EP1769007A2 - Polymeric compositions and related methods of use - Google Patents
Polymeric compositions and related methods of useInfo
- Publication number
- EP1769007A2 EP1769007A2 EP05857520A EP05857520A EP1769007A2 EP 1769007 A2 EP1769007 A2 EP 1769007A2 EP 05857520 A EP05857520 A EP 05857520A EP 05857520 A EP05857520 A EP 05857520A EP 1769007 A2 EP1769007 A2 EP 1769007A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- dopa
- mpeg
- modified
- peg
- dhpd
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 104
- 239000000203 mixture Substances 0.000 title description 83
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 claims abstract description 18
- 229960004502 levodopa Drugs 0.000 claims description 224
- 239000000758 substrate Substances 0.000 claims description 150
- 229920000642 polymer Polymers 0.000 claims description 78
- -1 DOPA halide Chemical class 0.000 claims description 47
- 230000004048 modification Effects 0.000 claims description 44
- 238000012986 modification Methods 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 239000000178 monomer Substances 0.000 claims description 34
- 239000007864 aqueous solution Substances 0.000 claims description 24
- 239000003999 initiator Substances 0.000 claims description 24
- 229920000233 poly(alkylene oxides) Polymers 0.000 claims description 21
- 239000010936 titanium Substances 0.000 claims description 14
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003505 polymerization initiator Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 5
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 229910052719 titanium Inorganic materials 0.000 claims description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical group C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims 2
- LGZVAJNPGRBFOC-UHFFFAOYSA-N 2-bromo-n-[2-(3,4-dihydroxyphenyl)ethyl]propanamide Chemical group CC(Br)C(=O)NCCC1=CC=C(O)C(O)=C1 LGZVAJNPGRBFOC-UHFFFAOYSA-N 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 239000012947 alkyl halide initiator Substances 0.000 abstract description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 152
- 239000000243 solution Substances 0.000 description 138
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
- 210000004027 cell Anatomy 0.000 description 96
- 229920001223 polyethylene glycol Polymers 0.000 description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- 239000010931 gold Substances 0.000 description 67
- 229910001868 water Inorganic materials 0.000 description 67
- 239000000499 gel Substances 0.000 description 64
- 239000002202 Polyethylene glycol Substances 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 230000001070 adhesive effect Effects 0.000 description 54
- 239000000853 adhesive Substances 0.000 description 52
- 230000015572 biosynthetic process Effects 0.000 description 51
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical class O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 39
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- 238000005259 measurement Methods 0.000 description 36
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- 230000027455 binding Effects 0.000 description 35
- 239000002105 nanoparticle Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 33
- 238000001179 sorption measurement Methods 0.000 description 33
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 32
- 239000012091 fetal bovine serum Substances 0.000 description 32
- 239000000017 hydrogel Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 238000002474 experimental method Methods 0.000 description 30
- 229910052737 gold Inorganic materials 0.000 description 27
- 238000001879 gelation Methods 0.000 description 26
- 235000018102 proteins Nutrition 0.000 description 26
- 102000004169 proteins and genes Human genes 0.000 description 26
- 108090000623 proteins and genes Proteins 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 description 25
- 238000000576 coating method Methods 0.000 description 25
- 238000001228 spectrum Methods 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000003556 assay Methods 0.000 description 24
- 238000005859 coupling reaction Methods 0.000 description 24
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 23
- 230000008878 coupling Effects 0.000 description 22
- 238000010168 coupling process Methods 0.000 description 22
- 210000001519 tissue Anatomy 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000001965 increasing effect Effects 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 21
- 230000021164 cell adhesion Effects 0.000 description 20
- 229920001992 poloxamer 407 Polymers 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- 230000001413 cellular effect Effects 0.000 description 19
- 239000000562 conjugate Substances 0.000 description 19
- 230000007480 spreading Effects 0.000 description 18
- 238000003892 spreading Methods 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- 230000003647 oxidation Effects 0.000 description 17
- 238000007254 oxidation reaction Methods 0.000 description 17
- 239000002953 phosphate buffered saline Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- 239000000872 buffer Substances 0.000 description 16
- 238000011068 loading method Methods 0.000 description 16
- 239000000463 material Substances 0.000 description 16
- 241000237536 Mytilus edulis Species 0.000 description 15
- 210000002950 fibroblast Anatomy 0.000 description 15
- 230000002265 prevention Effects 0.000 description 15
- KUDUQBURMYMBIJ-UHFFFAOYSA-N 2-prop-2-enoyloxyethyl prop-2-enoate Chemical compound C=CC(=O)OCCOC(=O)C=C KUDUQBURMYMBIJ-UHFFFAOYSA-N 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 230000001464 adherent effect Effects 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000011521 glass Substances 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- 210000002966 serum Anatomy 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 14
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 13
- 238000006116 polymerization reaction Methods 0.000 description 13
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 13
- 229910052939 potassium sulfate Inorganic materials 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- AHMIDUVKSGCHAU-LURJTMIESA-N L-dopaquinone Chemical compound [O-]C(=O)[C@@H]([NH3+])CC1=CC(=O)C(=O)C=C1 AHMIDUVKSGCHAU-LURJTMIESA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 229930040373 Paraformaldehyde Natural products 0.000 description 12
- 238000004630 atomic force microscopy Methods 0.000 description 12
- 238000003352 cell adhesion assay Methods 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 238000003384 imaging method Methods 0.000 description 12
- 229910044991 metal oxide Inorganic materials 0.000 description 12
- 150000004706 metal oxides Chemical class 0.000 description 12
- 239000003068 molecular probe Substances 0.000 description 12
- 235000020638 mussel Nutrition 0.000 description 12
- 229920002866 paraformaldehyde Polymers 0.000 description 12
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 12
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 229920001400 block copolymer Polymers 0.000 description 11
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical group OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 11
- 238000011109 contamination Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 150000002500 ions Chemical group 0.000 description 11
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 229920013639 polyalphaolefin Polymers 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 229910021642 ultra pure water Inorganic materials 0.000 description 11
- 239000012498 ultrapure water Substances 0.000 description 11
- 235000012431 wafers Nutrition 0.000 description 11
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000004793 Polystyrene Substances 0.000 description 10
- 230000002776 aggregation Effects 0.000 description 10
- 229920001577 copolymer Polymers 0.000 description 10
- 238000007654 immersion Methods 0.000 description 10
- 230000003993 interaction Effects 0.000 description 10
- 229920001983 poloxamer Polymers 0.000 description 10
- 229920002223 polystyrene Polymers 0.000 description 10
- 239000002243 precursor Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 230000010069 protein adhesion Effects 0.000 description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- AHMIDUVKSGCHAU-UHFFFAOYSA-N Dopaquinone Natural products OC(=O)C(N)CC1=CC(=O)C(=O)C=C1 AHMIDUVKSGCHAU-UHFFFAOYSA-N 0.000 description 9
- 229910052581 Si3N4 Inorganic materials 0.000 description 9
- 238000004220 aggregation Methods 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
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- 108010004563 mussel adhesive protein Proteins 0.000 description 9
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- 230000008569 process Effects 0.000 description 9
- HQVNEWCFYHHQES-UHFFFAOYSA-N silicon nitride Chemical compound N12[Si]34N5[Si]62N3[Si]51N64 HQVNEWCFYHHQES-UHFFFAOYSA-N 0.000 description 9
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
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- 239000000126 substance Substances 0.000 description 8
- UJEMVSDPTZRTIL-VIFPVBQESA-N (2s)-3-(3,4-dihydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C(O)=C1 UJEMVSDPTZRTIL-VIFPVBQESA-N 0.000 description 7
- VNQXSTWCDUXYEZ-UHFFFAOYSA-N 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione Chemical compound C1CC2(C)C(=O)C(=O)C1C2(C)C VNQXSTWCDUXYEZ-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000004215 Carbon black (E152) Substances 0.000 description 7
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 230000004888 barrier function Effects 0.000 description 7
- 229930006711 bornane-2,3-dione Natural products 0.000 description 7
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- 150000002430 hydrocarbons Chemical class 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000000693 micelle Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000000518 rheometry Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
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- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 230000007704 transition Effects 0.000 description 7
- ZJIFDEVVTPEXDL-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) hydrogen carbonate Chemical compound OC(=O)ON1C(=O)CCC1=O ZJIFDEVVTPEXDL-UHFFFAOYSA-N 0.000 description 6
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
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- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 6
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- 239000012071 phase Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- MSKSQCLPULZWNO-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanamine Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN MSKSQCLPULZWNO-UHFFFAOYSA-N 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000007995 HEPES buffer Substances 0.000 description 5
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 5
- 229920000463 Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) Polymers 0.000 description 5
- 229910018540 Si C Inorganic materials 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 235000010323 ascorbic acid Nutrition 0.000 description 5
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- 230000004481 post-translational protein modification Effects 0.000 description 5
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- 235000010288 sodium nitrite Nutrition 0.000 description 5
- 241000894007 species Species 0.000 description 5
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- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
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- HLLICFJUWSZHRJ-UHFFFAOYSA-N tioxidazole Chemical compound CCCOC1=CC=C2N=C(NC(=O)OC)SC2=C1 HLLICFJUWSZHRJ-UHFFFAOYSA-N 0.000 description 1
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- PISDRBMXQBSCIP-UHFFFAOYSA-N trichloro(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CC[Si](Cl)(Cl)Cl PISDRBMXQBSCIP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/46—Polymerisation initiated by wave energy or particle radiation
- C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
- C08F2/50—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light with sensitising agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D3/00—Pretreatment of surfaces to which liquids or other fluent materials are to be applied; After-treatment of applied coatings, e.g. intermediate treating of an applied coating preparatory to subsequent applications of liquids or other fluent materials
- B05D3/10—Pretreatment of surfaces to which liquids or other fluent materials are to be applied; After-treatment of applied coatings, e.g. intermediate treating of an applied coating preparatory to subsequent applications of liquids or other fluent materials by other chemical means
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
- C09D5/16—Antifouling paints; Underwater paints
- C09D5/1656—Antifouling paints; Underwater paints characterised by the film-forming substance
- C09D5/1662—Synthetic film-forming substance
Definitions
- MAPs Mussel adhesive proteins
- DOPA L- 3,4-dihydroxyphenylalanine
- Control of cell and protein adhesion on surfaces is critical to the performance of biosensors, medical diagnostic products, any instrumentation and assays used requiring handling serum and other human/animal fluids, tissue engineering, localized in vivo drug delivery, implanted medical devices, healing of surgical incisions, adhesion of tissues such as bone and cartilage for healing, and nanotechnology (nanoparticle-based therapies and diagnostic tools).
- control of cellular and protein adhesion to surfaces is also important. Such applications include prevention of mussel attachment to boats and ships, piers, and other structures used in oceans and fresh water, prevention of algal and bacterial growth on water lines used for industrial and drinking water, and sensors used to measure water quality and purity.
- PAO poly(alkylene oxides)
- PEG polyethylene glycol
- PPO polypropylene oxide
- PEO polyethylene oxide
- PEO-PPO-PEO block copolymers such as those available under the PLURONICS brand name
- PEG/tetraglyme poly(methoxyethyl methacrylate)
- PMEMA poly(methoxyethyl methacrylate)
- polyMPC Poly(methacryloyl phosphatidylcholine)
- compositions which function e.g., as an adhesive, in a substantially aqueous environment.
