Co-reporter:Xiaojie Li, Yasuo Watanabe, Eiji Yuba, Atsushi Harada, Takeharu Haino and Kenji Kono
Chemical Communications 2015 vol. 51(Issue 14) pp:2851-2854
Publication Date(Web):05 Jan 2015
DOI:10.1039/C4CC09082A
Well-defined fullerene–dendrimer supramolecular nanocomposites exhibiting uniform size, controlled morphology, high fullerene inclusion efficiency, excellent water solubility, and non-toxicity were facilely fabricated through complexation of carboxyfullerenes with poly(ethylene glycol)-modified poly(amidoamine) dendrimers.
Co-reporter:Kenji Kono, Munenobu Takashima, Eiji Yuba, Atsushi Harada, Yoshie Hiramatsu, Hiroyuki Kitagawa, Takayuki Otani, Kazuo Maruyama, Sadahito Aoshima
Journal of Controlled Release 2015 Volume 216() pp:69-77
Publication Date(Web):28 October 2015
DOI:10.1016/j.jconrel.2015.08.005
We designed functional liposomes with target specificity, temperature-triggered drug release, and near-infrared fluorescence imaging. We prepared the liposomes by triple functionalization of stable pegylated liposomes with thermosensitive poly[2-(2-ethoxy)ethoxyethyl vinyl ether] chains (lower critical solution temperature around 38 °C) with conjugation of antibody trastuzumab (Herceptin, HER), which targets human epidermal growth factor 2, and with incorporation of indocyanine green for near-infrared fluorescence imaging. The liposomes retained DOX in the interior below physiological temperature but released DOX immediately at temperatures higher than 40 °C. The liposomes exhibited excellent ability for association and internalization to target cells overexpressing Her-2, such as SK-OV3 and SB-BR3 cells, and killed these cells when heated at 45 °C for 5 min. When administered intravenously to mice bearing SK-OV3 tumor, the liposomes having HER accumulated in the tumor more efficiently than the liposomes without HER. They stayed there more than 48 h, as judged with near-infrared fluorescence imaging. Furthermore, when the tumor sites of the mice being administered with the DOX-loaded liposomes were heated mildly at 44 °C for 10 min at 7 h after administration, tumor growth was suppressed strongly thereafter. Treatment with the HER-conjugated liposomes produced more efficient tumor-suppressive effects. Results demonstrate that the synergy of target-specific association, temperature-triggered drug release, and imaging is important for efficient tumor chemotherapy.
Co-reporter:Tomohiro Doura, Megumi Yamada, Ryoma Teranishi, Yuhei Yamamoto, Takumi Sugimoto, Eiji Yuba, Atsushi Harada, and Kenji Kono
Langmuir 2015 Volume 31(Issue 18) pp:5105-5114
Publication Date(Web):April 21, 2015
DOI:10.1021/acs.langmuir.5b00183
Dendron lipids designed to consist of amine-terminated polyamidoamine G1 dendron and two octadecyl chains were used for the preparation of pH-responsive molecular assemblies having phase structures that are changed through their dynamic molecular shape. The dendron lipid contains two primary amines and two tertiary amines in the dendron moiety, changing its charged state in the pH region between pH 10 and pH 4. The assemblies were shown to take a vesicle structure at neutral and alkaline pHs, but their structure changed to a micelle-like structure below pH 6.4. Because this pH region corresponds to one in which tertiary amines of the dendron lipid became protonated, protonation of tertiary amines in addition to primary amines in the dendron moiety might affect its dynamic molecular shape, resulting in a sharp pH response of the assemblies. The assemblies tended to form aggregates when taking on a vesicle form with a gel phase, but incorporation of a poly(ethylene glycol)–lipid provided dendron lipid vesicles with both sharp pH response and high colloidal stability. The poly(ethylene glycol)-incorporated dendron lipid vesicles tightly retained ovalbumin molecules in their internal aqueous space but released them almost completely at pH 6.0. In addition, the vesicles were shown to achieve efficient ovalbumin delivery into cytosol of DC2.4 cells (mouse dendritic cell line) after internalization through endocytosis.
