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. ? ?