- the preferred compositions generally comprise an adhesive moiety and a polymer moiety, the polymer moiety having a desired surface active effect (or other desired characteristics).
- Methods of use including atom surface-initiated transfer, radical polymerization (SI-ATRP or ATRP) are also included. ⁇
- the adhesive moiety of a composition of this invention comprises dihydroxyphenyl derivatives including, di (DHPD) wherein a second DHPD can be
- the polymer moiety comprises poly (alkyleneoxide).
- the adhesive moiety comprises DHPD, e.g., DOPA (discussed herein), and the polymer moiety comprises PEO-PPO-PEO block polymers (also discussed herein).
- the adhesive moiety comprises DHPD including a pendent chain comprising ethylenic or vinylic unsaturation such as, for example, an alkyl acrylate.
- the present invention comprises a method of surface modification using an approach often referred to as atom transfer radical polymerization (ATRP).
- ATRP atom transfer radical polymerization
- Such a method can involve utilization of a DHPD-mimetic polymerization initiator capable of adsorbing or coupling to the material surface to be modified and initiating polymer growth from the surface via the initiator.
- the polymerization initiator is DOPA-mimetic.
- ATRP utilizes alkyl halide compounds to initiate a transition metal catalyzed polymerization.
- ATRP can be referred to as a "living" polymerization technique capable of producing homopolymers and block copolymers with well-defined molecular weights and low polydispersity.
- Components of the present initiators can comprise a DHPD-containing, e.g., DOPA-containing, peptide or a catechol moiety, that is linked or coupled via a hydrolytically stable bond or sequence to an alkyl halide compound.
- the catecholic moiety can provide linkage to a surface or substrate with a surface to be modified, whereas the alkyl halide can permit ATRP from the adsorbed molecule.
- Two such components can be linked or coupled via an amide or other stable linkage or bond sequence, providing robust and water-resistant coupling and surface modification.
- ATRP synthesis of a large variety of polymer structures and compositions can then be performed in aqueous medium and/or media substantially without organic solvents from the surface-bound initiator.
- Subsequent linkage of a polymer e.g., without limitation, PEG
- PEG polymer
- This invention can comprise dihydroxyphenyl derivative (DHPD) adhesive compound of formula (I):
- R 1 and R 2 may be the same or different and can be independently selected from hydrogen, saturated and unsaturated, branched and unbranched, substituted and unsubstituted C 1 to about C 4 hydrocarbon;
- P can be separately and independently selected from -NH 2 , -COOH, -OH, -SH,
- R 1 and R 2 are defined above, a single bond, halogen,
- a 1 and A 2 can be separately and independently selected from H, a single bond; a protecting group, substantially poly(alkyleneoxide),
- n ranges from 1 to about 3 and A 3 is
- °4 R 4 is H, ranges from C to about C 6 lower alkyl, or
- poly(alkylene oxide) can have the structure
- R3 and R.4 can be separately and independently H, or CH3 and m can have a value in the range from 1 to about 250, A 4 is NH2, COOH,
- DHPD can be any organic radical that has a very preferred form.
- R 1 , R 2 , and P being defined as above.
- DHPD can be of the structure:
- a 2 can be -OH and A 1 is substantially poly(alkylene oxide) of the structure
- a method of this invention can involve adhering substrates to one another comprising providing a DHPD of the structure:
- R 1 and R 2 can be defined as above; applying a DHPD of the above structure to one or the other or both of the substrates to be adhered; contacting the substrates to be adhered with the DHPD of the above structure therebetween to adhere the substrates to each other, and optionally repositioning the substrates relative to each other by separating the substrates and recontacting them to each other with the DHPD of the above structure therebetween.
- Rj and R 2 can be hydrogen.
- R 1 and R 2 can be hydrogen and P is, itself, dihydroxy phenyl.
- a preferred DHPD in a practice of the present invention is 1-3,4, dihydroxy phenyl alanine (DOPA), (generically),
- Substantially poly(alkylene oxide) shall mean predominantly or mostly alkyloxide or alkyl ether in composition. This definition contemplates the presence of heteroatoms e.g., N, O, S, P, etc. and of functional groups e.g., -COOH, -NH 25 -SH, as well as ethylenic or vinylic unsaturation. It is to be understood any such non-alkyleneoxide structures will only be present in such relative abundance as not to materially reduce, for example, the overall surfactant, non-toxicity, or immune response characteristics, as appropriate, or of this polymer.
- Figure 1 shows 1 H NMR spectra of PLURONIC® F 127, its carbonate intermediate (SC-P AO7) and DME-P AO7 in CDCl 3 .
- Figure 2 provides differential scanning calorimetry thermograms of 30 wt % DME-P AO7, DOPA-PAO7, and unmodified PLURONIC® F127 aqueous solutions. Arrows indicate the location of gelation endotherm.
- FIG. 3 plots shear storage modulus, G ', of a 22 wt % DME-P AO7 aqueous solution as a function of temperature at 0.1 Hz and a strain of 0.45%. Shown in the inset is the rheological profile of a 22 wt % unmodified-PLURONIC® F 127 aqueous solution as a function of temperature.
- FIG. 4 plots shear storage modulus, G ', of a 50 wt % DME-P AO8 aqueous solution as a function of temperature at 0.1 Hz and a strain of 0.45%. Shown in the inset is the rheological profile of a 50 wt % unmodified PLURONIC® F68 aqueous solution as a function of temperature.
- Figure 5 plots storage moduli of DME-P AO8 aqueous solutions at 45 wt % and 50 wt %, respectively, as a function of temperature at 0.1 Hz and a strain of
- Figures 6A and 6B show differential scanning calorimetry thermograms of (A) DOPA-PAO7 and (B) DME-P AO7 at different concentrations upon heating. Arrows indicate the location of gelation endotherm observed only at higher polymer concentrations.
- Figures 7A-C show high-resolution C(I s) XPS peaks for (A) un-modified Au, (B) m-PEG-OH, and (C) m-PEG-DOPA. A dramatic increase in the ether peak at 286.5eV in (C) indicated the presence of PEG.
- Figures 8 A-C provide TOF-SIMS positive spectrum showing peaks representing catechol binding of gold. Spectra were normalized to Au peak
- Figure 9 provides TOF-SIMS spectra showing the positive secondary ion peak at mass m/z ⁇ 43 for unmodified Au substrate, Au exposed to mPEG-OH, mPEG-DOPA powder and Au exposed to mPEG-DOPA.
- FIG. 10 shows TOF-SIMS spectra showing the positive secondary ion peaks for Au substrate chemisorbed with mPEG-DOPA. Catecholic binding of gold is observed at m/z ⁇ 225 (AuOC), 254 (AuOCCO), and 309. Less intense
- AuOaC b peaks are seen at m/z ⁇ 434, 450, 462, and 478.
- Figure 11 shows SPR spectra of protein (0.1 mg/ml BSA) adsorption onto modified and unmodified gold surfaces.
- mPEG-DOPA and mPEG-MAPd modified surfaces exhibited reduced protein adsorption compared to bare gold and mPEG-OH modified surfaces.
- Figure 13 compares cell attachment and spreading on bare gold, mPEG-OH-treated gold, and gold modified with mPEG-DOPA 5K, mPEG-MAPd
- Figures 14 A-C are a series of SEM micrographs indicating the morphology of NIH 3T3 fibroblasts on (A) unmodified Au, (B) Au treated with mPEG-OH, and (C) mPEG-DOPA-modified Au. All treatments were at 50mg/ml in
- Figure 15 shows the UV/vis absorption spectrum of mPEG-DOP A stabilized magnetite nanoparticles suspended in several aqueous NaCl solutions at the concentrations as shown and plotted therein. Addition of NaCl did not induce nanoparticle precipitation.
- Figure 16 shows addition of salt to untreated Au nanoparticles induces aggregation. Shown are UV/vis scans of lOnm untreated Au nanoparticles suspended in aqueous NaCl solutions (concentrations as shown and plotted therein). The attenuation and shift of the 520 nm absorption band with increasing NaCl concentration reflects aggregation of the nanoparticles.
- Figure 17 illustrates addition of salt to mPEG-DOPA stabilized Au nanoparticles does not induce aggregation. Shown are UV/vis scans of lOnm mPEG-
- DOPA stabilized Au nanoparticles suspended in aqueous NaCl solutions DOPA stabilized Au nanoparticles suspended in aqueous NaCl solutions
- Figure 18 plots the UV/vis absorption spectrum of mPEG-DOPA stabilized CdS nanoparticles suspended in aqueous NaCl solutions (concentrations as shown and plotted therein.
- Figure 19 plots XPS survey scans of unmodified TiO 2 and TiO 2 treated with mPEG-DOPAi -3 .
- Figure 20 plots the long-term resistance to cell adhesion on TiO 2
- TiO 2 modified with mPEG-DOPA 1-3 The duration of the non-fouling response is proportional to the length of the DOPA peptide anchoring group. Adherent cells were visualized with calcium AM.
- Figure 21 plots the high-resolution XPS scans of the CIs region of
- TiO 2 substrates modified with mPEG-D0PA 1-3 are TiO 2 substrates modified with mPEG-D0PA 1-3 .
- the increase in the ether carbon peak (286.OeV) with increasing length of the DOPA peptide anchor is also important.
- Figure 22 plots the high-resolution XPS scans of the 01 s region of
- TiO 2 substrates modified with HiPEG-DOPA 1-3 modified with HiPEG-DOPA 1-3 .
- the peak at 532.9eV representing polymeric oxygen increases while the Ti-O-H peak (531.7eV) decreases with increasing DOPA peptide length.
- Figure 23 plots the results of the Robust Design experiment on 316L stainless steel.
- Figure 24 plots the 4-hour cell attachment to a variety of surfaces modified by mPEG-DOPAi -3 using a 24-hour modification at 5O 0 C at the indicated pHs.
- Figure 25 plots the % gel conversion versus the UV exposure time in minutes.
- Figure 26 plots the mole fraction of DOPA incorporated versus the mol
- Figure 27 plots the % gel conversion versus mol % 1 or in the precursor solution.
- Figure 28 X-ray Photoelectron Spectroscopy XPS analysis of a silicon nitride surface.
- Figure 29 is a free monitoring of functionalized silicon nitride cantilevers.
- Figure 30 is an analysis of entropic elasticity of poly(ethylene glycol).
- Figure 31 is a force measure of side chain modified DOPA.
- Figure 32 is a proposed model of DOPA-TiO 2 binding mechanism.
- Figure 33 is an atomic force microscopy arrangement.
- Figure 34 is data regarding force measurement.
- Figure 35 is adhesion data.
- Figure 36 is synthetic route and data analysis.
- Figure 37 plots the PM-IRRAS spectrum of the grafted POEGMEMA layer.
- Figure 38 has two plots the XPS spectra of the grafted POEGMEMA layer on TiO 2 (Binding Energy vs. Intensity).