Co-reporter:Xiaojie Li, Keishi Takeda, Eiji Yuba, Atsushi Harada and Kenji Kono
Journal of Materials Chemistry A 2014 vol. 2(Issue 26) pp:4167-4176
Publication Date(Web):25 Apr 2014
DOI:10.1039/C4TB00132J
This study was conducted to attempt development of a new type of hybrid dendrimer consisting of a gold nanorod (GNR) core and PEG-modified PAMAM (PEG-PAMAM) dendrons by adding PEG-PAMAM G2–G4 dendrimers with a cystamine core at various timings during the GNR growing reaction. We obtained hybrids of the dendrimers and GNRs exhibiting surface plasmon resonance in the near infrared region. Whereas the PEG-PAMAM G4 dendrimer–GNR hybrid formed an aggregate in an aqueous solution, PEG-PAMAM G2 and G3 dendrimers respectively gave hybrids with average diameters of 24 nm and 31 nm. Especially, the spherical PEG-PAMAM G3 dendrimer–GNR hybrid might be regarded as a GNR-cored PEG-PAMAM dendrimer in which the GNR core was well stabilized by highly hydrated PEG-PAMAM G3 dendrons. The GNR-cored PEG-PAMAM G3 dendrimer exhibited excellent heat-generation capability under near-infrared light irradiation. Incubation with the GNR-cored PEG-PAMAM G3 dendrimer showed no damage to HeLa cells. However, dendrimer-treated cells were killed effectively by near-infrared laser irradiation, indicating excellent photothermal capability of the GNR-cored PEG-PAMAM G3 dendrimer. Furthermore, the GNR-cored PEG-PAMAM G3 dendrimer injected into mice tumor tissues significantly increased the temperature of the tumor when irradiated with near infrared light, resulting in a decreased tumor volume. These results demonstrate that GNR-cored PEG-PAMAM dendrimers might be a new nanomaterial for biomedical applications such as photothermal therapy.
Co-reporter:Kenji Kono, Keishi Takeda, Xiaojie Li, Eiji Yuba, Atsushi Harada, Tomoatsu Ozaki and Shigeo Mori
RSC Advances 2014 vol. 4(Issue 53) pp:27811-27819
Publication Date(Web):10 Jun 2014
DOI:10.1039/C4RA03947E
Stimuli-sensitive dendrimers of a new type were developed through dual functionalization of polyamidoamine (PAMAM) dendrimers with temperature-sensitive surface modification using propoxy diethylene glycol (PDEG) and Au nanoparticle (AuNP) loading. These AuNP-hybridized dendrimers were prepared by attaching PDEG to amine-terminated PAMAM G5 dendrimer using 4-nitrophenylchloroformate and subsequent loading of AuNPs into the dendrimer interior via reduction of AuCl4− ions with NaBH4 in the dendrimer interior. Transmission electron microscopy showed that AuNPs with diameters of about 2 nm were retained in the PDEG-modified dendrimers. These AuNP-loaded dendrimers were dissolved in aqueous solutions at low temperature but became water-insoluble above a specific temperature, because of the character change of the dendrimer surface from hydrophilic to hydrophobic depending on temperature. The AuNPs in the dendrimer interior generated heat under irradiation by a green laser and hence, their association could be induced in the specific area irradiated with the green laser. In addition, the combination of the temperature increase and light irradiation was shown to control their interaction with cells, enabling selective cell killing by the AuNP-hybridized temperature-sensitive dendrimers.
Co-reporter:Eiji Yuba, Naoki Tajima, Yuta Yoshizaki, Atsushi Harada, Hiroshi Hayashi, Kenji Kono
Biomaterials 2014 35(9) pp: 3091-3101
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.12.024
Co-reporter:Yuta Yoshizaki, Eiji Yuba, Naoki Sakaguchi, Kazunori Koiwai, Atsushi Harada, Kenji Kono
Biomaterials 2014 35(28) pp: 8186-8196
Publication Date(Web):
DOI:10.1016/j.biomaterials.2014.05.077
Co-reporter:Xiaojie Li, Munenobu Takashima, Eiji Yuba, Atsushi Harada, Kenji Kono
Biomaterials 2014 35(24) pp: 6576-6584
Publication Date(Web):
DOI:10.1016/j.biomaterials.2014.04.043
Co-reporter:Xiaojie Li, Yasuhiro Haba, Kanako Ochi, Eiji Yuba, Atsushi Harada, and Kenji Kono
Bioconjugate Chemistry 2013 Volume 24(Issue 2) pp:282
Publication Date(Web):January 8, 2013
DOI:10.1021/bc300190v
A novel type of temperature-sensitive dendrimer was synthesized using one-step terminal modification of polyamidoamine dendrimers (PAMAM) with various alkoxy diethylene glycols such as methoxy diethylene glycol, ethoxy diethylene glycol, and propoxy diethylene glycol. The obtained dendrimers exhibited tunable lower critical solution temperature (LCST), depending on PAMAM generation and terminal alkoxy groups. These dendrimers were shown to be taken up by HeLa cells through endocytosis and were trapped in intracellular compartments such as endosomes and lysosomes. Cellular uptake of the dendrimers was enhanced by increasing their incubation temperature above the LCST. In addition, the in vitro cytotoxicity of temperature-sensitive dendrimers at incubation temperatures below and above LCST was much lower than that of their parent PAMAM dendrimers. Results indicate that the dendrimers with oxyethylene unit-enriched surface might be promising to construct intelligent drug delivery systems.
