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

• 批准号: 10219981
• 负责人: Hongbo Pang
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-29 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219981
• 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; 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; in vivo evaluation; interstitial; multidisciplinary; nanomaterials; nanoparticle; neoplastic cell; novel; nuclease; pre-clinical; pressure; prevent; prototype; receptor; research clinical testing; small molecule; targeted delivery; tool; tumor

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.

摘要 基于核苷酸的药物，如反义（阿索），代表了一类重要的药物类型， 特别适用于小分子和抗体的那些所谓“不可用药”的靶点。不过有一 转译阿索药物的最大障碍之一是体内递送差。存在着若干障碍， 阻止ASO在体内有效到达其靶细胞：快速肾清除，核酸酶降解， 非特异性吸收，穿透内皮和在血管外组织中扩散的效率低。 在这个建议中，我的目标是应用肽靶向和纳米材料技术来增强递送 AS 0进入实体瘤的效率。 为了防止肾过滤和核酸酶降解，ASO将被封装在多孔硅中 纳米颗粒（pSiNPs）。pSiNP是可生物降解的，并且在体内具有低毒性或没有毒性。更重要的是， pSiNP对于ASO和其他寡核苷酸可能具有最高的装载效率。最重要的 我们的目标是帮助ASO优先在肿瘤中积聚，并穿透肿瘤血管 以接近那些远离血液循环的靶细胞。我们的肿瘤穿透CendR肽是一种 这是实现这一目标的几个工具。CendR通过与肿瘤血管上的某些受体结合， 肽激活了跨越肿瘤血管沿着的主动转运过程， 包括pSiNP。在目标1中，我将合成CendR官能化的、负载ASO的pSiNP。除了 除了化学表征外，我还将在体外验证该系统的细胞进入和基因沉默功效。 在目标2中，我将评价体内毒性、药代动力学和组织分布。在Aim 3中， CendR-pSiNP-阿索的基因调节和肿瘤抑制功效将使用动物肿瘤细胞来测定。 模型我提出的研究具有改善肿瘤递送和抗肿瘤疗效的巨大潜力， ASO，并加速原型阿索药物进入临床的过渡。