title: Enhanced transcellular penetration and drug delivery by crosslinked polymeric micelles into pancreatic multicellular tumor spheroids.
abstract: Many attempts have been made in the application of multicellular tumor spheroids (MCTS) as a 3D tumor model to investigate their biological responses upon introduction of polymeric micelles as nanocarriers for therapeutic applications. However, the micelle penetration pathways in MCTS are not yet known. In this study, micelles (uncrosslinked, UCM) were prepared by self-assembly of block copolymer poly(N-(2-hydroxypropyl) methacrylamide-co-methacrylic acid)-block-poly(methyl methacrylate) (P(HPMA-co-MAA)-b-PMMA). Subsequently, the shells were crosslinked to form relatively stable micelles (CKM). Both UCM and CKM penetrated deeper and delivered more doxorubicin (DOX) into MCTS than the diffusion of the free DOX. Additionally, CKM revealed higher delivery efficiency than UCM. The inhibition of caveolae-mediated endocytosis, by Filipin treatment, decreased the uptake and penetration of the micelles into MCTS. Treatment with Exo1, an exocytosis inhibitor, produced the same effect. Furthermore, movement of the micelles through the extracellular matrices (ECM), as modelled using collagen micro-spheroids, appeared to be limited to the peripheral layer of the collagen spheroids. Those results indicate that penetration of P(HPMA-co-MAA)-b-PMMA micelles depended more on transcellular transport than on diffusion through ECM between the cells. DOX-loaded CKM inhibited MCTS growth more than their UCM counterpart, due to possible cessation of endocytosis and exocytosis in the apoptotic peripheral cells, caused by faster release of DOX from UCM.
authors.affiliation: Centre for Advanced Macromolecular Design, School of Chemistry, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia. M.Stenzel@unsw.edu.au.
authors.forename: Hongxu
authors.initials: H
authors.lastname: Lu
authors.forename: Robert H
authors.initials: RH
authors.lastname: Utama
authors.forename: Uraiphan
authors.initials: U
authors.lastname: Kitiyotsawat
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Babiuch
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Martina H
authors.initials: MH
authors.lastname: Stenzel
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D050416:Glucagon-Secreting Cells / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008689:Methacrylates / Q000737:chemistry*; D008823:Micelles; D009369:Neoplasms; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000178:Acrylamides; D004337:Drug Carriers; D008689:Methacrylates; D008823:Micelles; D011108:Polymers; C008384:methacrylic acid; D011092:Polyethylene Glycols; C045985:methacrylamide