Worm-like Micelles for Targeted Delivery and Imaging

描述（由申请人提供）：该R21的"开发和探索"目标集中于由两亲性PEG基嵌段共聚物制成的蠕虫状胶束。长圆柱形蠕虫胶束是一类有前途的新型超分子载体，至少有三个原因值得探索。首先，即使只有几微米长，它们也可以通过小孔“蠕动”并循环数周。第二，目标蠕虫可以合作拉链-结合与高亲和力-表面或细胞携带合适的受体。第三，一旦结合，细胞的内化会导致相对大量的药物同时释放。聚合物蠕虫胶束是稳定的，但直径为纳米级。它们看起来类似于丝状噬菌体，丝状噬菌体已经在体内成功地用于靶向配体（包括肿瘤）的噬菌体展示。然而，与携带核酸的胶束不同，蠕虫胶束携带亲脂性药物，如紫杉醇和荧光染料（可见光或IR）。由于30%或更多的药物是疏水性的，因此开发和探索增溶这些药物的新载体当然很重要。我们认为蠕虫胶束解决的一个基本的药代动力学问题是：如果一个稳定但灵活的圆柱形物体具有d <30 nm的分子尺度横截面，那么它在体内的长度是多少？同样，长的圆柱形物体是否可以被细胞整体或部分内化？生物材料文献目前表明，颗粒半径远大于~100 - 200 nm将导致肝脏、脾脏等的快速清除或过滤。m的长将在大鼠的血流中循环数周，超过了具有相似长度PEG的STEALTH脂质体10 - 15小时的已发表循环半衰期。我们的初步结果还表明，非常有趣的是，在PEG末端具有靶向配体的几μ m长的蠕虫胶束将结合细胞并被内化。使用合适比例的嵌段共聚物如可生物降解的PEG-PLA或PEG-PCL，药物从这些胶束中的释放将基于再分配和载体分解的组合出现。为了初步的体内测试和了解蠕虫样胶束的可能应用，我们建议靶向大鼠的人肺癌模型。肺是用于证明靶向递送的极好靶点，因为我们已经知道类似的基于PEG的共聚物结构在大鼠肺中没有显示积累。由于肺癌也占所有癌症死亡的1/3，80 - 90%的患者死于疾病，因此它是一个需要新方法的重大健康问题。蠕虫胶束可能会在新疗法中找到一席之地。无论如何，蠕虫胶束将教会我们生物运输，生物相容性和多价靶向长圆柱形物体在循环和进入细胞。

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.