- Figure 39 shows the cell attachment to unmodified TiO 2 and grafted
- Figure 40 shows the fluorescence microscopy image of fibroblast cell attachment (4 hour) on a Ti substrate modified in the upper left corner by SI-ATRP of
- DHPD dihydroxyphenyl derivative
- DHPD adhesives can also be used as substitutes for sutures for a wound and as aids in healing bone fractures or cartilage- to-bone damage. These and other uses will be described in more detail below.
- the preferred polymer compositions of the present invention have the following structure:
- R 1 and R 2 are defined separately and independently as above,
- P 1 and P 2 are separately and independently defined as P in formula (I);.
- n and m are independently ranger from 0 to about 5, provided that at least one of n or m is at least 1 ;
- the adhesive moiety of the present invention is a dihydroxyphenyl derivative
- DHPD DHPD having the following preferred structure:
- the DHPD adhesive can function in an aqueous environment.
- an aqueous environment is any medium comprising water. This includes without limitation water, including salt water and fresh water, cell and bacterial growth media solutions, aqueous buffers, other water-based solutions, and body fluids.
- the DHPD moiety can be derivatized. As would be understood by those skilled in the art, such derivatization is limited by the retention of the desired adhesive characteristic.
- polymeric components providing a surface active effect and other desired characteristics will be well-known to those skilled in the art made aware of this invention.
- the desired surface active effect relates to reduced particulate agglomeration and anti-biofouling, including resistance to cell and/or protein adhesion.
- the polymer component can be water soluble, depending upon end-use application, and/or capable of micelle formation depending upon various other end-use applications.
- Polymers useful in the present invention include, but are not limited to, polyethylene glycol (PEG), polyethylene oxide (PEO), polypropylene oxide (PPO), PEO-PPO-PEO block copolymers, polyphenylene oxide, PEG/tetraglyme, PMEMA, polyMPC, and perfluorunated polyethers.
- the polymeric compositions can be synthesized in several ways.
- the polymeric compositions may be synthesized through a general synthetic procedure for polymer end-group activation.
- Various polymers or monomeric components thereof can be activated using carbonate chemistry.
- a succinimidyl carbonate-activated polymeric component reacted with DHPD moiety can provide a stable urethane conjugate.
- Two of the many possible pathways (a) and (b) in Scheme Ia and Ib, below, show coupling with a poly(alkylene oxide) in either aqueous or non-aqueous solvents, without compromising desired bioadhesion.
- a DHPD residue can be coupled to a polymeric component to provide the desired conjugate composition, through either urethane or amide bond formation.
- a carboxylic acid group of the DHPD component can be esterified or derivatized with various other functional groups.
- the DHPD component can be coupled to a polymeric component (e.g., amidation or esterification depending on polymer end group, -NH 2 or -OH) providing a DHPD functionality which can be derivatized by any of numerous known protecting groups, including without limitation Boc, Fmoc, borate, phosphate, and tributyldimethylsilyl.
- the present invention is also a method of using urethane synthesis to incorporate a DHPD residue into a polymeric system.
- a method includes (1) providing a polymeric component terminating in a plurality of monomers, each having a functional end group; (2) preparing a carbonate derivative of the polymeric component; and (3) preparing a urethane moiety upon reaction of the carbonate derivative and at least one DHPD moiety.
- a polymeric component utilized in conjunction with this method can include those having terminal monomeric functionality reactive with a reagent providing the desired carbonate derivative and, ultimately, providing a urethane moiety coupling the polymeric and DHPD components.
- Various other coupling reagents and/or hydroxy-terminating polymeric components can be used to provide the desired urethane moiety.
- the present invention is also a method of using a carbonate intermediate to maintain catecholic functionality of a DHPD-incorporated polymeric composition and/or system, or to otherwise enhance the adhesion properties thereof.
- Such a method includes (1) providing a polymeric component terminating in a plurality of monomers each having a functional end group; (2) reacting the polymeric component with a reagent to provide a carbonate intermediate; and (3) reacting the carbonate intermediate with at least one DHPD moiety.
- this inventive method can be considered a way of enhancing the reactivity of the polymeric component end group, via a suitable carbonate intermediate. Subsequent reaction at the amino-nitrogen of DHPD moiety provides the corresponding conjugate while maintaining catecholic functionality.
- various synthetic routes can be used to couple DHPD moieties to such carbonate activated intermediates.
- DOPA methyl ester prepared by the reaction of DOPA with methanol in the presence of thionyl chloride, can be used in organic solvents. Reaction progress can be monitored by TLC and NMR, with the coupling reaction virtually complete in one hour (with representative conjugates DME-P AO7 (from PAO PLURONIC® F127) and DME-P A08 (from PAO PLURONIC® F68)). High product yields were obtained upon purification from cold methanol. [0069] The free carboxylic form of DOPA can be coupled with the carbonate intermediate in alkaline aqueous solution.
- DOPA DOPA-quinone and other products
- a borate- protected DOPA can be first formed by adding DOPA to aqueous sodium borate (Scheme Ib).
- the resulting complex is remarkably stable in neutral or alkaline solutions, and can be readily deprotected under acidic conditions.
- DOPA was coupled to the ends of several commercially-available PAOs under alkaline aqueous conditions to yield DOPA-PAO7 and DOPA-PAO8.
- Table 1 of selected DOPA-modified PAOs synthesized in aqueous solution were found to be lower than those synthesized in organic solvent. This may be due to the surfactant properties of the starting PAO material, causing the low efficiency of extraction of DOPA-modified PAO with dichloromethane from water. It should be noted that the free carboxylic acid in DOPA-PAO7 and DOPA-PAO8 can be further functionalized using standard peptide chemistry to tailor the properties of the block copolymers.
- the four DOPA-modified PAOs of Table 1 could be stored at -20°C indefinitely with no discoloration or change in properties.
- Control of cell and protein adhesion on surfaces is critical to the performance of biosensors, medical diagnostic products, any instrumentation and assays used requiring handling serum and other human/animal fluids, tissue engineering, localized in vivo drug delivery, implanted medical devices, healing of surgical incisions, adhesion of tissues such as bone and cartilage for healing, and nanotechnology (nanoparticle-based therapies and diagnostic tools).
- control of cellular and protein adhesion to surfaces is also important.
- Such applications include without limitation prevention of mussel attachment to boats and ships, piers, and other structures used in oceans and fresh water, prevention of algal and bacterial growth on water lines used for industrial and drinking water, and sensors used to measure water quality and purity.
- the polymeric compositions of the present invention can be used as coatings to prevent protein and cellular adhesion to devices for medical and research applications. These include without limitation such uses as coatings for medical implants, coatings for surgical devices, coatings for devices that handle serum and other animal or human derived materials, medical diagnostic devices, and biosensors.
- the polymeric compositions can be tissue adhesive polymeric hydrogels for medical uses such as tissue sealants, gels for prevention of surgical adhesion (scar tissue formation), bone and cartilage adhesives, tissue engineering, and site specific drug elution and for research uses such as immobilization of proteins including antibodies and small molecule analytes including pharmaceuticals.
- coatings and hydrogels including without limitation prevention of marine biofouling (attachment of algae, bacteria, and mussels to surfaces underwater), prevention of bacteria contamination of water streams to industrial plants such as electronic and drug manufacturers, prevention of bacterial contamination of drinking water streams, dental and denture adhesives, underwater adhesives to deliver indicators, coatings for water purity and measurement sensors, paints used for prevention of biofouling, and use in cosmetics to adhere desired fragrances and colorants to hair, eyelids, lips, and skin, to form temporarily skin coloring such as tattoos and the like, and for resealable adhesives for consumer products such as storage bags.
- the present methods can be used to prepare a variety of polymer modified surfaces for both medical (diagnostics, devices, nanoparticle-based therapies) and nonmedical (paints and other particle dispersions, MEMS, quantum dots, nonfouling surfaces) technologies.
- Adhesive hydrogels can be also formed using the present methods.
- DHPD adhesive is attached to polymers capable of forming a hydrogels in vivo or in vitro.
- hydrogels can be formed by a number of methods including the use of self-assembling polymers that form gels at higher temperatures such as normal human body temperatures, the use of polymers that can be cross-linked by an enzymatic reaction, the use of polymers that can be subjected to oxidation to form cross-linked hydrogels, and the use of polymers that can be subjected to photoactivation to produce cross-linked hydrogels.
- the anti-biofouling coatings of the present invention may be applied to medical devices, such as vascular or arterial stents, pacemakers, heart valves, glucose monitors and other biosensors, vascular wraps, defibrillators, orthopedics devices, and surgical devices, including sutures and catheters.
- the polymeric compositions of the present invention can be used as coatings to prevent protein and/or cellular adhesion to a device for medical and research applications. These include without limitation such uses as coatings for medical implants, coatings for surgical devices, coatings for devices that handle serum and other animal or human derived materials, medical diagnostic devices, and biosensor.
- a surface may be modified by the polymeric composition of the present invention in any number of ways.
- the polymeric composition may be absorbed onto the surface or a DHPD moiety containing a polymerization initiator may be adsorbed onto the surface and polymer growth initiated from the surface.
- the ATRP method of this invention exploits a biological strategy that mimics key components of natural adhesive proteins.
- the synthesis of a new bifunctional initiator, described below, comprises an adhesive moiety coupled to a functional group capable of initiating polymer growth.
- the initiator can be used to modify a variety of surfaces with polymers of variable composition and properties.
- a surface or substrate surface modification method of this invention comprises: 1) immobilizing an initiator onto the surface to be modified by adsorption e.g., from a solution; 2) growing a polymer by surface-initiated polymerization from using the adsorbed initiator e.g., a monomer-containing solution to complete the modification.
- the resulting surface-bound polymer has nonfouling properties, such as by providing steric resistance to fouling of the modified surfaces by cells, proteins, and other particles.
- SI-ATRP of this invention can be used to prepare a variety of polymer modified surfaces for both medical (diagnostics, devices, nanoparticle-based therapies) and nonmedical (paints and other particle dispersions, MEMS, quantum dots, nonfouling surfaces) technologies.
- the water-resistant properties of the anchoring component are useful for permanent attachment of polymer coatings in aqueous environments.
- the biomimetic anchor may also have anticorrosive properties for metallic surfaces.
- the term "Adsorption" used above is to be broadly construed to include any and all interactions of sufficient strength to create the desired surface modification.
- the surface density of polymer can be increased by treating surfaces with PEG solutions near the lower critical solution temperature (LCST), or cloud point. While not wanting to be bound by any theory, applicants believe that under the high ionic strength and elevated temperature conditions used in the present invention, PEG molecules have a reduced hydrodynamic radius, which in principle allows a higher density of PEG chains to pack on a surface than under standard conditions.
- the thickness of the coating layer can be from about 20 A to about 100 ⁇ m, including 30 A, depending on the polymer composition used and the pH of the modification buffer.
- the concentration of the polymer composition used for modification of a surface can be from about .1 mg/ml to about 75 mg/ml.
- the pH of the modification buffer can be from about 3 to about 9.
- the modification time can be from about 10 minutes to about 72 hours.
- the temperature of the modification can be from about 25°C to about 60°C.
