title: A Multilayered Cell Culture Model for Transport Study in Solid Tumors: Evaluation of Tissue Penetration of Polyethyleneimine Based Cationic Micelles.
abstract: Limited drug distribution is partially responsible for the efficacy gap between preclinical and clinical studies of nano-sized drug carriers for cancer therapy. In this study, we examined the transport behavior of cationic micelles formed from a triblock copolymer of poly(D,L-lactide-co-glycolide)-block-branched polyethyleneimine-block-poly(D,L-lactide-co-glycolide) using a uniquein vitrotumor model composed of a multilayered cell culture (MCC) and an Ussing chamber system. The Cy3-labeled cationic micelles showed remarkable Cy3 distribution in the MCC whereas charge-shielded micelles with a poly(ethylene glycol) surface accumulated on the surface of the MCC. Penetration occurred against convectional flow caused by a hydraulic pressure gradient. The study using fluorescence resonance energy transfer (FRET) showed that the cationic micelles dissociate at the interface between the culture media and the MCC or possibly inside of the first-layer cells and penetrates into the MCC as unimers. The penetration and distribution were energy-dependent and suppressed by various endocytic inhibitors. These suggest that cationic unimers mainly utilized clathrin-mediated endocytosis and macropinocytosis for cellular entry and a significant fraction were exocytosed by an unknown mechanism.
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112, United States ; Fuji Research Laboratories, Pharmaceutical Division, Kowa Co. Ltd., 332-1 Ohnoshinden, Fuji, Shizuoka, Japan.
authors: Seiji
authors: S
authors: Miura
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112, United States ; Fuji Research Laboratories, Pharmaceutical Division, Kowa Co. Ltd., 332-1 Ohnoshinden, Fuji, Shizuoka, Japan.
authors: Hidenori
authors: H
authors: Suzuki
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112, United States.
authors: You Han
authors: YH
authors: Bae
keywords: cationic surface; endocytosis; intratumoral distribution; micelle; multilayered cell culture; penetration