconjugates. The efficacy of our targeted delivery system will be examined in IVM models using fluorescence microscopy and in non-IVM Her2/Neu tumor models with whole-body animal imaging. The long-term goal of this project is to translate our key basic discoveries into an innovative drug delivery platform in order to improve therapeutic efficacy and reduce toxicity in the breast cancer treatment.

拟议的研究的总体目的是利用新发现的活跃的跨内皮运输 途径是小窝抽水系统，以便为输送和毒性提供有效的解决方案 乳腺癌中基于PT（II）的化学治疗剂的问题。全身化疗是常见的 乳腺癌治疗的形式，但是PT（II）抗肿瘤药物的临床功效受到了显着的限制 体内屏障抑制这些药物将这些药物递送到实体瘤中，需要使用高剂量，产生 严重的副作用，并促进耐药性的发展。为了解决这些问题， 显着改善了对乳腺癌的治疗，我们提出了两个新型范式：1）我们新发现的 内皮细胞（EC）Caveolae靶向系统，以避开被动输送并大大提高速度 肿瘤渗透的效率和2）设计和发展新型铂（II）超分子 配位复合物（PT（ii）-SCC），纳米颗粒（NP），在肿瘤中表现出了显着疗效 临床前乳腺癌模型的破坏，同时是单分散，稳定且表征良好的。我们的 主要假设是完全利用靶向抗体抗体优势的免疫共轭物将 增加pt（ii）-SCCS到肿瘤中的递送以提高疗效和毒性降低，可能导致A 从根本上讲，新的抗癌治疗疗法。该假设将通过以下特定进行检验 目的：在AIM 1中，我们计划设计和合成PT（II）-SCC免疫缀合物。在此目标中也将设计 合成并表征我们pt（ii）-SCCS的化学身份，纯度和物理化学特性 免疫共轭。我们将使用针对小窝的抗体，我们显示的抗体可以移动附件 以空前的速度和特异性，从血液中的货物从EC屏障到实体瘤。在目标2中 我们将表征PT（II）-SCC免疫偶联物的体内递送，靶向肿瘤中的Ec Caveolae。我们 将在活体内实时实时对抗体-PT（II）-SCC靶向靶向的动态监测 使用组装的SCC的荧光发射显微镜（IVM）。在AIM 3中，我们将评估 EC靶向PT（II）-SCC免疫偶联物的治疗功效。我们目标交付的功效 将在IVM模型中使用荧光显微镜和非IVM HER2/NEU肿瘤检查系统 具有全身动物成像的模型。该项目的长期目标是翻译我们的关键基本 发现创新的药物输送平台，以提高治疗功效并降低毒性 在乳腺癌治疗中。

项目成果

Supramolecular Pt(II) and Ru(II) Trigonal Prismatic Cages Constructed with a Tris(pyridyl)borane Donor.

• DOI: 10.1021/acs.inorgchem.8b01830
• 发表时间: 2018-09-17
• 期刊: Inorganic chemistry
• 影响因子: 4.6
• 作者: Ryu JY;Lee JM;Van Nghia N;Lee KM;Lee S;Lee MH;Stang PJ;Lee J
• 通讯作者: Lee J

Recent developments in the construction and applications of platinum-based metallacycles and metallacages via coordination.

• DOI: 10.1039/d0cs00038h
• 发表时间: 2020-06-21
• 期刊: Chemical Society reviews
• 影响因子: 46.2
• 作者: Sun Y ;Chen C ;Liu J ;Stang PJ
• 通讯作者: Stang PJ

Assembly of Metallacages into Soft Suprastructures with Dimensions of up to Micrometers and the Formation of Composite Materials.

• DOI: 10.1021/jacs.8b11199
• 发表时间: 2018-11
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Yan Sun;Fengmin Zhang;Shao-Yong Jiang;Zhifeng Wang;Ruidong Ni;Heng Wang;Wei-dong Zhou;Xiaopeng Li;P. Stang

Alanine-Based Chiral Metallogels via Supramolecular Coordination Complex Platforms: Metallogelation Induced Chirality Transfer.

• DOI: 10.1021/jacs.7b10769
• 发表时间: 2018-03-07
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Sun Y;Li S;Zhou Z;Saha ML;Datta S;Zhang M;Yan X;Tian D;Wang H;Wang L;Li X;Liu M;Li H;Stang PJ
• 通讯作者: Stang PJ

Understanding the Effects of Coordination and Self-Assembly on an Emissive Phenothiazine.

• DOI: 10.1021/jacs.9b00363
• 发表时间: 2019-01
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Zhixuan Zhou;Cory E. Hauke;B. Song;Xiaopeng Li;P. Stang;Timothy R. Cook