Co-reporter:Eiji Yuba, Atsushi Harada, Yuichi Sakanishi, Shinobu Watarai, Kenji Kono
Biomaterials 2013 34(12) pp: 3042-3052
Publication Date(Web):
DOI:10.1016/j.biomaterials.2012.12.031
Co-reporter:Eiji Yuba, Yoshikazu Kono, Atsushi Harada, Shoichi Yokoyama, Masaya Arai, Kazuhiro Kubo, Kenji Kono
Biomaterials 2013 34(22) pp: 5711-5721
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.04.007
Co-reporter:Kenji Kono, Ryuji Ikeda, Kota Tsukamoto, Eiji Yuba, Chie Kojima, and Atsushi Harada
Bioconjugate Chemistry 2012 Volume 23(Issue 4) pp:871
Publication Date(Web):February 29, 2012
DOI:10.1021/bc200368b
Recently, we demonstrated that octadecyl chains are important as alkyl chain moieties of polyamidoamine (PAMAM) dendron-bearing lipids for their serum-resistant transfection activity [Bioconjugate Chem.2007, 18, 1349–1354]. Toward production of highly potent vectors, we examined the influence of the generation of dendron moiety on transfection activity of PAMAM dendron-bearing lipids having two octadecyl chains. We synthesized dendron-bearing lipids with PAMAM G1, G2, and G3 dendrons, designated respectively as DL-G1–2C18, DL-G2–2C18, and DL-G3–2C18. The DL-G2–2C18 and DL-G3–2C18 interacted with plasmid DNA effectively and formed stable lipoplexes with small sizes and spherical shape. However, DL-G1–2C18 interacted with plasmid DNA less effectively and formed tubular-shaped lipoplexes with lower stability and larger size. Cells took up DL-G2–2C18 and DL-G3–2C18 lipoplexes efficiently, but cellular uptake of the DL-G1–2C18 lipoplexes was less efficient. Nevertheless, DL-G1–2C18 lipoplexes achieved 100–10 000 times higher levels of transgene expression, which was evaluated using luciferase gene as a reporter gene. Confocal scanning laser microscopic analysis of intracellular behaviors of the lipoplexes revealed that DL-G1–2C18 lipoplexes generated free plasmid DNA molecules in the cytosol more effectively than other lipoplexes did. Moderate binding ability of DL-G1–2C18 might be responsible for generation of lipoplexes which deliver plasmid DNA into cells, liberate it in the cytoplasm, and induce efficient transgene expression.
Co-reporter:Kenji Kono
Polymer Journal 2012 44(6) pp:531-540
Publication Date(Web):April 18, 2012
DOI:10.1038/pj.2012.39
Because of their highly defined chemical structure and globular shape, dendrimers are very attractive as base materials to be used in the production of nanomaterials for applications in various fields. Therefore, many attempts have been made to develop functional materials using dendrimers. This review specifically examines dendrimer-based nanomaterials intended for application to the biomedical field. The design, preparation and function of bionanomaterials, using various strategies such as surface modification, assembly and hybrid formation, are described briefly along with their potential applications.
Co-reporter:Eiji Yuba, Atsushi Harada, Yuichi Sakanishi, Kenji Kono
Journal of Controlled Release 2011 Volume 149(Issue 1) pp:72-80
Publication Date(Web):5 January 2011
DOI:10.1016/j.jconrel.2010.03.001
Previous reports by the authors described intracellular delivery using liposomes modified with various carboxylated poly(glycidol) derivatives. These linear polymer-modified liposomes exhibited a pH-dependent membrane fusion behavior in cellular acidic compartments. However, the effect of the backbone structure on membrane fusion activity remains unknown. Therefore, this study specifically investigated the backbone structure to obtain pH-sensitive polymers with much higher fusogenic activity and to reveal the effect of the polymer backbone structure on the interaction with the membrane. Hyperbranched poly(glycidol) (HPG) derivatives were prepared as a new type of pH-sensitive polymer and used for the modification of liposomes. The resultant HPG derivatives exhibited high hydrophobicity and intensive interaction with the membrane concomitantly with the increasing degree of polymerization (DP). Furthermore, HPG derivatives showed a stronger interaction with the membrane than the linear polymers show. Liposomes modified with HPG derivatives of high DP delivered contents into the cytosol of DC2.4 cells, a dendritic cell line, more effectively than the linear polymer-modified liposomes do. Results show that the backbone structure of pH-sensitive polymers affected their pH-sensitivity and interaction with liposomal and cellular membranes.
