Worm-like Micelles for Targeted Delivery and Imaging

描述（由申请人提供）：本R21的“开发和探索”目标侧重于由两亲性peg基嵌段共聚物制成的蠕虫状胶束。长和圆柱形蠕虫胶束是一种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，即使只有几微米长，它们也能“蠕动”穿过细小的毛孔，并循环数周。其次，目标蠕虫可以合作地与携带合适受体的表面或细胞紧密结合。第三，一旦结合，细胞的内化会导致一次运送相对大量的药物。聚合物蠕虫胶束稳定，但直径仅为纳米级。它们看起来与丝状噬菌体相似，丝状噬菌体已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%或更多的药理学制剂是疏水的，因此开发和探索可溶解这些制剂的新载体当然很重要。我们认为蠕虫胶束解决的一个基本药代动力学问题是：如果一个稳定但有弹性的圆柱形物体的分子尺度截面d< 30nm，那么它在体内的长度是多少？同样，长而圆柱形的物体可以被细胞整体或部分内化吗？目前的生物材料文献表明，颗粒半径远大于-100- 200nm将导致肝脏、脾脏等快速清除或飘浮。然而，我们在体内的初步结果令人惊讶地表明，几米长的蠕虫胶束可以在大鼠的血液中循环数周，超过了具有相似长度PEG的STEALTH脂质体的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PEG末端具有靶向配体的几微米长的蠕虫胶束将与细胞结合并被内化。使用合适比例的嵌段共聚物，如可生物降解的PEG-PLA或PEG-PCL，药物从这些胶束中释放将基于重新分配和载体分解的结合。为了初步的体内测试和深入了解蠕虫样胶束的可能应用，我们建议在大鼠中靶向人类肺癌模型。肺是证明靶向递送的一个极好的靶标，因为我们已经知道类似的PEG-based共聚物结构在大鼠肺中没有积累。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，以及在循环和进入细胞的长圆柱形物体的多价靶向。

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.