title: Membrane Translocation and Organelle-Selective Delivery Steered by Polymeric Zwitterionic Nanospheres.
abstract: The majority of nanoparticles designed for cellular delivery of drugs and imaging agents enter the cell via endocytotic pathways leading to their entrapment in endosomes that present a robust barrier to further trafficking of the nanoparticles within the cells. A few materials, such as the cell penetrating peptides (CPPs), are known to enter cells not only via endocytosis, but also via translocation through the cell membrane into the cytoplasm, successfully bypassing the endosomes. We report here that random copolymers of 3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate and poly(ethylene glycol) methacrylate, p(DMAPS-ran-PEGMA), are internalized in cells primarily via translocation through the cell membrane rather than endocytosis. The properties of the polymers and their modes of uptake were investigated systematically by dynamic light scattering, confocal fluorescence microscopy, and flow cytometry. Using specific inhibitors of the cellular uptake machinery in a human cervical carcinoma cell line (HeLa), we show that these nontoxic synthetic polyzwitterions exist in cell media as self-assembled nanospheres that unravel as they adsorb on the plasma membrane and translocate through it. Conjugates of p(DMAPS-ran-PEGMA) with rhodamine B were delivered selectively to the mitochondria, whereas doxorubicin (Dox)-p(DMAPS-ran-PEGMA) conjugates were accumulated in both the nucleus and the mitochondria, effectively inducing apoptosis in HeLa cells. These findings suggest that the noncytotoxic and readily synthesized p(DMAPS-ran-PEGMA) can find applications as bioimaging tools and drug nanocarriers.
authors.affiliation: Department of Materials Processing, Graduate School of Engineering, Tohoku University , 6-6-02 Aramaki-aza Aoba, Aoba-ku, Sendai, 980-8579, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Morimoto
authors.affiliation: Department of Materials Processing, Graduate School of Engineering, Tohoku University , 6-6-02 Aramaki-aza Aoba, Aoba-ku, Sendai, 980-8579, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Wakamura
authors.affiliation: Department of Materials Processing, Graduate School of Engineering, Tohoku University , 6-6-02 Aramaki-aza Aoba, Aoba-ku, Sendai, 980-8579, Japan.
authors.forename: Kanna
authors.initials: K
authors.lastname: Muramatsu
authors.affiliation: Department of Chemistry and Faculty of Pharmacy, University of Montreal , CP6128 Succursale Center Ville, Montreal, QC H3C 3J7, Canada.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Toita
authors.affiliation: Frontier Research Institute for Interdisciplinary Sciences (FRIS), Tohoku University , Aramaki aza Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Frontier Research Institute for Interdisciplinary Sciences (FRIS), Tohoku University , Aramaki aza Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shoji
authors.affiliation: Department of Materials Processing, Graduate School of Engineering, Tohoku University , 6-6-02 Aramaki-aza Aoba, Aoba-ku, Sendai, 980-8579, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Chemistry and Faculty of Pharmacy, University of Montreal , CP6128 Succursale Center Ville, Montreal, QC H3C 3J7, Canada.|National Institute for Materials Science, WPI International Center for Materials Nanoarchitectonics (MANA), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
authors.forename: Françoise M
authors.initials: FM
authors.lastname: Winnik
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D016466:CHO Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D057846:Cell-Penetrating Peptides; D003412:Cricetulus; D004317:Doxorubicin / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry*; D000067493:Dynamic Light Scattering; D005434:Flow Cytometry; D018922:HL-60 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008689:Methacrylates / Q000737:chemistry / Q000378:metabolism*; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects; D054118:Nanospheres / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000378:metabolism*; D012235:Rhodamines / Q000378:metabolism*
chemical_list: C530265:3-dimethyl(methacryloyloxyethyl)ammonium propane sulfonate; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D008689:Methacrylates; D000644:Quaternary Ammonium Compounds; D012235:Rhodamines; C450003:poly(ethylene glycol) methacrylate polymer; D011092:Polyethylene Glycols; D004317:Doxorubicin; C029773:rhodamine B