Co-reporter:Tomohiro Kaiden, Eiji Yuba, Atsushi Harada, Yuichi Sakanishi, and Kenji Kono
Bioconjugate Chemistry 2011 Volume 22(Issue 10) pp:1909
Publication Date(Web):August 23, 2011
DOI:10.1021/bc2000353
For production of a new type of functional liposome whose destabilization can be triggered by a combination of a temperature signal and acidic pH signal, we prepared liposomes modified with hyperbranched poly(glycidol) derivatives having N-isopropylamide and carboxyl groups. HeLa cells incubated with the dual signal-responsive liposomes encapsulating a water-soluble fluorescent dye pyranine at 28 °C displayed punctate fluorescence of pyranine, indicating that the liposomes were trapped in endosome. However, after heating at 45 °C for 15 min, the same cells exhibited diffuse fluorescence of pyranine, indicating that destabilization of the liposomes in endosome with an acidic environment in combination with the brief heating caused efficient transfer of the contents into cytosol. The dual signal-responsive liposomes might have usefulness for site-specific delivery of membrane-impermeable molecules, which exhibit bioactivities in the intracellular spaces, such as siRNA and proteins.
Co-reporter:Kenji Kono, Seiji Nakashima, Daisuke Kokuryo, Ichio Aoki, Hiroaki Shimomoto, Sadahito Aoshima, Kazuo Maruyama, Eiji Yuba, Chie Kojima, Atsushi Harada, Yukihito Ishizaka
Biomaterials 2011 32(5) pp: 1387-1395
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.10.050
Co-reporter:Dr. Kenji Kono;Etsuo Murakami;Yuki Hiranaka;Dr. Eiji Yuba;Dr. Chie Kojima;Dr. Atsushi Harada;Dr. Kazuo Sakurai
Angewandte Chemie 2011 Volume 123( Issue 28) pp:6456-6460
Publication Date(Web):
DOI:10.1002/ange.201101007
Co-reporter:Dr. Kenji Kono;Etsuo Murakami;Yuki Hiranaka;Dr. Eiji Yuba;Dr. Chie Kojima;Dr. Atsushi Harada;Dr. Kazuo Sakurai
Angewandte Chemie International Edition 2011 Volume 50( Issue 28) pp:6332-6336
Publication Date(Web):
DOI:10.1002/anie.201101007
Co-reporter:Yasuhito Umeda, Chie Kojima, Atsushi Harada, Hiromichi Horinaka and Kenji Kono
Bioconjugate Chemistry 2010 Volume 21(Issue 8) pp:1559
Publication Date(Web):July 28, 2010
DOI:10.1021/bc1001399
Recently, we demonstrated that loading of HAuCl4 in poly(ethylene glycol) (PEG)-attached poly(amidoamine) (PAMAM) G4 dendrimers and subsequent reduction with NaBH4 yield dendrimers encapsulating gold nanoparticles (Au NPs), which have photoinduced heat-generating properties. This study was undertaken to enhance photothermal properties of the Au NP-incorporated PEG-attached dendrimers by growing Au NPs in the dendrimers. Repeated loading of HAuCl4 in the PEG-attached dendrimers and subsequent reduction with NaBH4 enhanced the surface plasmon resonance, indicating that Au NPs were grown in the PEG-attached dendrimers using that procedure. Transmission electron microscopy (TEM) analysis revealed that the size of Au NPs formed in the dendrimers increased with the number of repetitions of HAuCl4 loading and subsequent reduction in the dendrimers, although the size distribution of the Au NPs remained narrow. The photoinduced-heat generation capability of the Au NPs-encapsulating dendrimers increased as the Au NPs grew. These dendrimers with Au NPs exhibited strong cytotoxicity against HeLa cells under visible light irradiation. The result demonstrates that PEG-attached dendrimers encapsulating the grown Au NPs might be useful as devices for target-specific therapy when used with light irradiation.
Co-reporter:Eiji Yuba, Chie Kojima, Atsushi Harada, Tana, Shinobu Watarai, Kenji Kono
Biomaterials 2010 31(5) pp: 943-951
Publication Date(Web):
DOI:10.1016/j.biomaterials.2009.10.006
Co-reporter:Kenji Kono, Toshiaki Ozawa, Tomohide Yoshida, Fuminori Ozaki, Yukihito Ishizaka, Kazuo Maruyama, Chie Kojima, Atsushi Harada, Sadahito Aoshima
Biomaterials 2010 31(27) pp: 7096-7105
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.05.045
Co-reporter:Chie Kojima ; Sayako Tsumura ; Atsushi Harada
Journal of the American Chemical Society 2009 Volume 131(Issue 17) pp:6052-6053
Publication Date(Web):April 8, 2009
DOI:10.1021/ja809639c
A collagen model peptide-attached dendrimer was synthesized as a potential functional collagen material. The peptides that clustered at the surface of the dendrimer formed a thermally reversible collagen-like triple helix. This dendrimer worked as a drug carrier with thermosensitive release capabilities, although it did not exhibit a lower critical solution temperature. From this dendrimer, the hydrogel could be made at low temperature.
