CN112716885A - Nucleic acid micro needle and preparation method and application thereof - Google Patents
Nucleic acid micro needle and preparation method and application thereof Download PDFInfo
- Publication number
- CN112716885A CN112716885A CN202110042010.1A CN202110042010A CN112716885A CN 112716885 A CN112716885 A CN 112716885A CN 202110042010 A CN202110042010 A CN 202110042010A CN 112716885 A CN112716885 A CN 112716885A
- Authority
- CN
- China
- Prior art keywords
- nucleic acid
- microneedle
- gas
- needle
- bromide
- 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.)
- Pending
Links
- 108020004707 nucleic acids Proteins 0.000 title claims abstract description 132
- 102000039446 nucleic acids Human genes 0.000 title claims abstract description 132
- 150000007523 nucleic acids Chemical class 0.000 title claims abstract description 132
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 239000000758 substrate Substances 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 5
- 238000007920 subcutaneous administration Methods 0.000 claims abstract description 5
- 239000011550 stock solution Substances 0.000 claims description 21
- 108020004414 DNA Proteins 0.000 claims description 17
- -1 cidentamine Chemical compound 0.000 claims description 9
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 9
- LEJBBGNFPAFPKQ-UHFFFAOYSA-N 2-(2-prop-2-enoyloxyethoxy)ethyl prop-2-enoate Chemical compound C=CC(=O)OCCOCCOC(=O)C=C LEJBBGNFPAFPKQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 229910002651 NO3 Inorganic materials 0.000 claims description 6
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- IWOUKMZUPDVPGQ-UHFFFAOYSA-N barium nitrate Chemical compound [Ba+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O IWOUKMZUPDVPGQ-UHFFFAOYSA-N 0.000 claims description 6
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 6
- 229960004316 cisplatin Drugs 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 6
- 238000001723 curing Methods 0.000 claims description 6
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 6
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 6
- 229960005277 gemcitabine Drugs 0.000 claims description 6
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Chemical class 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 6
- 208000017520 skin disease Diseases 0.000 claims description 5
- 102000053602 DNA Human genes 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229920002477 rna polymer Polymers 0.000 claims description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 3
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 claims description 3
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 3
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 claims description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 3
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 3
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims description 3
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
- 229910021575 Iron(II) bromide Inorganic materials 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 3
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- 108091093037 Peptide nucleic acid Proteins 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 3
- 108091046915 Threose nucleic acid Proteins 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 claims description 3
- 229960004176 aclarubicin Drugs 0.000 claims description 3
- NKQIMNKPSDEDMO-UHFFFAOYSA-L barium bromide Chemical compound [Br-].[Br-].[Ba+2] NKQIMNKPSDEDMO-UHFFFAOYSA-L 0.000 claims description 3
- 229910001620 barium bromide Inorganic materials 0.000 claims description 3
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 claims description 3
- 229910001626 barium chloride Inorganic materials 0.000 claims description 3
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 3
- 229960002707 bendamustine Drugs 0.000 claims description 3
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 3
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 3
- 229940127093 camptothecin Drugs 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- WIVXEZIMDUGYRW-UHFFFAOYSA-L copper(i) sulfate Chemical compound [Cu+].[Cu+].[O-]S([O-])(=O)=O WIVXEZIMDUGYRW-UHFFFAOYSA-L 0.000 claims description 3
- 239000002537 cosmetic Substances 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 229960000684 cytarabine Drugs 0.000 claims description 3
- 229960000975 daunorubicin Drugs 0.000 claims description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 3
- 125000004386 diacrylate group Chemical class 0.000 claims description 3
- RJYMRRJVDRJMJW-UHFFFAOYSA-L dibromomanganese Chemical compound Br[Mn]Br RJYMRRJVDRJMJW-UHFFFAOYSA-L 0.000 claims description 3
- 229960002918 doxorubicin hydrochloride Drugs 0.000 claims description 3
- 229960003265 epirubicin hydrochloride Drugs 0.000 claims description 3
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960005073 erlotinib hydrochloride Drugs 0.000 claims description 3
- 229940046149 ferrous bromide Drugs 0.000 claims description 3
- 229960002089 ferrous chloride Drugs 0.000 claims description 3
- 239000011790 ferrous sulphate Substances 0.000 claims description 3
