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

基本信息

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
项目类别：
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

项目摘要

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 克服儿童脑肿瘤的药物输送障碍项目概要/摘要儿童脑肿瘤（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，但其无法穿过血脑屏障 (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 PBT 提供足够数量的药物，同时存在多重障碍包括血液中严重不稳定的情况，BBB/BBTB，相对较弱的增强渗透性脑肿瘤中的滞留（EPR）效应以及肿瘤细胞的有限摄取都应考虑在内考虑设计全流程交付策略。该 SBIR 的目标是开发一种高效的在临床前动物模型中，针对 PBT 的毒性较低的忍者型纳米颗粒负载 VCR (Ninja-V)，提供有关 II 期研究可行性的验证，最终将向 IND 提交申请美国食品和药物管理局。 Ninja-V 可以通过多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级靶向方法（顺序靶向 BBB/BBTB 与葡萄糖转运蛋白以及通过过度表达唾液酸的肿瘤细胞）在一个简单的设计。这种纳米粒子可以实现图像引导的药物输送，提高药物输送效率，并且尽量减少神经毒性。我们的假设是： 1) 可变换的多级靶向 Ninja-V 将能够穿过 BBB/BBTB 并促进封装药物专门向 PBT 的递送，具有增强的肿瘤细胞摄取和深层组织穿透，从而大大提高治疗指数并最大限度地减少毒性。 2) Ninja-V 由刺激响应交联组成，可最大限度地减少药物过早释放血液循环允许，同时不伤害正常脑组织和正常器官，因此会更多与游离药物形式相比，对 PBT 有效且毒性较小。最先进的纳米载体设计通过工程设计具有明确结构的末端树枝状聚合物代表了该领域的前沿发展纳米医学，在易于大规模生产、可微调和高度可重复的结构以及特性。它将解决纳米治疗剂的许多转化障碍。这种简单而独特的设计具有顺序靶向能力的交联和双靶向纳米粒子，以及刺激响应和可转换属性具有高度创新性。这是防止药物过早释放的绝佳方法在循环过程中向肿瘤输送高浓度的药物。预计这项研究将引领一种新的 PBT 管理方法。