Co-reporter:Chie Kojima, Kohei Yoshimura, Atsushi Harada, Yuichi Sakanishi and Kenji Kono
Bioconjugate Chemistry 2009 Volume 20(Issue 5) pp:1054
Publication Date(Web):April 24, 2009
DOI:10.1021/bc900016x
Hyperbranched poly(glycidol)s with varying degrees of polymerization were modified by reaction with succinic anhydride and isopropylamine to obtain novel pH- and thermosensitive polymers. These polymers exhibited phase transitions in response to decreasing pH and/or increasing temperature, depending on the degree of polymerization and the ratio of succinyl group to N-isopropylamide. It was possible to harvest a bioactive molecule, rose bengal, from solution using the phase transition of thermosensitive hyperbranched poly(glycidol).
Co-reporter:Toshinari Takahashi;Eiji Yuba;Chie Kojima
Research on Chemical Intermediates 2009 Volume 35( Issue 8-9) pp:
Publication Date(Web):2009 November
DOI:10.1007/s11164-009-0083-z
We have so far developed a new type of cationic lipid that consists of an amine-terminated poly(amidoamine) dendron and two long alkyl chains. In this study, we designed a dendron-bearing lipid (DL) modified with sugar moieties as the ligand at the terminal groups of the dendron to improve the transfection activities. We combined lactobionic acid at the end of every dendritic branch of the DL to produce galactose moieties-attached DL (Gal-DL). The lipoplexes containing Gal-DL exhibited enhancement of transfection of HepG2 cells. Moreover, Gal-DL significantly promoted the transfection activity of the lipoplexes including poly(ethylene glycol)-attached dendron-bearing lipid (PEG-DL).
Co-reporter:Eiji Yuba, Chie Kojima, Naoki Sakaguchi, Atsushi Harada, Kazunori Koiwai, Kenji Kono
Journal of Controlled Release 2008 Volume 130(Issue 1) pp:77-83
Publication Date(Web):25 August 2008
DOI:10.1016/j.jconrel.2008.05.007
Dendritic cells (DCs) are potent professional antigen presenting cells that are useful for cancer immunotherapy. We previously reported the preparation and characterization of complexes of lipoplexes with pH-sensitive fusogenic liposomes, which comprise polymers based on poly(glycidol) with carboxyl groups, to transfect various malignant cell lines. The present study applied this kind of vectors to transfection of a murine DC line DC2.4. We first optimized the ratios of their components for efficient transfection. We subsequently investigated the effects of ligands and pH-sensitive polymers to improve transfection activities. Our results indicate that the anionic surface derived from pH-sensitive polymers might be recognized by scavenger receptors on DC2.4 cells. In addition, no effects on transfection or cell association were observed by attaching ligands such as transferrin and mannan. We found that more sensitive pH-responding polymers led to higher transfection activities into DC2.4 cells, which suggest that endosomal escape is important for transfection into DC2.4 cells. These complexes with pH-sensitive fusogenic polymers exhibited higher transfection activity toward DC2.4 cells than some commercial reagents and hence may be useful as a gene vector for DCs.
Co-reporter:Naoki Sakaguchi, Chie Kojima, Atsushi Harada and Kenji Kono
Bioconjugate Chemistry 2008 Volume 19(Issue 5) pp:1040
Publication Date(Web):April 18, 2008
DOI:10.1021/bc7004736
We have previously shown that modification with succinylated poly(glycidol) (SucPG) provides stable egg yolk phosphatidylcholine (EYPC) liposomes with pH-sensitive fusogenic property. Toward production of efficient pH-sensitive liposomes, in this study, we newly prepared three carboxylated poly(glycidol) derivatives with varying hydrophobicities by reacting poly(glycidol) with glutaric anhydride, 3-methylglutaric anhydride, and 1,2-cyclohexanedicarboxylic anhydride, respectively, designated as GluPG, MGluPG, and CHexPG. Correlation between side-chain structures of these polymers and their respective abilities to sensitize stable liposomes to pH was investigated. These polymers are soluble in water at neutral pH but became water-insoluble in weakly acidic conditions. The pH at which the polymer precipitated was higher in the order SucPG < GluPG < MGluPG < CHexPG, which is consistent with the number of carbon atoms of these polymers’ side chains. Although CHexPG destabilized EYPC liposomes even at neutral pH, attachment of other polymers provided pH-sensitive properties to the liposomes. The liposomes bearing polymers with higher hydrophobicity exhibited more intense responses, such as content release and membrane fusion, at mildly acidic pH and achieved more efficient cytoplasmic delivery of membrane-impermeable dye molecules. As a result, modification with appropriate hydrophobicity, MGluPG, produced highly potent pH-sensitive liposomes, which might be useful for efficient cytoplasmic delivery of bioactive molecules, such as proteins and genes.
