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

忍者神学克服儿童脑肿瘤的药物传递障碍 项目摘要/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，但其无法通过血脑屏障(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， 主要挑战是向难以接触到的PBT提供足够数量的药物，同时存在多重障碍 包括血液中严重的不稳定状态，BBB/BBTB，相对较弱的通透性增强 脑肿瘤的EPR效应和肿瘤细胞的摄取受限都应该考虑到 考虑设计一种全程交付策略。这项SBIR的目标是开发一种高效的 在临床前动物模型中，毒性较低的忍者类型纳米颗粒负载的VCR(忍者-V)对抗PBTS， 为第二阶段研究的可行性提供验证，这些研究最终将导致IND向 美国食品和药物管理局。忍者-V可以用几种终极技术克服多种障碍。它集成了独特的刺激- 响应性交联策略和可转换的多阶段靶向方法(顺序靶向 BBB/BBTB与葡萄糖转运蛋白以及通过过表达的唾液酸对肿瘤细胞的作用)在一个简单的 设计。这种纳米颗粒可以实现图像引导的药物传递，提高药物传递效率，以及 把神经毒性降到最低。我们的假设是：1)可变形的多级靶向忍者-V将能够 跨越BBB/BBTB并促进将胶囊药物专门运送到具有增强功能的PBT 肿瘤细胞摄取和组织深层渗透，大大提高了治疗指数，最大限度地减少了 毒性。2)由刺激反应交叉链接组成的忍者-V将最大限度地减少过早的药物释放 血液循环允许的同时，保留正常的脑组织和正常的器官，因此会更多 与游离药物形式相比，对PBTS有效且毒性较低。纳米载体的最新设计 具有明确结构的Via工程端树形分子代表了 纳米医学，在易于大规模生产、可微调和高度可重复性的结构和 属性。它将解决纳米治疗剂的许多翻译障碍。这个简单而独特的设计 具有顺序靶向能力的交联和双靶向纳米颗粒，以及刺激响应和 可变形的特性具有很高的创新性。这是防止药物过早释放的一个很好的方法。 在循环过程中，并向肿瘤输送高浓度的药物。预计这项研究将引领 为PBTS的管理提供一种新的方法。

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.