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.

Ninja Theranostics克服小儿脑肿瘤的药物输送障碍 项目总结/摘要 小儿脑肿瘤（PBT）是儿童癌症相关发病率和死亡率的主要原因。 长春新碱（VCR）已被批准用于治疗PBT，但其不能穿过血脑屏障（BBB）/血液， 脑肿瘤屏障（BBTB）和剂量限制性神经病变极大地限制了其临床应用。因此 主要挑战是向难以到达的PBTs提供足够数量的药物， 包括血液中严重的不稳定状态、BBB/BBTB、相对弱的增强渗透性 脑肿瘤中的EPR效应和肿瘤细胞中的有限摄取都应考虑在内。 考虑设计全过程交付战略。该SBIR的目标是开发一种高效的 以及在临床前动物模型中对PBT毒性较小的Ninja型纳米颗粒负载VCR（Ninja-V）， 为II期研究的可行性提供验证，最终将导致IND提交给 FDA. Ninja-V可以用几种终极技术克服多重障碍。它整合了独特的刺激- 响应性交联策略和可转化的多阶段靶向方法（顺序靶向 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）在一个简单的 设计这种纳米颗粒可以允许图像引导的药物递送，提高药物递送功效， 最大限度地减少神经毒性。我们的假设是：1）可转换的多级瞄准Ninja-V将能够 以穿过BBB/BBTB并促进包封的药物特异性地递送至具有增强的生物相容性的PBT。 肿瘤细胞摄取和深层组织渗透，从而大大提高治疗指数，并最大限度地减少 毒性和2）Ninja-V由刺激响应性交联组成，将最小化药物的过早释放， 血液循环允许，同时保留正常的脑组织和正常器官，因此将更多 与游离药物形式相比，其对PBT有效且毒性较小。纳米载体的最新设计 通过工程化具有明确结构的末端树枝状聚合物代表了 纳米医学，在易于大规模生产，精细可调和高度可重复的结构， 特性.它将解决纳米药物的许多翻译障碍。这种简单而独特的设计 交联和双靶向纳米颗粒，具有顺序靶向能力，刺激响应性和 可转化的性质是高度创新的。这是一种防止药物过早释放的极好方法 并将高浓度的药物输送到肿瘤中。预计这项研究将导致 一种新的PBTs管理方法。