Co-reporter:Naoki Sakaguchi, Chie Kojima, Atsushi Harada, Kazunori Koiwai, Nobuhiko Emi and Kenji Kono
Bioconjugate Chemistry 2008 Volume 19(Issue 8) pp:1588
Publication Date(Web):July 16, 2008
DOI:10.1021/bc800126s
We previously developed potent nonviral vectors based on complexation of lipoplexes and pH-sensitive fusogenic liposomes, which achieve efficient transfection through membrane fusion with intracellular acidic compartments such as endosomes. Because transferrin receptor is known to be overexpressed in cancer cells, in this study, we investigated the effect of transferrin as a ligand for transfection of various cancer-derived cell lines mediated by the liposome−lipoplex hybrid complexes. Results showed that these hybrid complexes with transferrin exhibited higher transfection efficiency toward these cells than complexes without transferrin, but the extent of the transferrin-induced enhancement was dependent on the cell line. Conjugation of transferrin increased their transfection activity for HeLa and KB cells, although it only slightly enhanced transfection for HT1080, HepG2, and K562. Transferrin receptors in HT1080, HepG2, and K562 cells were internalized slowly, whereas those in HeLa and KB cells were internalized quickly and actively. These results indicate that transfection mediated by the ligand-attached hybrid complex does not correlate with the amount of transferrin receptor in the cell surface but correlate with the activity of internalization of transferrin receptor into the cells.
Co-reporter:Chie Kojima, Yoko Toi, Atsushi Harada and Kenji Kono
Bioconjugate Chemistry 2008 Volume 19(Issue 11) pp:2280
Publication Date(Web):October 10, 2008
DOI:10.1021/bc8001503
Fullerene has a unique structure and notable chemical and physical properties, which have been studied in diverse fields including biological applications. The extremely poor solubility of fullerenes in water limits their usage for biomedical applications. In this study, we synthesized polyamidoamine dendrimers having both β-cyclodextrin (CD) and poly(ethylene glycol) (PEG) and characterized the resulting dendrimers by 1H NMR, IR, and gel permeation chromatography. We prepared 2.8 μM of aqueous fullerene solutions using these dendrimers. The clustering effect of CD and PEG at the surface of the dendrimer might be crucial for the solubilization of fullerene.
Co-reporter:Kenji Kono, Chie Kojima, Nobuyuki Hayashi, Eiko Nishisaka, Katsuyuki Kiura, Shinobu Watarai, Atsushi Harada
Biomaterials 2008 Volume 29(Issue 11) pp:1664-1675
Publication Date(Web):April 2008
DOI:10.1016/j.biomaterials.2007.12.017
We have developed poly(amidoamine) (PAMAM) dendrimers that have poly(ethylene glycol) (PEG) grafts at all dendrimer chain ends. To obtain PEG-modified dendrimers with sites for conjugation of anticancer drugs for this study, we prepared PAMAM G4 dendrimers that have a glutamic acid (Glu) residue at every chain end of dendrimer; PEG chains were attached to amino groups of Glu residues. We then combined the anticancer drug adriamycin to side chains of the Glu residues using an amide bond, [PEG–Glu(ADR)-G4], or hydrazone bond, [PEG–Glu(NHN–ADR)-G4]. For the dendrimers bearing adriamycin through amide linkage, adriamycin was released only slightly at pH 7.4 and 5.5. Although a negligible level of release occurred at pH 7.4 for dendrimers with adriamycin via hydrazone linkage, a remarkable extent of adriamycin release was induced at pH 5.5, which corresponds to the pH of late endosome. These adriamycin-bearing dendrimers showed much lower toxicity to HeLa cells than did free adriamycin. However, compared to PEG–Glu(ADR)-G4, PEG–Glu(NHN–ADR)-G4 exhibited 7 times higher cytotoxicity, suggesting the importance of pH-sensitive hydrazone linkage for high cytotoxicity. Furthermore, the PEG-modified dendrimers exhibited an equivalent level of toxicity to that of adriamycin-resistant SBC-3/ADR100 cells and their parent adriamycin-sensitive SBC-3 cells.