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 229960002949 fluorouracil Drugs 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 229920002674 hyaluronan Polymers 0.000 claims description 3
- 229960003160 hyaluronic acid Drugs 0.000 claims description 3
- 229960004768 irinotecan Drugs 0.000 claims description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 3
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 3
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 3
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 3
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 0.000 claims description 3
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 3
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 239000011565 manganese chloride Substances 0.000 claims description 3
- 235000002867 manganese chloride Nutrition 0.000 claims description 3
- 229940099607 manganese chloride Drugs 0.000 claims description 3
- MIVBAHRSNUNMPP-UHFFFAOYSA-N manganese(2+);dinitrate Chemical compound [Mn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MIVBAHRSNUNMPP-UHFFFAOYSA-N 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- 244000005700 microbiome Species 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- 229960005079 pemetrexed Drugs 0.000 claims description 3
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 3
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 3
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 claims description 3
- 229960000487 sorafenib tosylate Drugs 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
- 229960004528 vincristine Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 3
- 229940102001 zinc bromide Drugs 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 3
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 3
- 229960001763 zinc sulfate Drugs 0.000 claims description 3
- 229920000945 Amylopectin Polymers 0.000 claims description 2
- 238000013007 heat curing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims 1
- 238000005086 pumping Methods 0.000 claims 1
- 201000004681 Psoriasis Diseases 0.000 abstract description 4
- 230000002159 abnormal effect Effects 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 239000011159 matrix material Substances 0.000 abstract description 4
- 231100000241 scar Toxicity 0.000 abstract description 4
- 230000000149 penetrating effect Effects 0.000 abstract description 3
- 241001391944 Commicarpus scandens Species 0.000 abstract description 2
- 206010020751 Hypersensitivity Diseases 0.000 abstract description 2
- 208000030961 allergic reaction Diseases 0.000 abstract description 2
- 238000004132 cross linking Methods 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 238000001415 gene therapy Methods 0.000 abstract description 2
- 230000009885 systemic effect Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
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- 210000003491 skin Anatomy 0.000 description 16
- 210000001519 tissue Anatomy 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
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Abstract
The invention provides a nucleic acid micro-needle and a preparation method and application thereof, wherein the micro-needle comprises a substrate and a needle body on the substrate; the substrate and the needle body in the micro needle both use nucleic acid as matrix materials, have wide sources, are a gene therapy means based on nucleic acid, and can load trace drugs to break through the obstruction of the skin cuticle and enable the drugs to be locally released on the skin; in addition, the nucleic acid microneedle prepared by the reverse mould method has excellent mechanical property, is not easy to break, and can smoothly penetrate into the skin, thereby achieving the painless administration effect, and further being used for medical cosmetology, subcutaneous tumor, abnormal scar, psoriasis and other diseases; the microneedle material of the present invention is preferably a naturally extracted nucleic acid, and a crosslinked nucleic acid obtained by crosslinking the naturally extracted nucleic acid and the artificial nucleic acid with a crosslinking agent, and the microneedle does not cause allergic reaction, local tissue reaction or systemic toxic reaction after penetrating into the skin, and therefore, the microneedle should have good biocompatibility.
Description
Technical Field
The invention belongs to the technical field of biomedical engineering, and particularly relates to a nucleic acid microneedle, and a preparation method and application thereof.
Background
Transdermal administration is an administration mode in which a drug is absorbed through the skin route and exerts its drug effect locally or systemically on the skin. Compared with the most common clinical injection administration and oral administration, the transdermal administration can greatly reduce the pain, avoid the first pass effect of the liver and avoid the metabolism of the gastrointestinal tract. However, due to the obstruction of the stratum corneum, which is the outermost layer of the skin, hydrophilic or high molecular weight drugs are difficult to permeate the skin effectively, resulting in low permeation efficiency and low utilization rate of the drugs.
