Vital microscopic analysis of polymeric micelle extravasation from tumor vessels: macromolecular delivery according to tumor vascular growth stage.
Particles larger than a specific size have been thought to extravasate from tumor vessels but not from normal vessels. Therefore, various nanoparticles incorporating anticancer drugs have been developed to realize selective drug delivery to solid tumors. However, it is not yet clear whether nanoparticles extravasate readily from all tumor vessels including vessels of microtumors. To answer this question, we synthesized new polymeric micelles labeled with fluorescein isothiocyanate (FITC) and injected them into the tail vein of rats with implanted skinfold transparent chambers. We also analyzed, by means of time-lapse vital microscopy with image analysis, extravasation of FITC micelles from tumor vessels at different stages of growth of Yoshida ascites sarcoma LY80. Polymeric micelles readily leaked from vessels at the interface between normal and tumor tissues and those at the interface between tumor tissues and necrotic areas. The micelles showed negligible extravasation, however, from the vascular network of microtumors less than 1 mm in diameter and did not accumulate in the microtumor. Our results suggest that we must develop a novel therapeutic strategy that can deliver sufficient nanomedicine to microtumors.
Hori
Katsuyoshi
K
Division of Cancer Control, Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan. k-hori@idac.tohoku.ac.jp
Nishihara
Masamichi
M
Yokoyama
Masayuki
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001224:Aspartic Acid / Q000737:chemistry; D001704:Biopolymers / Q000737:chemistry; D002199:Capillary Permeability / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000493:pharmacokinetics; D046911:Macromolecular Substances / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008823:Micelles; D008856:Microscopy, Fluorescence / Q000379:methods; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D011919:Rats, Inbred Strains; D012517:Sarcoma, Yoshida / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology
D000970:Antineoplastic Agents; D001704:Biopolymers; D046911:Macromolecular Substances; D008823:Micelles; C416210:poly(ethylene oxide)-block-poly(beta-benzyl aspartate); D001224:Aspartic Acid; D011092:Polyethylene Glycols; D016650:Fluorescein-5-isothiocyanate