Co-reporter:Naoki Sakaguchi, Chie Kojima, Atsushi Harada, Kazunori Koiwai, Kazuhiro Shimizu, Nobuhiko Emi, Kenji Kono
Biomaterials 2008 Volume 29(Issue 9) pp:1262-1272
Publication Date(Web):March 2008
DOI:10.1016/j.biomaterials.2007.11.016
We reported previously that complexation of lipoplexes containing 3,5-dipentadecyloxybenzamidine (TRX-20) and transferrin-bearing succinylated poly(glycidol) (SucPG)-modified liposome, which becomes fusogenic under weakly acidic conditions, might produce gene carriers with high transfection activity. For the present study, we prepared the lipoplex–SucPG-modified liposome complexes by mixing them either in phosphate-buffered saline or in an aqueous 5% glucose solution. The complexes prepared in phosphate-buffered saline have large particles of more than 800 nm, whereas the complexes prepared in the glucose solution were remarkably small: 200–300 nm. The small complexes were taken up more effectively by HeLa cells, and their transfection was induced more efficiently than the large complexes'. In addition, the small complexes achieved cellular transfection more efficiently in the presence of serum than in the absence of serum, without marked cytotoxicity. Considering that their affinity to the cell is based on ligand–receptor interaction, the small complexes are highly promising as a safe vector with high transfection activity and high target cell specificity.
Co-reporter:Yasuhiro Haba;Chie Kojima Dr.;Atsushi Harada Dr. Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 1‐2) pp:
Publication Date(Web):24 NOV 2006
DOI:10.1002/anie.200603346
The sensitive type: A lower critical solution temperature (LCST) is observed for dendrimers with N-isopropylamide (NIPAM) groups at all chain terminals and for poly(N-isopropylacrylamide) (PNIPAAm; see picture). A much smaller endothermic peak occurs around the LCST for NIPAM-terminated dendrimers. The globular structure of the dendrimers may cause inefficient hydration and dehydration around NIPAM groups below and above the LCST, respectively.
Co-reporter:Yasuhiro Haba;Chie Kojima Dr.;Atsushi Harada Dr. Dr.
Angewandte Chemie 2007 Volume 119(Issue 1‐2) pp:
Publication Date(Web):24 NOV 2006
DOI:10.1002/ange.200603346
Vermischtes: Eine untere kritische Mischungstemperatur (LCST) wird bei Dendrimeren mit N-Isopropylamid(NIPAM)-Gruppen an allen Kettenenden sowie bei Poly(N-isopropylacrylamid) (PNIPAAm) beobachtet (siehe Bild). Ein viel kleinerer endothermer Peak tritt bei NIPAM-terminierten Dendrimeren um die LCST auf. Die kugelförmige Struktur der Dendrimere könnte eine ineffiziente Hydratisierung und Dehydratisierung um die NIPAM-Gruppen herum unter bzw. über der LCST bewirken.
Co-reporter:Kazuhiro Kawakami;Keiji Morimoto;Toru Takagishi
Journal of Applied Polymer Science 1999 Volume 72(Issue 13) pp:1763-1773
Publication Date(Web):13 APR 1999
DOI:10.1002/(SICI)1097-4628(19990624)72:13<1763::AID-APP12>3.0.CO;2-N
Copolymers of acrylic acid and styrene with styrene unit contents of 2.7, 5.7, and 9.5% were synthesized by free radical copolymerization. Poly(ethylenimine)s with benzylated unit contents of 2.4, 6.0, 10.6, and 16.7% were obtained by the reaction of poly(ethylenimine) with benzyl bromide. Polyelectrolyte complex capsules consisting of these polymers were prepared. Influence of the hydrophobic units on pH-responsive release property of the capsules was studied using phenylethylene glycol as a permeant. When the copolymer with styrene unit content of 5.7% or the poly(ethylenimine) with the benzylated unit content of 2.4–10.6% was used as the membrane components, the permeability of the capsule membrane became minimum and was 10–20 fold lower than that of the poly(acrylic acid)–poly(ethylenimine) complex capsule membrane in the pH region between 3 and 7. In contrast, the hydrophobic units did not lower the permeability of the capsule membranes significantly below pH 3 and above pH 7. Thus, the capsule membranes containing hydrophobic units exhibited remarkable permeability changes in the narrow pH regions of 2–3 and 7–9. Also, the capsule containing the benzylated PEI in the membrane changed the release rate of the contents very quickly, in response to the ambient pH alteration. Therefore, polyelectrolyte complex capsules, which are highly sensitive to pH change, were obtained by using the polyelectrolytes with the hydrophobic units as membrane components. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 72: 1763–1773, 1999
Co-reporter:Xiaojie Li, Yasuo Watanabe, Eiji Yuba, Atsushi Harada, Takeharu Haino and Kenji Kono
Chemical Communications 2015 - vol. 51(Issue 14) pp:NaN2854-2854
Publication Date(Web):2015/01/05
DOI:10.1039/C4CC09082A
Well-defined fullerene–dendrimer supramolecular nanocomposites exhibiting uniform size, controlled morphology, high fullerene inclusion efficiency, excellent water solubility, and non-toxicity were facilely fabricated through complexation of carboxyfullerenes with poly(ethylene glycol)-modified poly(amidoamine) dendrimers.
