Improving the in vivo delivery and antitumor efficacy of antisense drugs

提高反义药物的体内递送和抗肿瘤功效

基本信息

批准号：
9289598
负责人：
Hongbo Pang
金额：
$ 11.06万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-14 至 2017-12-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9289598
关键词：
Active Biological Transport Adsorption Animals Antibodies Antisense Oligonucleotides Area Automobile Driving Blood Circulation Blood Vessels Cells Charge Chemicals Clinic Clinical Complex Disease Drug Delivery Systems Drug Kinetics Drug Targeting Drug or chemical Tissue Distribution Encapsulated Endothelium Evaluation Extracellular Matrix Filtration Formulation Gene Silencing Genes Goals Half-Life Human In Vitro Industrialization Kidney Methods Modeling Modification Molecular Weight Nanotechnology Nucleotides Oligonucleotides Participant Penetration Peptides Pharmaceutical Preparations Pharmacologic Substance Renal Circulation Renal clearance function Research Research Personnel Sailor Silicon Site Solid Neoplasm Stromal Cells System Technology Tissues Toxic effect Translations Transport Process Tumor Tissue Validation Work absorption antitumor effect base clinical efficacy clinical investigation design drug development drug market experience improved in vivo interstitial multidisciplinary nanomaterials nanoparticle neoplastic cell novel nuclease pre-clinical pressure prevent prototype receptor research clinical testing small molecule targeted delivery tool tumor

项目摘要

Abstract Nucleotide-based drugs, such as antisense (ASO), represent an essential class of drug types that are particularly useful for those so-called “undruggable” targets by small molecules and antibodies. However, one of the biggest hurdles in the translation of ASO drugs is the poor in vivo delivery. Several barriers exist to prevent ASOs from efficiently reaching their target cells in vivo: rapid renal clearance, nuclease degradation, unspecific absorption, low efficiency to penetrate across the endothelium and spread in extravascular tissue. In this proposal, I aim to apply the technologies of peptide targeting and nanomaterial to enhance the delivery efficiency of ASOs into solid tumors. To prevent renal filtration and nuclease degradation, ASOs will be encapsulated within porous silicon nanoparticles (pSiNPs). pSiNPs are biodegradable and have low or no toxicity in vivo. More importantly, pSiNPs have likely the highest loading efficiency for ASOs and other oligonucleotides. The most important goal of our proposal is to help ASOs preferentially accumulate in tumors, and penetrate across tumor vessels to access to those target cells far away from the circulation. Our tumor-penetrating CendR peptides are one of the few tools available to achieve this goal. By engaging with certain receptor on the tumor vessels, CendR peptides activate an active transport process across tumor vessels along with a wide range of cargo types, including pSiNPs. In the Aim 1, I will synthesize CendR-functionalized, ASO-loaded pSiNPs. Besides chemical characterization, I will also validate the cell entry and gene-silencing efficacy of this system in vitro. In the Aim 2, I will evaluate the in vivo toxicity, pharmacokinetics and tissue distribution. In the Aim 3, the gene modulation and tumor-inhibitory efficacy of CendR-pSiNP-ASO will be determined using animal tumor models. My proposed studies hold great potential for improving the tumor delivery and antitumor efficacy of ASOs, and accelerating the transition of prototype ASO drugs into the clinic.

抽象的基于核苷酸的药物，例如反义（ASO），代表了必不可少的药物类型对于那些小分子和抗体的所谓“不良”靶标特别有用。但是，一个 ASO药物翻译中最大的障碍是体内差的差。存在几个障碍防止ASO有效地在体内达到其靶细胞：快速肾脏清除率，核酸酶降解，非特异性滥用，效率低，可以穿透整个内皮并扩散在血管外组织中。在此提案中，我旨在应用胡椒靶向和纳米材料的技术来增强交付 ASOS效率为实体瘤。为了防止肾脏过滤和核酸酶降解，ASO将封装在多孔硅内纳米颗粒（PSINPS）。 PSINP可生物降解，体内毒性低或无毒性。更重要的是， PSINP可能是ASO和其他寡核苷酸的最高负载效率。最重要的我们建议的目标是帮助ASO优先积累在肿瘤中，并穿透在肿瘤容器中进入远离循环的那些目标细胞。我们的肿瘤穿透辣椒是一个在实现此目标的少数工具中。通过在肿瘤血管上与某些受体接触，Cendr 肽与各种货物类型一起激活跨肿瘤容器的主动运输过程，包括psinps。在AIM 1中，我将合成Cendr官能化的ASO负载PSINP。除了化学表征，我还将在体外验证该系统的细胞输入和基因沉默效率。在目标2中，我将评估体内毒性，药代动力学和组织分布。在目标3中 CENDR-PSINP-ASO的基因调节和抑制肿瘤抑制效率将使用动物肿瘤确定型号。我提出的研究具有提高肿瘤递送和抗肿瘤效率的巨大潜力 ASO，并加速原型ASO药物向诊所的过渡。