- XPS survey scans of unmodified TiO 2 revealed strong peaks at -458 eV (Ti2p) and -530 eV (Ols) characteristic of native oxide, as well as a small peak at 248.7 eV (CIs) as a result of adventitious hydrocarbon contamination.
- TiO 2 substrates treated with mPEG-DOPAj- 3 under cloud point conditions demonstrated dramatic increases in surface-bound carbon as reflected by the CIs peak, suggesting the presence of PEG on the surface.
- the increases in the CIs peaks observed after modification with mPEG-DOPA 1-3 were directly proportional to the number of terminal DOPAs present.
- NIs amide nitrogen in DOPA.
- Table 2 shows the titanium, oxygen, and carbon atomic composition calculations for Ti ⁇ 2 -modified with HiPEG-DOPA 1 -3 .
- the oxygen signal is further subdivided into metal oxide (Ti-O-Ti), surface hydroxide (Ti-O-H), and organic oxygen and coupled water (C-O, H 2 O) species.
- DOPA creates strong, reversible bonds with TiO 2 .
- the energy of the bond is 30.56 kcal/mol and needs about 800 pN to be detached from TiO 2 at the single molecule level, which is four times stronger than the interaction between Avidin and Biotin.
- the DOPA-TiO 2 strength of interaction is about midway between that of Avidin-Biotin, one of the strongest hydrogen bond based interactions in biology (0.1- 0.2 nN) and a covalent bond (>2nN).
- DOPA conjugated cantilevers displayed significant adhesion accompanied by entropic elasticity of the PEG chain (Fig 34).
- a histogram of the force distribution shows a uni-modal shape indicating only single adhesive event, which is different compared to the case of a multivalent protein, Avidinl2.
- the length of stretched PEG (36 nm) was consistent with the expected contour length of a PEG molecule (37 nm, Fig 30).
- d is the z-displaced distance of piezoelectric device when a single DOPA-PEG molecule was fully stretched during retraction (Fig 34C).
- the 'd' values appeared to be almost constant throughout many repeated cycles although it did vary slightly (Fig 34A). This small variation might be due to DOPA binding to the surface at different angles.
- An important feature of our experiment is that the unbinding signals are epetitions using the 'identical' DOPA molecule. This is compared to the traditional approach of single molecule pulling experiments where tips picked up one molecule randomly. This also demonstrates that the DOPA adhesion chemistry was completely reversible. This reversibility led us to the conclusion that the weakest chemical linkage from substrate to tip (TiO2 ⁇ Si3N4) is the Ti(surface)- 0(DOPA) bond.
- Mussels developed an interesting way to create such a strong binding in water, a post-translational modification of tyrosine by tyrosine hydroxylase. This enzyme catalyzes a reaction of adding one hydroxyl group using tyrosine as a substrate and a large amount is found in threads and plaques where DOPA exists as well. It is surprising to say that the small post-translational modification (-OH) seems to produce a huge change of adhesive ability. Thus, experiments were designed to show a correlation between the posttranslational modification and binding ability. [0094] A tyrosine tethered cantilever was prepared instead of DOPA, and tyrosine adhesion on TiO2 was investigated.
- Aryl-aryl ring coupling (di-DOPA) has been found in mussel adhesive proteins 20 but Michael addition (quinone-alkylamine adducts) products have been found in other species not mussels (Fig 36A). Therefore, these structures may occur as results of oxidation in mussels as well. It is clear in terms of crosslinking but is under debate with respect to adhesive properties after maturation i.e. oxidation. It was demonstrated that the DOPAquinone structure is not a major player for adhesiveness.
- the DOPAquinone-PEG chain is spatially and chemically stabilized by excess co-conjugation of methoxy-PEG molecules (5 ⁇ 10 molar equivalent) which is an important molecular configuration for preventing further reactions of DOPAquinone.
- the DOPA anchoring system can be a new platform to study other extensible biological macromolecules such as polysaccharides, DNA, and proteins.
- This method is also highly contrasted with the conventional single molecule experiments where a tip 'sees' different molecules at every single movement of a cantilever. It has been a big barrier to investigate molecular responses upon external stimuli if a given stimulus was not hundred percent effective23,.
- the DOPA- based anchorage system can be an alternative technique to overcome these problems in current single molecule pulling experiments.
- FIG 33 An experimental design and a single molecular DOPA adhesion [0099] A picture describes how the blue mussel (Mytilus Edulis) sticks to metal oxide surfaces. The circle included one plaque where the unusual amino acid, DOPA, was found.
- Mefp-3 and Mefp-5 These mussel adhesive proteins have high content of DOPA: 27 mole % of Mefp-5 and 21 % of Mefp-3.
- (D) A plot of bonding strength (linear) vs. loading rate (log). Loading rate was the product of spring constant of a cantilever and a pulling speed. Four different loading rates were selected: 1500, 180.7, 28.4 and 2 nN/sec. Averaged forces with standard deviation were plotted at each given loading rate. Forces were 846.48 ⁇
- FIG. 35 Molecular identification of the adhesive origin of DOPA
- (B) Confirmation of tyrosine existence on the tip surface. Pi ( ⁇ ) electrons of tyrosine phenyl group specifically interact with gold ⁇ -electron.
- (C) Force distributions of tyrosine binding to a gold surface.
- the antifouling coating of the present invention can either be essentially permanent i.e., lasting 120 days or more, or biodegradable depending on the number of DOPA or DOPA-derived moieties in the adhesive component.
- Figure 20 shows the results of a 28-day 3T3 fibroblast cell adhesion and spreading assay on TiO 2 treated with mPEG-DOPA ⁇ s. At early time points (i.e. less than 7 days), the protein and cell attachment resistance correlates well with the length of the DOPA peptide anchoring group, with resistance increasing in the order mPEG-DOP A ⁇ mPEG-DOPA 2 ⁇ mPEG- DOPA 3 .
- the polymeric compositions of the present invention can be also used to coat the surfaces of devices and instrumentation used for handling body fluids including sera.
- the coating on the surface of the device or instrument blocks protein binding to the surfaces thus reducing or eliminating the need for extensive washing or cleaning of the device or instrument between uses.
- the devices need to be thoroughly cleaned to prevent cross contamination between samples of bodily fluids applied top the device.
- caustic agents such as 50% bleach and/or elevated temperatures.
- the coating process would be to circulate an aqueous solution of 1 mg/ml of DHPD polymer through the device at room temperature for a period of a few hours.
- the coatings of the present invention can be used on medical implants for a wide variety of uses.
- the coatings can be used to block bacterial adhesion and therefore growth on the implanted device reducing the possibility of infection at the site of implant.
- the coatings can be used to reduce the amount of acute inflammation on the device by reducing protein binding and cell adhesion to the device.
- the coatings of the present invention can also be used as nanoparticles to prevent aggregation of these particle in the presence of serum. Hvdrogels
- the polymeric compositions of the present invention can also be as surgical adhesives for medical and dental uses and as vehicles for drug delivery to mucosal surfaces.
- the polymeric compositions can be used as tissue adhesive polymeric hydrogels for medical uses such as tissue sealants, gels for prevention of surgical adhesions (scar tissue formation), bone and cartilage adhesives, tissue engineering, and site specific drug elution and for research uses such as immobilization of proteins including antibodies and small molecule analytes including pharmaceuticals.
- the polymeric compositions of the present invention may also be used as interfacial bonding agents, wherein the neat monomers or solution of monomers are applied to a surface as a primer or bonding agent between a tissue surface or a metal or metal oxide implant/device surface and a bulk polymer or polymer hydrogel.
- the polymeric compositions of the present invention can be injected or delivered in a fluid form and harden in situ to form a gel network.
- the in situ hardening can occur through photocuring, chemical oxidation, enzymatic reaction or through the natural increase in temperature resulting from delivery into the body.
- the present invention is also a method for the non-oxidative gelation of a polymeric composition of the present invention.
- One such method includes (1) providing a polymeric composition of the present invention; (2) admixing water and the polymeric composition; and (3) increasing admixture temperature sufficient to gel the polymeric composition, such temperature increase without oxidation of the polymer or DOPA or DOPA-derived moiety residue incorporated therein.
- an increase in admixture concentration can reduce the temperature required to effect gelation.
- a larger hydrophilic block thereof can increase the temperature required to gel the corresponding composition.
- Various other structural and/or physical parameters can be modified to tailor gelation, such modifications as can be extended to other polymeric compositions and/or systems which are consistent with the broader aspects of this invention.
- PLURONIC® block copolymers self-assemble in a concentration- and temperature- dependent manner into micelles consisting of a hydrophobic PPO core and a water- swollen corona consisting of PEO segments.
- certain PEO-PPO- PEO block copolymers such as PLURONIC® F127 and PLURONIC® F68, transform from a low viscosity solution to a clear thermoreversible gel at elevated temperature. While not wanting to be bound by theory, it is generally assumed that the interactions between micelles at elevated temperature lead to the formation of a gel phase, which is stabilized by micelle entanglements.
- micellization and gelation processes depend on factors such as block copolymer molecular weight, relative block sizes, solvent composition, polymer concentration, and temperature. For example, increasing the length of the hydrophilic PEO blocks relative to the hydrophobic PPO block results in an increase in micellization and gelation temperature (r ge i).
- DSC Differential scanning calorimetry
- DOPA-PAO7 (22 wt %) 22.0 ⁇ 1.0 20.4 ⁇ 0.5 21.7 ⁇ 0.2
- Aqueous solutions with concentrations ranging from 10 to 30 % (w/w) of DOPA-PAO7 copolymers and 35 to 54 % (w/w) of DOPA-PAO8 copolymers were prepared by the cold method, in which DOPA conjugate was dissolved in distilled water at about 4°C with intermittent agitation until a clear solution was obtained. Thermal gelation of concentrated solutions was initially assessed using the vial inversion method. In this method, the temperature at which the solution no longer flows is taken as the gelation temperature.
- the gelation temperature was found to be strongly dependent on copolymer concentration and block copolymer composition (i.e., PAO7 versus PAO8).
- PAO7 block copolymer composition
- 22 wt % solutions of DOPA-PAO7 and DME-P AO8 were found to form a transparent gel at approximately 22.0 ⁇ 1.0 0 C; decreasing the polymer concentration to 18 wt % resulted in a gelation temperature of approximately 31.0 ⁇ 1.0 0 C.
- DOPA-PAO7 solutions with concentrations less than 17 wt % did not form gels when heated to 60 0 C.
- DOPA-PAO7 exhibits a slightly higher gel temperature than that (17.0 ⁇ 1.0 0 C) of unmodified PLURONIC® F127.
- DOPA- PAO8 The gelation behavior of DOPA- PAO8 was found to be qualitatively similar, except that much higher polymer concentrations were required to form a gel. 54 wt % solutions of DOPA-PAO8 and DME-P AO8 formed gels at 23.0 ⁇ 1.0 0 C, while 50 wt % of DOPA-PAO8 gels at 33.0 ⁇ 1.0 0 C. However, DOPA-PAO8 solutions with concentrations less than 35 wt % did not form gels when heated to 60 0 C. DOPA-PAO8 exhibits a much higher gel temperature than that (16.0 ⁇ 1.0 0 C) of unmodified PLURONIC® F68. These gels were found to be resistant to flow over long periods of time.
