title: Rigidity of polymer micelles affects interactions with tumor cells.
abstract: Controlling the interaction of drug delivery systems (DDS) with tissues is critical for the success of therapies. Specifically in cancer, due to the high density of the tumors, tissue penetration of DDS is critical and may be challenging. In previous work we have shown that Solidified Polymer Micelles (SPMs) rapidly internalize into cells and tissues. Using AFM analysis, in the present work we measured differences in rigidity of SPM compared with Wet Polymer Micelles (WPM). We further examined whether the semi-solid form of hydrated SPMs has an effect on the interaction with tumor cells both in mono-layer systems and in multi-layer clusters of cells as spheroids. For that we have performed detailed characterization of SPM compared to WPM, including examinations of particle size, stability, drug release kinetics and cell transcytosis, in melanoma A-375 cells. Cell uptake measurements were done using fluorescent signal analysis, FACS and microscopy imaging, showing enhanced abilities of SPMs to penetrate cells and tissues. A simple physical model is presented that well agrees with the experiments and provides insight about the role of particle rigidity in the engulfment mechanism. We conclude that particle rigidity enhances cellular uptake and tissue penetration and that SPMs have a promising potential as an effective and highly permeable DDS. Our findings can be important in future rational design of DDS for particle adjustment to specific tissues and pathologies.
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Stern
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Inon
authors.initials: I
authors.lastname: Kaner
authors.affiliation: Institute of Chemistry, the Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Laser Zer
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Shoval
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Dvir
authors.initials: D
authors.lastname: Dror
authors.affiliation: The Hebrew University of Jerusalem, Core Research, Israel.
authors.forename: Zakhariya
authors.initials: Z
authors.lastname: Manevitch
authors.affiliation: Institute of Chemistry, the Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Liraz
authors.initials: L
authors.lastname: Chai
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Brill-Karniely
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: ofrab@ekmd.huji.ac.il.
authors.forename: Ofra
authors.initials: O
authors.lastname: Benny
mesh_terms: D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems; D055119:Elastic Modulus; D005089:Exocytosis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008823:Micelles; D009369:Neoplasms / Q000378:metabolism; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011092:Polyethylene Glycols