Flexible filaments for in vivo imaging and delivery: persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage.
Shape effects of synthetic carriers are largely unexplored in vivo, although recent findings suggest that flexible filaments can persist in the circulation even if microns in length. Here, to better assess biodistribution, a near-infrared fluorophore (NIRF) was incorporated into such block copolymer "filomicelles", and both in vivo and ex vivo imaging show that the majority of these wormlike micelles remain in the circulation for at least a day after intravenous injection. NIRF imaging further suggests that filomicelles convect into a tumor and some fragments can penetrate into the tumor stroma. To assess a functional effect, the hydrophobic drug paclitaxel (tax) was loaded into both filomicelles and sonication-generated spherical micelles of the same copolymer. Intravenous injection of tax-loaded filomicelles nearly doubles the maximum tolerated dose of tax in normal mice compared to tax-loaded spherical micelles. In tumor-bearing mice, the higher dose of tax produces greater and more sustained tumor shrinkage and tumor cell apoptosis. These results thus begin to address mechanisms for how nonspherical carriers deliver both imaging agents and anticancer therapeutics to solid tumors.
Christian
David A
DA
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cai
Shenshen
S
Garbuzenko
Olga B
OB
Harada
Takamasa
T
Zajac
Allison L
AL
Minko
Tamara
T
Discher
Dennis E
DE
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D008856:Microscopy, Fluorescence; D049329:Nanostructures / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D005456:Fluorescent Dyes; D008823:Micelles; D017239:Paclitaxel