Co-reporter:Xiaojie Li, Keishi Takeda, Eiji Yuba, Atsushi Harada and Kenji Kono
Journal of Materials Chemistry A 2014 - vol. 2(Issue 26) pp:NaN4176-4176
Publication Date(Web):2014/04/25
DOI:10.1039/C4TB00132J
This study was conducted to attempt development of a new type of hybrid dendrimer consisting of a gold nanorod (GNR) core and PEG-modified PAMAM (PEG-PAMAM) dendrons by adding PEG-PAMAM G2–G4 dendrimers with a cystamine core at various timings during the GNR growing reaction. We obtained hybrids of the dendrimers and GNRs exhibiting surface plasmon resonance in the near infrared region. Whereas the PEG-PAMAM G4 dendrimer–GNR hybrid formed an aggregate in an aqueous solution, PEG-PAMAM G2 and G3 dendrimers respectively gave hybrids with average diameters of 24 nm and 31 nm. Especially, the spherical PEG-PAMAM G3 dendrimer–GNR hybrid might be regarded as a GNR-cored PEG-PAMAM dendrimer in which the GNR core was well stabilized by highly hydrated PEG-PAMAM G3 dendrons. The GNR-cored PEG-PAMAM G3 dendrimer exhibited excellent heat-generation capability under near-infrared light irradiation. Incubation with the GNR-cored PEG-PAMAM G3 dendrimer showed no damage to HeLa cells. However, dendrimer-treated cells were killed effectively by near-infrared laser irradiation, indicating excellent photothermal capability of the GNR-cored PEG-PAMAM G3 dendrimer. Furthermore, the GNR-cored PEG-PAMAM G3 dendrimer injected into mice tumor tissues significantly increased the temperature of the tumor when irradiated with near infrared light, resulting in a decreased tumor volume. These results demonstrate that GNR-cored PEG-PAMAM dendrimers might be a new nanomaterial for biomedical applications such as photothermal therapy.
![9-Octadecenoic acid(9Z)-, 1,1'-[1-[[[(2-aminoethoxy)hydroxyphosphinyl]oxy]methyl]-1,2-ethanediyl]ester](http://img.cochemist.com/ccimg/2500/2462-63-7.png)
![9-Octadecenoic acid(9Z)-, 1,1'-[1-[[[(2-aminoethoxy)hydroxyphosphinyl]oxy]methyl]-1,2-ethanediyl]ester](http://img.cochemist.com/ccimg/2500/2462-63-7_b.png)
![3,5,9-Trioxa-4-phosphaheneicosan-1-aminium,4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(1-oxododecyl)oxy]-, inner salt, 4-oxide](http://img.cochemist.com/ccimg/18700/18656-40-1.png)
![3,5,9-Trioxa-4-phosphaheneicosan-1-aminium,4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(1-oxododecyl)oxy]-, inner salt, 4-oxide](http://img.cochemist.com/ccimg/18700/18656-40-1_b.png)
![9-Octadecenoic acid(9Z)-,1,1'-[(1R)-1-[[[(2-aminoethoxy)hydroxyphosphinyl]oxy]methyl]-1,2-ethanediyl]ester](http://img.cochemist.com/ccimg/4100/4004-05-1.png)
![9-Octadecenoic acid(9Z)-,1,1'-[(1R)-1-[[[(2-aminoethoxy)hydroxyphosphinyl]oxy]methyl]-1,2-ethanediyl]ester](http://img.cochemist.com/ccimg/4100/4004-05-1_b.png)
![3',6'-Dihydroxy-3H-spiro[isobenzofuran-1,9'-xanthen]-3-one](http://img.cochemist.com/ccimg/2400/2321-07-5.png)
![3',6'-Dihydroxy-3H-spiro[isobenzofuran-1,9'-xanthen]-3-one](http://img.cochemist.com/ccimg/2400/2321-07-5_b.png)