- FIG. 3 shows the elastic storage modulus, G', of 22 wt % solutions of unmodified PLURONIC® F 127 and DME-P AO7 aqueous solutions as a function of temperature. Below the gelation temperature, storage modulus G' was negligible, however G ' increased rapidly at the gel temperature (r ge ⁇ , defined as the onset of the increase of the G' vs. Temperature plot. DOPA-PAO7 (not shown) exhibited a similar rheological profile.
- T g ⁇ of 22 wt % solutions of DME-P AO7 and DOPA-PAO7 were found to be identical (20.3 ⁇ 0.6 0 C), which is approximately 5 degrees higher than an equivalent concentration of unmodified- PLURONIC® F127 (15.4 ⁇ 0.4 0 C).
- G' of DME-PAO7 or DOPA-PAO7 approaches a plateau value of 13 kPa, which is comparable to that of unmodified PLURONIC® F127.
- FIG. 4 Shown in Figure 4 are the rheological profiles of 50 wt % solutions of unmodified PLURONIC® F68 and DME-P AO8 as a function of temperature.
- the T ⁇ e ⁇ of a 50 wt % DME-P AO8 solution was found to be 34.1 ⁇ 0.6°e, whereas the T ge i of an equivalent concentration of unmodified PLURONIC® F68 was approximately 18°C lower (16.2 ⁇ 0.8 0 C).
- the plateau storage moduli of 50 wt % solutions of DME-P AO8 and unmodified PLURONIC® F68 were not significantly different, approaching a plateau value as high as 50 kPa.
- T ge ⁇ The concentration dependence of T ge ⁇ is illustrated in Figure 5, which shows the rheological profile of DME-P AO8 at two different concentrations as a function of temperature.
- T ge ⁇ of 45 wt % solution of DME-P AO 8 was observed to be approximately 12°C higher than that of 50 wt % solution of DME- PAO8.
- micellization As seen in Table 5, the onset temperature of micellization, the temperature at maximum heat capacity and T ge ⁇ of unmodified PLURONIC® F 127 were found to be lower than those of DOPA-PAO7, whereas the specific enthalpies determined from the areas under the transition ( Figure 2) are approximately the same. These enthalpies include contributions from both micellization and gelation. However, due to the small enthalpy of gelation, the observed enthalpy changes can be largely attributed to micellization.
- DOPA-PAO7 (30 wt %) 4.6 ⁇ 0.2 8.0 ⁇ 0.6 19.3 ⁇ 1.4 14.0 ⁇ 0.2
- micellization peak was seen to extend to temperatures above the onset of gelation, indicating that additional monomers aggregate into micelles at temperatures above the gelation point.
- concentration dependence of DOPA-PAO7 and DME-P AO7 aggregation is shown in Figure 6.
- DSC thermograms indicate a decrease in micellization temperature and r ge i with increasing polymer concentration.
- the broad endothermic peak corresponding to micellization can also be observed in solutions at concentrations at which no gelation takes place; the characteristic temperature of the broad peak increases linearly with decreasing copolymer concentration, whereas the small peak was observed to coincide to the gel temperature of the concentrate copolymers but disappears as copolymer concentration decreases.
- various polymeric compositions of this invention can be designed and prepared to provide various micellization and/or thermal gelation properties.
- degradation into excretable polymer components and metabolites can be achieved using, for instance, polyethylene glycol and lactic/glycolic acids, respectively.
- the polymeric compositions of this invention provide improved adhesion by incorporation of one or more DHPD residues, such incorporation resulting from the coupling of a terminal monomer of the polymeric component to such a residue.
- a photocurable DHPD-moiety-containing monomer is copolymerized with PEG-DA (PEG-diacrylate) to form adhesive hydrogels through photopolymerization.
- Photopolymerization can be achieved at any visible of UV wavelength depending on the monomer used. This is decidedly determined by one skilled in the art.
- the photocurable monomers consist of an adhesive moiety coupled to a polymerizeable monomer with a vinyl group, such as a methacrylate group with or without an oligomeric ethylene oxide linker or fluorinated ether linker in between.
- DMPA 2,2'-dimethoxy-2-phneyl-acetonephenone
- CQ/DMAB camphorquinone/4- (dimethylamino)-benzoic acid
- AAT 1 FNa 2
- gel conversion as determined by measuring the mass of the sondgel reached more than 75 wt % after 2 minutes of UV irradiation and increased to greater than 85 wt % upon irradiation for more than 5 minutes.
- Gelation of PEG-DA occurred in 4 minutes or less when visible light initiators were used (4 minutes for CQ/DMAB and 3 minutes for AATFNa 2 ).
- Copolymerization of PEG-DA with 1 or 7 was qualitatively similar to polymerization of pure PEG- DA, although addition of 1 or 7 to the PEG-DA precursor solution resulted in a decrease in gel conversion that was dependent on DOPA monomer concentration and initiating system.
- gel conversion was reduced to less than 85 wt % in the presence of 2.5 mol % or more of 1 or 7.
- the extent of gel conversion was not statistically different between the gels. Similar DOPA concentration dependent inhibition was observed for the visible light induced initiators.
- Figure 26 shows the mole fraction of DOPA incorporated into the gel network, as a function of mol % monomer 1 and 7 in the precursor solution. There was no significant difference in the mole fraction of DOPA incorporated between samples containing 1 and 7. As much as 24.9 ⁇ mol/g of DOPA was incorporated into the PEG hydrogels. [00136] Direct evidence for the presence of DOPA in the gels was obtained by immersing the intact dialyzed hydrogels in nitrite reagent followed by NaOH. The initially colorless gels turned bright yellow after the addition of the nitrite reagent and then red following the addition of excess base.
- Equation (1) where R is the radius of curvature of the hemispherical gel.
- Equation (1) which allowed the elastic moduli to be calculated based on the proportionality factor of the curve fit.
- E average Young's moduli (E) for DOPA-containing gel of around 50 kPa was obtained.
- hydrogel can also be loaded with an analgesic and used to deliver pain relief at a localized site. They hydrogel can also be loaded with a chemotherapy drug and inserted into malignant tissue to deliver localized cancer therapy. The hydrogel can also be loaded with a cell proliferation inhibitor therapeutic drug and used as a coating stent or other vascular device and used to control cell proliferation at the site of an implant of the vascular device.
- a tissue adhesive hydrogel capable of being cross-linked in vivo can be used as a tissue sealant for replacing metal or plastic sutures. The adhesive bends to the surrounding tissue at a surgical or injury site and the polymer forms a cohesive link to close the wound. The hydrogel can also be used for repair of bone fractures and cartilage to bone damage.
- compositions of this invention can include but are not limited to a urethane moiety between each such terminal monomer and DOPA residue. As described more fully below, such a moiety is a synthetic artifact of the agent/reagent utilized to couple the DOPA residue with the polymeric component.
- a urethane moiety is a synthetic artifact of the agent/reagent utilized to couple the DOPA residue with the polymeric component.
- compositions and/or methods of the present invention including the production of various polymeric or co-polymeric compositions having incorporated therein one or more DHPD components, as are available through the synthetic methodology described herein. While the utility of this invention is illustrated through the use of several polymeric or co-polymeric systems, it will be understood by those skilled in the art that comparable results are obtainable with various other compositions and/or methods for preparation, as are commensurate with the scope of this invention.
- PE0 100 PP0 65 PEO JOO (PLURONIC® F127, avg. M 11 , 12,600),
- L-DOPA thionyl chloride, methacroyloyl chloride, t-butyldimethylsilyl chloride (TBDMS-Cl), di-t-butyl dicarbonate, methacrylic anhydride, 2,2'-dimethoxy-2-phenyl-acetonephenone (DMPA), acryloyl chloride, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetrabutylammonium fluoride (TBAF), 4-(dimethylamino)-benzoic acid (DMAB), l-vinyl-2-pyrrolidone (VP), N,N- disuccinimidyl carbonate, sodium borate, sodium molybdate dihydf ate, sodium nitrite, 4-(dimethylamino)pyridine (DMAP), N-hydroxysuccinimide, N 9 N- diisopropylethylamine, dimethylformamide, and
- Camphorquinone (CQ) was obtained from Polysciences, Inc. (Warrington, PA). Acetone was dried over 4A molecular sieve and distilled over P 2 O 5 prior to use. Triethylamine was freshly distilled prior to use. All other chemical reagents were used as received.
- L-DOPA methyl ester hydrochloride was prepared according to the procedure of Patel and Price, J. Org. Chem., 1965, 30, 3575, which is incorporated herein by reference.
- Shearwater Polymers, Inc. Hauntsville, AL
- Ethyl acetate saturated with HCl was prepared by bubbling HCl gas through ethyl acetate (50 mL) for approximately 10 minutes.
- Glass coverslips (12mm dia.) used in the following examples were cleaned by immersing in 5% Contrad70 solution, a detergent which is an emulsion of anionic and nonionic surfactants in an allealtine aqueous base (Decon Labs, Inc., Bryn Mawr, PA) in an ultrasonic bath for 20 minutes, rinsed with deionized (DI) H 2 O, sonicated in DI H 2 O for 20 minutes, rinsed in acetone, sonicated in acetone for 20 minutes, rinsed in hexanes, sonicated in hexanes for 20 minutes, rinsed in acetone, sonicated in acetone for 20 minutes, rinsed in DI H 2 O, and sonicated in DI H 2 O for 20 minutes.
- DI deionized
- coverslips were subsequently air-dried in a HEPA-f ⁇ ltered laminar flow hood.
- clean coverslips were sputtered (Cressington 208HR) with 2 nm Cr followed by 10 urn Au (99.9% pure).
- Titanium oxide (TiO 2 ) surfaces were prepared by electron beam physical evaporation onto silicon (Si) wafer and cleaned in a plasma chamber prior to testing.
- Si wafers MEMC Electronic Materials, St. Peters, MO, surface orientation (100)
- the Si wafer was then cut into 8mm x 8mm pieces which were subsequently cleaned by ultrasonication in the following media: 5% Contrad70, ultrapure water (ultrapure water is deionized and distilled), acetone, and petroleum ether.
- the substrates were further cleaned in an oxygen plasma chamber (Harrick Scientific, Ossining, NY) at ⁇ 200 mTorr and IOOW for 3 minutes.
- XPS X-ray photoelectron spectroscopy
- a custom-built contact angle goniometer (components from Rame-Hart, Mountain Lakes, NJ) equipped with a humidified sample chamber was used to measure both advancing and receding contact angles of ultrapure water (18.2M ⁇ -cm; Barnstead, Dubuque, IA) on unmodified and modified substrates. For each surface, four measurements were made at different locations and the mean and standard deviation were reported. [00151] Surface Plasmon Resonance (SPR) measurements were made on a
- NIH 3T3 -Swiss albino fibroblasts obtained from ATCC (Manassas, VA) were maintained at 37°C and 10% CO 2 in Dulbecco's modified Eagle's medium (DMEM; Cellgro, Herndon, VA) containing 10% (v/v) fetal bovine serum (FBS) and 100U/ml of both penicillin and streptomycin.
