Ninja Theranostics for overcoming the drug delivery barriers to pediatric brain tumor

Ninja Theranostics 克服儿童脑肿瘤的药物输送障碍

• 批准号: 9681305
• 负责人: Paul Thomas Henderson
• 金额: $ 22.5万
• 依托单位: THERANOSTEC, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-26 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9681305
• 关键词: Acids; Active Sites; Address; Affect; Animal Model; Animals; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain Neoplasms; Cancer Etiology; Canis familiaris; Cells; Child; Childhood Brain Neoplasm; Childhood Central Nervous System Neoplasm; Childhood Malignant Brain Tumor; Cleaved cell; Clinical; Companions; Comprehensive Cancer Center; Cytotoxic agent; Daunorubicin; Deterioration; Development; Dose-Limiting; Doxorubicin; Drug Delivery Systems; Encapsulated; Endocrine; Engineering; Exhibits; FDA approved; Formulation; Functional disorder; Generations; Glucose; Glucose Transporter; Goals; Growth; Heat-Shock Proteins 90; Histone Deacetylase; Histone Deacetylase Inhibitor; Hydrophobicity; Impairment; Indocyanine Green; Kyocristine; Lead; Liposomes; Malignant Neoplasms; Mediating; Membrane Glycoproteins; Methods; Micelles; Modeling; Morbidity - disease rate; Neoplasm Metastasis; Neuraxis; Neuropathy; Neuropsychology; Organ; Paclitaxel; Patients; Penetration; Permeability; Pharmaceutical Preparations; Phase; Preparation; Process; Production; Property; Proteasome Inhibitor; Quality of life; Reproducibility; Research; SN-38; Schools; Sialic Acids; Site; Small Business Innovation Research Grant; Solid Neoplasm; Stimulus; Structure; Survival Rate; Techniques; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Translations; Tumor Tissue; Validation; Vincristine; Xenograft Model; anti-cancer; anticancer activity; base; bench to bedside; brain tissue; cGMP production; cancer therapy; childhood cancer mortality; clinical application; crosslink; design; docetaxel; experience; first-in-human; frontier; image-guided drug delivery; improved; inhibitor/antagonist; innovation; large scale production; mortality; nanocarrier; nanoformulation; nanomedicine; nanoparticle; nanoparticle drug; nanotheranostics; nanotherapeutic; neoplastic cell; neurotoxicity; novel; overexpression; phase 2 study; phase I trial; pilot trial; pre-clinical; premature; prevent; targeted delivery; theranostics; transcytosis; tumor; uptake

Ninja Theranostics for overcoming the drug delivery barriers to pediatric brain tumor Project Summary/Abstract Pediatric brain tumors (PBTs) are the leading cause of cancer-related morbidity and mortality among children. Vincristine (VCR) has been approved to treat PBTs, but its inability to cross blood brain barrier (BBB)/blood brain tumor barriers (BBTB) and dose-limiting neuropathy have greatly limited its clinical application. Thus the main challenge is to deliver sufficient amount of drugs to the hard reached PBTs, while multiple barriers including the severe destabilizing condition in the blood, BBB/BBTB, relatively weak enhanced permeability and retention (EPR) effects in brain tumor, and limited uptake in tumor cells should all be taken into consideration to design a whole-process delivery strategy. The goal of this SBIR is to develop a highly effective and less toxic Ninja-type nanoparticle loaded VCR (Ninja-V) against PBTs in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to the FDA. Ninja-V could overcome multi-barriers with several ultimate techniques. It integrates unique stimuli- responsive crosslinking strategy and transformable multistage targeting approach (sequentially targeting BBB/BBTB with glucose transporter as well as tumor cells via overexpressed sialic acid) in a simple one design. This nanoparticle could allow image-guided drug delivery, improve the drug delivery efficacy, and minimize the neurotoxicity. Our hypotheses are: 1) The transformable multistage targeting Ninja-V will be able to cross the BBB/BBTB and facilitate the delivery of encapsulated drugs specifically to PBTs with enhanced tumor cell uptake and deep tissue penetration, thus greatly improving the therapeutic index and minimizing the toxicity. and 2) the Ninja-V consist of stimuli-responsive crosslinkages will minimize premature drug release in blood circulation allow while sparing normal brain tissue and normal organs, and therefore will be more efficacious and less toxic against PBTs compared to the free drug form. State-of-the-art design of nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of ease of large-scale production, fine-tunable and highly reproducible structure and properties. It will address many translational barriers of nanotherapeutic agents. This simple and unique design of crosslinking and dual targeting nanoparticles with sequential targeting capability, and stimuli-responsive and transformable properties are highly innovative. It is an excellent approach to prevent premature drug release during circulation and deliver high concentrations of drug to tumors. It is expected that this research will lead to a new method for the management of PBTs.

忍者疗法用于克服儿科脑肿瘤的药物输送障碍 项目摘要/摘要 小儿脑肿瘤（PBT）是儿童与癌症相关的发病率和死亡率的主要原因。 vincristine（VCR）已被批准治疗PBT，但无法跨越血脑屏障（BBB）/血液 脑肿瘤障碍（BBTB）和限制剂量的神经病已大大限制了其临床应用。因此 主要的挑战是将足够数量的药物输送到硬触及的PBT，而多个障碍 包括血液中的严重不稳定状况，BBB/BBTB，相对较弱的渗透性相对较弱 和保留（EPR）在脑肿瘤中的作用，以及肿瘤细胞中的摄取量有限 考虑设计整个过程交付策略。 SBIR的目标是发展高效 以及毒性较小的忍者型纳米粒子在临床前动物模型中针对PBT的VCR（Ninja-V）， 提供有关第二阶段研究的可行性的验证，最终将导致IND提交给 FDA。 Ninja-V可以通过多种最终技术克服多攻击者。它整合了独特的刺激 - 响应迅速的交联策略和可转换的多阶段靶向方法（依次定位 BBB/BBTB与葡萄糖转运蛋白以及肿瘤细胞通过过表达的唾液酸） 设计。该纳米颗粒可以允许图像引导的药物输送，提高药物递送功效，并且 最小化神经毒性。我们的假设是：1）可转换的多阶段靶向忍者V将能够 越过BBB/BBTB并促进专门为PBT提供的封装药物 肿瘤细胞的摄取和深层组织渗透，从而大大改善了治疗指数并最小化 毒性。 2）忍者V由刺激反应的交联将最大程度地减少过早的药物释放 血液循环允许在放大正常脑组织和正常器官时，因此会更 与游离药物形式相比，对PBT的有效且毒性较小。纳米载体的最先进设计 通过具有明确定义的结构的工程他迪德里大合合体代表了 纳米医学，就大规模生产，微调和高度可重现的结构而言， 特性。它将解决纳米治疗剂的许多翻译障碍。这个简单独特的设计 具有连续靶向能力的交联和双重靶向纳米颗粒的 可转换的属性具有很高的创新性。这是防止过早药物释放的绝佳方法 在循环过程中，将高浓度的药物输送到肿瘤。预计这项研究将领导 采用新的PBT管理方法。