Worm-like Micelles for Targeted Delivery and Imaging

用于靶向递送和成像的蠕虫状胶束

• 批准号: 6947329
• 负责人: Dennis E. Discher
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947329
• 关键词: biodegradable product; biomaterials; copolymer; drug delivery systems; drug screening /evaluation; enzyme linked immunosorbent assay; imaging /visualization /scanning; laboratory rat; ligands; liposomes; micelles; microscopy; nuclear magnetic resonance spectroscopy; phage display; pharmacokinetics; polyethylene glycols; technology /technique development

DESCRIPTION (provided by applicant): This R21's "develop and explore" objectives focus on worm-like micelles made from amphiphilic, PEG-based block copolymers. Long and cylindrical worm micelles are a promising new class of supermolecular carriers to explore for at least three reasons. First, even if microns long, they can "worm" through small pores and circulate for week(s). Second, targeted worms can cooperatively zip up - binding with high avidity - to surfaces or cells that bear suitable receptors. And third, once bound, internalization by the cell leads to delivery of a relatively large amount of drug all at once. Polymeric worm micelles are stable but nano-scale in diameter. They appear similar to filamentous phages that have been used with great success in vivo for phage display of targeting ligands (including tumors). Unlike phages which carry nucleic acid, however, worm micelles carry lipophilic drugs such as taxol and fluorescent dyes (visible or IR). Since 30% or more of all pharmacological agents are hydrophobic, new carriers that solubilize such agents are certainly important to develop and explore. One fundamental pharmacokinetics question that we believe worm micelles address is: what length can a stable but flexible cylindrical object be in vivo if it has a molecular scale cross-section of d<30 nm? Likewise, can long and cylindrical objects be internalized by cells either whole or in parts? The biomaterials literature currently suggests that a particle radius much greater than -100-200 nm will lead to rapid clearance or flitration by the liver, spleen, etc. However, our preliminary in vivo results surprisingly show that worm micelles several ¿m's long will circulate in the bloodstream of a rat for week(s), exceeding published circulation half-lives of 10-15 hrs for STEALTH liposomes with similar length PEG. Our preliminary results also suggest, very interestingly, that worm micelles several ¿m's long with targeting ligands on the PEG termini will bind cells and be internalized. With block copolymers such as biodegradable PEG-PLA or PEG-PCL of suitable proportions, drug release from these micelles would appear based on a combination of re-partitioning and carrier breakdown. For initial in vivo testing and insight into possible application of worm-like micelles, we propose targeting to a human lung cancer model in rat. Lung is an excellent target for proof of targeted delivery because we already know that similar PEG-based copolymer structures show no accumulation in rat lung. Since lung cancer also accounts for 1/3rd of all cancer deaths with 80-90% of patients dying of disease, it is a significant health problem in need of new approaches. Worm micelles may find a place in novel therapies. Regardless, worm micelles will teach us about biotransport, biocompatibility, and multi-valent targeting of long cylindrical objects both in the circulation and into cells.

描述(申请人提供)：这个R21‘S“开发和探索”的目标集中在由两亲性聚乙二醇基嵌段共聚物制成的蠕虫状胶束。长柱形蠕虫胶束是一类很有前途的新型超分子载体，至少有三个原因值得探索。首先，即使微米长，它们也可以通过细小的毛孔“蠕虫”并循环数周(S)。其次，靶向蠕虫可以协同拉链--以高亲和力结合--到带有合适受体的表面或细胞上。第三，一旦结合，细胞的内化导致相对大量的药物一次性输送。聚合物蠕虫胶束稳定，但直径为纳米级。它们看起来类似于丝状噬菌体，在体内已被成功地用于靶向配体(包括肿瘤)的噬菌体展示。然而，与携带核酸的噬菌体不同，蠕虫胶束携带亲脂性药物，如紫杉醇和荧光染料(可见或红外)。由于30%或更多的药物是疏水性的，因此开发和探索能够溶解这些药物的新载体无疑是非常重要的。我们认为蠕虫胶束解决的一个基本药代动力学问题是：如果一个稳定但灵活的圆柱形物体的分子尺度横截面为30纳米，它在体内能有多长？同样，长的和圆柱形的物体能被整个或部分细胞内化吗？目前的生物材料文献表明，远大于-100-200 nm的颗粒半径会导致肝脏、脾等的快速清除或过滤。然而，我们在体内的初步结果令人惊讶地显示，数米长的蠕虫胶束将在大鼠的血液中循环数周(S)，超过已公布的类似长度的聚乙二醇隐形脂质体10-15小时的循环半衰期。我们的初步结果还表明，非常有趣的是，在聚乙二醇端带有靶向配体的蠕虫胶束将结合细胞并被内化。对于适当比例的嵌段共聚物，如可生物降解的聚乙二醇聚乳酸或聚乙二醇聚乳酸，药物从这些胶束中释放将基于重新分配和载体破裂的组合。为了初步的体内测试和深入了解蠕虫状胶束的可能应用，我们建议以大鼠的人肺癌模型为靶点。肺是一个很好的靶向给药的证据，因为我们已经知道类似的基于聚乙二醇基的共聚物结构在大鼠肺中没有蓄积。由于肺癌也占所有癌症死亡的三分之一，80%-90%的患者死于疾病，这是一个重大的健康问题，需要新的方法。蠕虫胶束可能会在新的治疗方法中找到一席之地。无论如何，蠕虫胶束将教我们关于生物传输、生物兼容性以及长圆柱状物体在循环中和进入细胞中的多价靶向。