- DMEM Dulbecco's modified Eagle's medium
- FBS fetal bovine serum
- modified and unmodified substrates were pretreated in 12-well TCPS plates with 1.0 ml of DMEM containing 10% FBS for 30 minutes at 37°C and 10% CO 2 .
- Fibroblasts of passage 12-16 were harvested using 0.25% trypsin-EDTA, resuspended in DMEM with 10% FBS, and counted using a hemocytometer.
- Cells were seeded at a density of 2.9 x 10 3 cell/cm 2 by diluting the suspension to the appropriate volume and adding 1 ml to each well.
- the substrates were maintained in DMEM with 10% FBS at 37°C and 10% CO 2 for 4 hours, after which time unattached cells were aspirated.
- Adherent cells on the substrates were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently treated with 5 ⁇ M l,l'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI; Molecular Probes, Eugene, OR) in DMSO for 30 minutes at 37°C.
- the stain was then aspirated and substrates were washed (3x) with DMSO for 10 minutes and mounted on glass slides using Cytoseal (Stephens Scientific, Kalamazoo, MI) to preserve fluorescence.
- PLURONIC® F127 (0.60 mmols) was dissolved in 30 mL of dry dioxane. ⁇ N'-Disuccinimidyl carbonate (6.0 mmols) in 10 mL dry acetone was added. DMAP (6.0 mmols) was dissolved in 10 mL dry acetone and added slowly under magnetic stirring. Activation proceeded 6 hours at room temperature, after which SC-PAO7 was precipitated into ether. The disappearance of the starting materials during the reaction was followed by TLC in chloroform-methanol (5:1) solvent system. The product was purified by dissolution in acetone and precipitation with ether four times. The product yield was 65%.
- PLURONICs® F 127 and F68 were determined using the colorimetric method of Waite and Benedict. Briefly, samples were analyzed in triplicate by diluting aliquots of standards or unknown solutions with 1 N HCl to a final volume of 0.9 mL. 0.9 mL of nitrite reagent (1.45 M sodium nitrite and 0.41 M sodium molybdate dihydrate) was added to the DOPA solution, followed immediately by the addition of 1.2 mL of 1 N NaOH. Due to time-dependent changes in absorbance intensity, care was taken to ensure that the time between the addition of NaOH and recording of the absorbance was 3 minutes for all standards and samples. The absorbance was recorded at 500 run for all standards and samples. DOPA was used as the standard for both the DOPA methyl ester and DOPA conjugates. Example 8
- the strain amplitude dependence of the viscoelastic data was checked for several samples, and measurements were only performed in the linear range where moduli were independent of strain amplitude.
- Mineral oil was applied to a ring surrounding the outer surfaces of the sample compartment to prevent dehydration during measurements.
- the crude product was concentrated under reduced pressure and purified by column chromatography on Sephadex® LH-20 with methanol as the mobile phase.
- the product, mPEG-DOPA was further purified by precipitation in cold methanol three times, dried in vacuum at room temperature, and stored under nitrogen at -20°C.
- DOPA-containing peptides and oligopeptides whether natural or synthetic in origin.
- use of an N-terminal protecting group may be optional.
- various other DOPA-like adhesive components can also be utilized, as would be well-known to those skilled in the art made aware of this invention. For instance, B-amino acids and N-substituted glycine DOPA analogs can be used.
- DHPD adhesive component a variety of polymeric components can be used in accordance with the synthetic techniques and procedures described above.
- the polymeric component can vary in molecular weight limited only by corresponding solubility concerns.
- a variety of other polymers can be used for surface anti-fouling and/or particle stabilization, such polymers including but not limited to hyaluronic acid, dextrans and the like.
- the polymeric component can be branched, hyperbranched or dendrimeric, such components available either commercially or by well-known synthetic techniques.
- Example 10a is the amidation product of the referenced starting materials
- comparable polymer-DHPD conjugates can be prepared coupling the N-terminus of a DHPD component to an end group, back bone or side chain of a suitably functionalized natural or synthetic polymer, including those described above.
- a suitable polymeric component terminating with a carbonate functionality can be used to provide the desired conjugate by reaction with the N-terminus of the desired DHPD component.
- the consensus decapeptide repeat sequence (mussel adhesive protein decapeptide, MAPd, NH 2 - Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOP A-LyS-CO 2 H) of the blue mussel Mytilus edulis foot protein 1 (Mefp 1) was synthesized by solid phase peptide synthesis on Rink resin (0.6 mMol/g) using Fmoc protected amino acids, BOP, HOBt, and DIEA as activating agents, and NMP as solvent. Fmoc deprotection was performed using a 25% piperidine solution in NMP for twenty minutes.
- Couplings of amino acids were performed using two equivalents of the Fmoc-amino acid BOP:HOBt:DIEA in a 1 : 1 : 1 : 1 ratio for twenty minutes, with an initial,Jen-minute preactivation step.
- the PEG-decapeptide conjugates (mPEG-MAPd, 2k or 5k) were cleaved at 0°C for two hours using 1 M TMSBr in TFA, with EDT, thioanisole, and m-cresol.
- the crude mPEG-MAPd products were precipitated in ether at O 0 C, and purified by preparative HPLC using a Vydac 218TP reverse phase column (22Ox 22mm x lO ⁇ m). The purity of the products was determined to be >90% using analytical HPLC, and the structures confirmed using a PerSeptive Biosystem MALDI-TOF-MS.
- Example 11a The synthesis and procedures of Example 11a can be extended analogous to and consistent with the variations illustrated in Example 10b.
- other conjugates can be prepared using DOPA-containing polymers prepared by enzymatic conversion of tyrosine residues therein.
- Other techniques well-known in the field of peptide synthesis can be used with good effect to provide other desired protein sequences, peptide conjugates and resulting adhesive/anti-fouling effects.
- Gold surfaces were modified by adsorption of mPEG-DOPA or mPEG-
- MAPd (2k, 5k) from solution in DCM or phosphate-buffered saline (PBS; pH 3, 7.4, and 11) at polymer concentrations ranging from 0.1-75 mg/ml.
- Au-coated glass coverslip Au thickness ⁇ 10 run
- Analysis of the modified surfaces by advancing/receding contact angle, XPS, and TOF- SIMS revealed the formation of a chemisorbed layer of mPEG-DOPA or mPEG- MAPd.
- Figures 7A-C shows the XPS spectra for the unmodified, mPEG-OH modified, and mPEG-DOPA modified surfaces.
- the ether peak at 286.5 eV increased only slightly with the mPEG-OH treatment, while a dramatic increase was observed after adsorption of mPEG-DOPA, indicating a large presence of ether carbons.
- An ether peak from a pure PEG with the same binding energy has been reported in the literature.
- the smaller peak at 285.0 eV in Figure 7 can be attributed to the aliphatic and aromatic carbons in the PEG and DOPA headgroup, as well as some hydrocarbon contamination resulting from the preparation/evacuation process.
- Time-of-flight SIMS data corroborated the XPS findings.
- TOF-SIMS analysis was carried out on unmodified and mPEG-DOPA-modif ⁇ ed Au substrates, as well as mPEG-DOPA powder and a gold substrate exposed to mPEG-OH. Data was collected from each substrate for about 4 minutes.
- DOPA was dominated by the presence of C a H b O c + peaks representing the adsorbed molecule.
- the relative abundance Of C 2 HsO + and C 2 H 5 O + increased with respect to unmodified and mPEG-OH modified surfaces.
- C 3 H 7 (m/z ⁇ 43) and C 4 H 5 + (m/z ⁇ 53) were also attributed to hydrocarbon contamination or the fragmentation of the t-butyl in the Boc protection group.
- the contact angle data demonstrated a firm dependence on the character of the adsorption solvent used when modifying the gold films with mPEG-DOPA (data not shown).
- the surface modified in DCM showed a significantly lower ⁇ a than the unmodified surface (pO.OOl) and the surfaces modified in all aqueous solutions (p ⁇ 0.05).
- the hydrophilicity of the treated surfaces was decreased, indicating a diminished ability to PEGylate the surfaces, perhaps due to the propensity of DOPA to be oxidized to its less adhesive quinone form at elevated pH, an interpretation that is supported by previous studies that showed the unoxidized catechol form of DOPA is primarily responsible for adhesion.
- Example 12a can be extended to other noble metals, including without limitation, silver and platinum surfaces.
- Such application can also be extended, as described herein, to include surface modification of any bulk metal or metal alloy having a passivating or oxide surface.
- bulk metal oxide and related ceramic surfaces can be modified, as described herein.
- semiconductor surfaces such as those used in the fabrication of integrated circuits and MEMS devices, as also illustrated below in the context of nanoparticulate stabilization.
- Silicate glass surfaces were modified by adsorption of mPEG-MAPd (2k) from a 10 niM solution in water, using the method described in Example 12a.
- the cell density of NIH 3T3 cells attached to modified and unmodified glass surfaces were evaluated as described, above. Glass surfaces modified for 24 hours with mPEG-MAPd exhibited a 43% reduction in cell density compared to unmodified glass surfaces (Cell Density (cells/mm 2 ): 75.5 +/- 6.5 on unmodified glass; 42.7 +/- 9.8 on mPEG-MAPd modified glass).
- mPEG-DOPA 50 mg was dissolved in water (18 M ⁇ -cm, Millipore) and combined with 1 mg of magnetite (Fe 3 O 4 ) powder. Similar preparations were also prepared using a HiPEG-NH 2 (5k) (Fluka) and a mPEG-OH (2k) (Sigma) as controls. Each of these aqueous solutions was sonicated using a Branson Ultrasonics 450 Probe Sonicator for one hour while being immersed in a 25°C bath. The probe had a frequency of 20 kHz, length of 160 mm, and tip diameter of 4.5 mm.
- mPEG-DOPA stabilized nanoparticles were characterized by transmission electron microscopy (TEM), thermogravimetric analysis (TGA), fourier transform, infrared spectroscopy (FTIR), and UV/vis spectroscopy.
- TEM results demonstrated that the majority of nanoparticles were of diameter of 5-20 nm (data not shown).
- the dry PEG-DOPA stabilized magnetite nanoparticles readily dispersed in aqueous and polar organic solvents (e.g., dichloromethane) to yield clear brown suspensions that were stable for months without the formation of noticeable precipitates.
- Suspensions of mPEG-DOPA stabilized nanoparticles in various solvents were prepared by dispersing 1 mg of mPEG-DOPA treated magnetite in 1 ml of water (18 M ⁇ -cm filtered using a Millex® AP 0.22 ⁇ m filter (Millipore)), DCM or Toluene. Suspensions were placed in a bath sonicator for ten minutes to disperse the nanoparticles. All three solutions were stable at room temperature for at least six months, whereas control suspensions of unmodified magnetite and magnetite stabilized by mPEG-OH or HiPEG-NH 2 precipitated out in less than 24 hours in each solvent.
- CdS nanoparticles (quantum dots) were prepared by a standard method based on the slow mixing of dilute Cd(NO 3 ) 2 and Na 2 S solutions. Fresh stock solutions (2 niM) of Cd(NO 3 ) 2 and Na 2 S were prepared in nanopure water. The Na 2 S solution was injected slowly into 50 ml of Cd(NOs) 2 solution using a gastight syringe at a rate of 20 ⁇ l s "1 . The solution turned yellow with the addition OfNa 2 S, and after 2 mL OfNa 2 S was injected, a yellow precipitate appeared due to the aggregation of CdS nanoparticles.
- the CdS precipitate was isolated and dried for further use. Using the method described above for magnetite, the dry CdS powder was dispersed in a mPEG- DOPA solution by sonication to yield a clear yellow solution. The yellow aqueous suspension was stored in the dark for several months at room temperature without visible formation of precipitate. Control experiments performed in the absence of polymer and in the presence of mPEG-OH or mPEG-NH 2 yielded yellow precipitate and a clear, colorless supernatant. mPEG-DOPA stabilized CdS nanoparticles remained stably suspended in the presence of aqueous NaCl ( Figure 18).
- polymeric conjugate compositions of this invention can also be used to stabilize a variety of other semiconductor materials.
- core-shell nanoparticles can be surface stabilized in accordance herewith.
- the contact angle data would support the use of an organic solvent in an optimal modification protocol as a means to reduce catechol oxidation. Additionally, only the surface modified in DCM demonstrated significantly fewer cells on the surface and lower total projected cellular area.
- Figure 13 illustrates the differences in attachment and spreading of fibroblasts on bare Au, mPEG-OH-treated Au, and Au modified with mPEG-DOPA 5K, mPEG-MAPd 2K, or mPEG-MAPd 5K under optimal conditions (50 mg/ml for 24 hours).
- the surfaces modified with DOPA- containing conjugates have significantly less cellular adhesion and spreading than either of the other two surfaces.
- the mPEG-MAP 5K modification though, accounted for a 97% reduction in total projected cellular area and a 91% reduction in density of cells on the surface, a far greater reduction than that achieved by mPEG-DOPA 2K.
- N-hydroxysuccinimide (0.110 g, 0.95 mmol) was added to a solution ofBoc-DOPA(TBDMS) 2 (0.500 g, 0.95 mmol) in dry dichloromethane (DCM) (8.0 mL). The solution was stirred on an ice bath, and 1,3-dicyclohexylcarbodiimide (DCC) (0.197 g, 0.95 mmol) was added under nitrogen atmosphere. The reaction was stirred for 20 minutes at 0 0 C and then warmed to room temperature and stirred for an additional 4 hours. The reaction mixture was filtered to remove the urea byproduct and subsequently evaporated to 1/5 of its original volume.
- DCM dry dichloromethane
- Boc-DOPA(TBDMS) 2 -OSu (0.567 g, 0.91 mmol) was dissolved in dry dimethylformamide (DMF) (2.5 mL), and DOPA(TBDMS) 2 (0.405 g, 0.95 mmol) was added at once under a nitrogen atmosphere. The mixture was stirred on an ice bath, and diisopropylethylamine (DIEA) (158 ⁇ L, 0,91 mmol) was added dropwise via a syringe.
- DIEA diisopropylethylamine
- Boc-DOPA 2 (TBDMS) 4 (0.5 g, 0.54 mmol) was dissolved in saturated
- Solid metal substrates Al, 316L stainless steel and NiTi
- Si wafers were ground and polished, ultimately with 0.04 m colloidial silica (Syton, DuPont).
- Si wafers were evaporated with either 20 nm TiO 2 or 10 nm Ti ⁇ 2/40 nm Au using an Edwards FL400 electron beam evaporator at ⁇ 10 "6 Torr and were subsequently diced in 8 mm x 8 mm pieces.
- AU substrates were cleaned ultrasonically for 20 minutes in each of the following: 5% Contrad70 (Fisher Scientific), ultrapure H 2 O 3 acetone, and petroleum ether.
- TiO 2 substrates were modified under cloud point conditions by immersion in HiPEG-DOPA 1-3 solutions in 0.6 M K 2 SO 4 buffered with 0.1 MN- morpholinopropanesulfonic acid (MOPS) at 5O 0 C for 24 hours. Modified substrates were rinsed with ultrapure H 2 O and dried under a stream of nitrogen.
- MOPS morpholinopropanesulfonic acid
- 316L Stainless Steel (Goodfellow, Devon PA) was modified under cloud point conditions by immersion in mPEG-DOPAj- 3 solutions in 0.6 M K 2 SO 4 buffered with 0.1 M N-morpholinopropanesulfonic acid (MOPS) at 5O 0 C for 24 hours. Modified substrates were rinsed with ultrapure H 2 O and dried under a stream of nitrogen.
- MOPS N-morpholinopropanesulfonic acid
- Al 2 O 3 (Goodfellow, Devon PA) was modified under cloud point conditions by immersion in mPEG-DOPA 1-3 solutions in 0.6 M K 2 SO 4 buffered with 0.1 M N-morpholinopropanesulfonic acid (MOPS) at 5O 0 C for 24 hours. Modified substrates were rinsed with ultrapure H 2 O and dried under a stream of nitrogen.
- MOPS N-morpholinopropanesulfonic acid
- SiO 2 (1500A thermal oxide, University Wafer, South Boston, MA) was modified under cloud point conditions by immersion in mPEG-DOPA 1-3 solutions in 0.6 M K 2 SO 4 buffered with 0.1 M N-morpholinopropanesulfonic acid (MOPS) at 50 0 C for 24 hours. Modified substrates were rinsed with ultrapure H 2 O and dried under a stream of nitrogen.
- MOPS N-morpholinopropanesulfonic acid
- NiTi alloy (10mm x 10mm x lmm) was obtained from Nitinol Devices
- Au electro beam evaporated onto Si Wafer from University Wafer
- HiPEG-DOPA 1-3 solutions in 0.6 M K 2 SO 4 buffered with 0.1 M N-morpholinopropanesulfonic acid (MOPS) at 5O 0 C for 24 hours.
- Modified substrates were rinsed with ultrapure H 2 O and dried under a stream of nitrogen.
- MOPS N-morpholinopropanesulfonic acid
- Au 2 O 3 (Au samples as described in Example 28f were exposed to an oxygen plasma to form Au2O3) was modified under cloud point conditions by immersion in mPEG-DOPAi- 3 solutions in 0.6 M K 2 SO 4 buffered with 0.1 M N- morpholinopropanesulfonic acid (MOPS) at 5O 0 C for 24 hours. Modified substrates were rinsed with ultrapure H 2 O and dried under a stream of nitrogen.
- MOPS N- morpholinopropanesulfonic acid
- GaAs Universal Wafer, South Boston, MA
- MOPS N-morpholinopropanesulfonic acid
- 3T3 Swiss albino fibroblasts (ATCC, Manassas, VA) of passage 12-16 were cultured normally at 37 0 C and 5% CO 2 in Dulbecco's modified Eagle's medium (DMEM) (Cellgro, Herndon, VA) supplemented with 10% fetal bovine serum (FBS) (Cellgro, Herndon, VA), 100 g/mL penicillin, and 100 U/mL steptomycin. Prior to cell adhesion assays, fibroblasts were harvested using 0.25% trypsin-EDTA, resuspended in growth medium, and counted with a hermacytometer.
- DMEM Dulbecco's modified Eagle's medium
- FBS fetal bovine serum
- Test substrates were prepared in 12-well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 cells/cm and maintained in DMEM with 10% FBS at 37 0 C and 5% CO 2 for 4 hours.
- Test substrates were prepared in 12-well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 cells/cm and maintained in DMEM with 10% FBS at 37 0 C and 5% CO 2 for 4 hours.
- adherent cells were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently stained with 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR) in DMSO for 45 minutes at 37 0 C.
- DI 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate
- Test substrates were prepared in 12-well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 3 cells/cm 2 and maintained in DMEM with 10% FBS at 37 0 C and 5% CO 2 for 4 hours.
- adherent cells were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently stained with 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR) in DMSO for 45 minutes at 37 0 C.
- DI 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate
- Test substrates were prepared in 12-well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 3 cells/cm 2 and maintained in DMEM with 10% FBS at 37 0 C and 5% CO 2 for 4 hours.
- adherent cells were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently stained with 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR) in DMSO for 45 minutes at 37 0 C.
- DI 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate
- Test substrates were prepared in 12- well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 cells/cm and maintained in DMEM with 10% FBS at 37°C and 5% CO 2 for 4 hours.
- adherent cells were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently stained with 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR) in DMSO for 45 minutes at 37 0 C.
- DI 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate
- Test substrates were prepared in 12-well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 cells/cm and maintained in DMEM with 10% FBS at 37 0 C and 5% CO 2 for 4 hours.
- adherent cells were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently stained with 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR) in DMSO for 45 minutes at 37°C.
- DI 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate
- Test substrates were prepared in 12- well tissue culture polystyrene plates with 1.0 niL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 cells/cm and maintained in DMEM with 10% FBS at 37 0 C and 5% CO 2 for 4 hours.
- Test substrates were prepared in 12-well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 cells/cm and maintained in DMEM with 10% FBS at 37 0 C and 5% CO 2 for 4 hours.
- adherent cells were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently stained with 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR) in DMSO for 45 minutes at 37 0 C.
- DI 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate
- GaAs substrate (4-hour assay)
- Test substrates were prepared in 12-well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 cells/cm and maintained in DMEM with 10% FBS at 37°C and 5% CO 2 for 4 hours.
- adherent cells were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently stained with 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR) in DMSO for 45 minutes at 37 0 C.
- DI 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate
- Test substrates were prepared in 12-well tissue culture polystyrene plates with 1.0 mL DMEM with FBS for 30 minutes at 37 0 C and 5% CO 2 . Cells were seeded onto the substrates at a density of 2.9 x 10 3 cells/cm and maintained in DMEM with 10% FBS at 37 0 C and 5% CO 2 for 4 hours.
- adherent cells were fixed in 3.7% paraformaldehyde for 5 minutes and subsequently stained with 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR) in DMSO for 45 minutes at 37 0 C.
- DI 5 ⁇ M l,r-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate
- Silicon wafers (WaferNet GmbH, Germany) were coated with TiO 2 (20 nm) by physical vapor deposition using reactive magnetron sputtering (PSI, Villigen, Switzerland). Metal oxide coated wafers were subsequently diced into 1 cm x 1 cm pieces for ex-situ ellipsometry measurements.
- Optical waveguide chips for OWLS measurements were purchased from Microvacuum Ltd. (Budapest, Hungary) and consisted of a AF45 glass substrate (8 x 12 x 0.5 mm) and a 200 nm-thick Si O-25 Ti 0J sO 2 waveguiding surface layer.
- TiO 2 -coated silicon wafers and waveguide chips were sonicated in 2-propanol for 10 minutes, rinsed with ultrapure water, and dried under a stream of nitrogen, followed by a 3 minute exposure to O 2 plasma (Harrick Scientific, Ossining, USA) to remove all organic components from the surface.
- O 2 plasma Hard Scientific, Ossining, USA
- waveguides were regenerated for reuse by sonication (10 minute) in cleaning solution (300 niM HCl, 1% detergent; Roche Diagnostics, Switzerland) and subsequent rinsing with ultrapure water to remove adsorbates.
- XPS X-ray Photoelectron Spectroscopy
- Measured intensities were converted to normalized intensities by atomic sensitivity factors, from which atomic compositions of surfaces were calculated. Average values obtained from three substrate replicates is reported in Tables 8-9. Standard deviations were typically ⁇ 10% of the mean and are omitted for clarity.
- a B A clean TiO 2 0.27 2.10 0.28 0.33 0.42 0.20 mPEG-
- OWLS Optical Waveguide Lightmode Spectroscopy
- the incoupling angles, CX TM and ⁇ E5 were recorded and converted to refractive indices (N TM5 N-re) by the manufacturer-supplied software. Real-time changes in the effective refractive index of the sensor were converted to adsorbed mass using de Feijter's formula.
- the refractive index increment, dn/dc, for each mPEG-DOPA polymer was calculated by linear interpolation between 0.13 cm 3 /g for pure PEG and 0.18 cm 3 /g for pure poly(amino acid).
- the temperature of the measurement head was equilibrated at 37 °C until the signal stabilized, after which serum was injected for 15 minutes followed by injection of buffer. Substantial differences in adsorbed mass were not observed with increases in serum exposure time.
- the crude product was loaded onto silica gel and eluted with DCM, 5% methanol in DCM, 10% methanol in DCM, and 15% methanol in DCM.
- the solvent was removed under vacuum to yield 5 as a white solid. The yield was 63%.
- Precursor solutions of PEG-DA, 1, 7, and photoinitiator were prepared and mixed immediately before photopolymerization.
- Stock solutions of PEG-DA (200 mg/mL) and 1 (40 mg/mL) were dissolved in N 2 -purged phosphate buffered saline (PBS 5 pH 7.4), where 7 (60 mg/mL) was dissolved in 50:50 PBS/95% ethanol previously purged with N 2 .
- solutions of 1 or 7 were combined with PEG-DA to achieve a final concentration of PEG-DA and DHPD derivatives of 150 mg/mL.
- the final VP concentration was adjusted to be between 135 and 300 mM.
- the amount of DOPA incorporated into the photopolymerized gel was determined using a modification of the colorimetric DOPA assay developed by Waite and Benedict. Photocross-linked gels were stirred in 3 mL of 0.5 N HCI to extract DOPA monomers that were not incorporated into the gel network. 0.9 mL of the nitrite reagent (1.45 M sodium nitrite and 0.41 M sodium molybdate dihydrate) and 1.2 mL of IM NaOH were added to 0.9 mL of the extraction solution, and the absorbance (500 urn) of the mixture were recorded using a Hitachi U-2010 U V- Vis spectrophotometer with 2 to 4 minutes of NaOH addition. Standard curves were constructed using known 1 to 7 concentrations.
- the other end of the cylinder was attached to a piezoelectric stepping motor (IW-701-00, Burleigh Instruments, NY) aligned in series with a 50 g load transducer (FTD-G-50, Schaevitz Sensors, VA) with a resolution of approximately 0.1 mN.
- a fiber optic displacement sensor (RC100-GM2OV, Philtec, Inc., MD) measured the axial movement of the steel rod.
- a Ti ⁇ 2 -coated Si wafer was positioned below the hydrogel, and the Tio 2 surface was flooded with PBS in order to maintain the hydration of the gel. The indenter was advanced at 5 ⁇ m/s until a maximum compressive load of 4 mN was measured.
- Elastic moduli were calculated by assuming Hertzian mechanics for the specific case of non-adhesive contact between an incompressible elastic hemisphere and a rigid plane, in which case the Hertzian relationship between load (P h ) and displacement ( ⁇ h) becomes: 16R 1/2 E s 3/ 2 (u
- R and E are the radius of curvature and the elastic modulus of the hemispherical gel, respectively.
- the radius of curvature of the gels was determined from height and width measurements obtained from a photograph of the gel.
- Triethylamine (Et 3 N), hydrogen peroxide (30 wt%, H 2 O 2 ), sodium molybdate dihydrate, and sodium nitrite were purchased from Aldrich Chemical Company (Milwaukee, WI). L-Dopa was purchased from Lancaster (Windham, NH). 1-Hydroxybenzotriazole (HOBt) was obtained from Novabiochem Corp. (La Jolla, CA) and O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) was acquired from Advanced ChemTech (Louisville, KY). Synthesis ofDOPA-ModifiedPEG
- DOPA endgroups were synthesized using standard carbodiimide coupling chemistry as described below.
- the structure of the four DOPA-modified PEG's are shown in Figure 1.
- the solution was successively washed with saturated sodium chloride solution, 5% NaHCO 3 , diluted HCl solution, and distilled water.
- the crude product was concentrated under reduced pressure and purified by column chromatography on Sephadex® LH-20 with methanol as the mobile phase.
- the product was further purified by precipitation in cold methanol three times, dried in vacuum at room temperature, and stored under nitrogen at -2O 0 C.
- the DOPA assay was based on the previously described method of Waite and Benedict. Briefly, PEG-DOPA aqueous solutions were treated with nitrite reagent
- PEG-DOPA hydrogels sodium periodate (NaIO 4 ), horseradish peroxidase and hydrogen peroxide (HRPZH 2 O 2 ), or mushroom tyrosinase and oxygen
- MT/0 2 were added to solutions of PEG-DOPA (200 mg/mL) in phosphate buffered saline (PBS 5 pH 7.4).
- PBS 5 pH 7.4 phosphate buffered saline
- Gelation time was qualitatively determined to be when the mixture ceased flowing, as measured by inversion of a vial containing the fluid.
- Oscillatory rheometry was used to monitor the process of gelation and to determine the mechanic properties of the hydrogels.
- Cross-linking reagent was added to aqueous solution of PEG-DOPA and the well-mixed solution was loaded onto a Bohlin VOR rheometer. The analysis was performed at a frequency of 0.1 Hz, a strain of 1%, and a 30 mm diameter cone and plate fixture with a cone angle of 2.5°.
- DOP A-modified PEG was dissolved in 10 mM PBS solution (bubbled with argon for HRP/H 2 O 2 and NaIO 4 or air for MT experiments). After adding the oxidizing reagent, the time-dependent UV/vis spectra of the solution were monitored at wavelengths from 200 to 700 nm at a scan rate of 800 nm/min. AU samples were initially blanked against PBS buffer and recorded at room temperature using a Hitachi U-2010 UV/vis spectrophotometer. Molecular Weight Analysis
- PEG polyethylene glycol
- Fmoc- PEG-NHS provides an amine for Boc-DOPA conjugation after Fmoc cleavage.
- Piperidine (20% v/v in NMP) was used to deprotect Fmoc for 5 min and subsequently cantilevers were transferred to BOP/HOBt/DOPA (a molar ratio of 1:1:1, final 8mM in NMP) solution with 10 ⁇ L DIPEA. The same procedure was used for Tyrosine modification.
- Loading rate dependent force measurement revealed the energy landscape of DOPA binding (17).
- the binding energy barrier is calculated by the force of logarithmic intercept at zero loading rate from the force transition occurred by pulling rate change and xb from the slope.
- Silicon nitrite AFM cantilevers (Bio-Levers, Olympus, Japan) were used because of their small string constants ( ⁇ 5 pN/nm and -28 pN/nm).
- XPS X-ray photoelectron microscopy
- Silicon nitride surfaces (0.7 x 0.7 cm2) prepared in the high temperature chamber (ask to Keun Ho) were cleaned and modified as the same procedures described in AFM tip modification.
- the photoelectron signal from carbon Is orbital was the major indicator for surface modification considering all abundant species of Si, O, and N in Si3N4 surfaces.
- OEGMEMA monomers (Aldrich) were passed through an activated basic alumina (Aldrich) column to remove the inhibitor.
- Other reagents for initiator synthesis and polymerization were purchased from commercial sources and used without further purification.
- Si- wafer MEMC Electronic Materials, St.
- OEGMEMA oligo(ethylene glycol) methyl ether methacrylate
- Mn oligo(ethylene glycol) methyl ether methacrylate
- n can range from about 4 to about 9.
- the modified substrates were placed in a 3 -neck flask under Ar flow.
- PM-IRRAS Polarization-modulation infrared reflection-adsorption spectroscopy
- NEXUS 870 Fourier transform infrared spectrometer equipped with a tablet optics module (TOM) and a mercury-cadmium-tellurium (CAT) detector.
- TOM tablet optics module
- CAT mercury-cadmium-tellurium
- T3-Swiss albino fibroblasts obtained from ATCC (Manassas, VA) were maintained at 37 0 C and 10% CO 2 in Dulbecco's modified Eagle's medium (DMEM; Cellgro, Herndon, VA) containing 10% fetal bovine serum (FBS) and 100 ⁇ g/mL of penicillin and 100 U/mL of streptomycin.
- DMEM Dulbecco's modified Eagle's medium
- FBS fetal bovine serum
- fibroblasts of passage 12-16 were harvested using 0.25% trypsin-EDTA, resuspended in DMEM with 10% FBS, and counted using a hemocytometer. Quantification of Cell Adhesion
- DMEM containing FBS for 30 min at 37 0 C and 10% CO 2 DMEM containing FBS for 30 min at 37 0 C and 10% CO 2 .
- Cells were seeded onto the substrates at a concentration of 10 x 10 3 cells/mL and maintained for 4 hours in DMEM with 10% FBS at 37 0 C and 10% CO 2 .
- Nonadherent cells were removed by aspirating the medium in each well.
- Adherent cells were fixed in 3.7% paraformaldehyde for 5 min and subsequently stained with 5 ⁇ M l,l'-dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine perchlorate (DiI; Molecular Probes, Eugene, OR) in DMSO for 45 min.
- DI 5 ⁇ M l,l'-dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine perchlorate
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Non-Patent Citations (5)
Title |
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DALSIN J L ET AL: "Mussel Adhesive Protein Mimetic Polymers for the Preparation of Nonfouling Surfaces" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, NEW YORK, USA, vol. 125, no. 14, 1 January 2003 (2003-01-01), pages 4253-4258, XP003013546 ISSN: 0002-7863 * |
GU B ET AL: "Synthesis of Aluminium Oxide/Gradient Copolymer Composites by Atom Transfer Radical Polymerization" MACROMOLECULES, ACS, WASHINGTON, DC, US, vol. 35, no. 23, 1 January 2002 (2002-01-01), pages 8913-8916, XP003013545 ISSN: 0024-9297 * |
PYUN J ET AL: "Synthesis of Polymer Brushes Using Atom Transfer Radical Polymerization" MACROMOLECULAR: RAPID COMMUNICATIONS, WILEY VCH VERLAG, WEINHEIM, DE, vol. 24, no. 18, 1 January 2002 (2002-01-01), pages 1043-1059, XP003013544 ISSN: 1022-1336 * |
RAJH T ET AL: "Surface Restrcturing of Nanoparticles: An Efficient Route for Ligend-Metal Oxide Grosstalk" JOURNAL OF PHYSICAL CHEMISTRY. B (ONLINE), AMERICAN CHEMICAL SOCIETY, COLUMBUS, OH, US, vol. 106, no. 41, 1 January 2002 (2002-01-01), pages 10543-10552, XP003013547 ISSN: 1520-5207 * |
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