The microneedle is used as a novel transdermal drug delivery system, can puncture the stratum corneum without touching nerves or blood vessels when acting on the skin, relieves the pain of patients, improves the use compliance and improves the transdermal drug permeation efficiency. The soluble microneedle is prepared by taking soluble or biodegradable polymer or saccharide as a matrix, can be completely dissolved at an action part after penetrating into skin, and releases the drug so as to play a drug effect. The nucleic acid is a biological material with wide source, good biocompatibility, biodegradability and low toxicity, and the pure nucleic acid is used as the material of the microneedle body and has not been documented.
Disclosure of Invention
In view of the deficiencies of the prior art, it is a primary object of the present invention to provide a nucleic acid microneedle.
The second object of the present invention is to provide a method for preparing the above nucleic acid microneedles.
The third purpose of the invention is to provide the application of the nucleic acid micro-needle.
In order to achieve the above primary object, the solution of the present invention is:
a nucleic acid micro needle comprises a substrate and a needle body on the substrate, wherein the substrate is made of more than one material selected from nucleic acid, hyaluronic acid, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, sodium carboxymethylcellulose and amylopectin;
the needle body is made of nucleic acid.
In a preferred embodiment of the invention, the nucleic acid is selected from one or more of natural nucleic acids, artificial nucleic acids and cross-linked nucleic acids.
In a preferred embodiment of the invention, the natural nucleic acid comprises at least one of DNA or RNA of animal tissue, plant tissue, a microorganism; artificial nucleic acids include in vitro synthesis of DNA.
In a preferred embodiment of the present invention, the crosslinked nucleic acid includes nucleic acids synthesized with a crosslinking agent between natural nucleic acids, nucleic acids synthesized with a crosslinking agent between artificial nucleic acids, and nucleic acids synthesized with a crosslinking agent between natural nucleic acids and artificial nucleic acids.
In a preferred embodiment of the present invention, the crosslinking agent is selected from one or more of diethylene glycol diacrylate, polyethylene glycol diacrylate, a metal salt, and cisplatin.
In a preferred embodiment of the present invention, the metal salt is selected from one or more of zinc sulfate, zinc nitrate, zinc chloride, zinc bromide, ferrous sulfate, ferrous nitrate, ferrous chloride, ferrous bromide, cuprous sulfate, cuprous nitrate, cuprous chloride, cuprous bromide, cupric sulfate, cupric nitrate, cupric chloride, cupric bromide, magnesium sulfate, magnesium nitrate, magnesium chloride, magnesium bromide, calcium nitrate, calcium chloride, calcium bromide, barium nitrate, barium chloride, barium bromide, manganese nitrate, manganese chloride, and manganese bromide.
In a preferred embodiment of the invention, the nucleic acid is selected from one or more of deoxyribonucleic acid, ribonucleic acid, and nucleic acid analogs.
In a preferred embodiment of the invention, the nucleic acid analogue is selected from more than one of a peptide nucleic acid and a threose nucleic acid.
In the preferred embodiment of the invention, the radius of the needle body is 1-400 μm, the height is 100-3000 μm, and the distance between the adjacent needle bodies is 1-2000 μm.
In a preferred embodiment of the present invention, the shape of the needle body is selected from one or more of a conical shape, a pyramidal shape, a bullet shape, and a polygonal star-like conical shape.
In the preferred embodiment of the invention, the needle body can be loaded with medicine, and the medicine content is 0-1 g.
In a preferred embodiment of the invention, the drug is selected from one or more of cisplatin, bendamustine, doxorubicin hydrochloride, daunorubicin, gemcitabine, cidamide, cytarabine, methotrexate, pemetrexed, hydroxyurea, 10-hydroxycamptothecin, irinotecan, paclitaxel, vincristine, erlotinib hydrochloride, sorafenib tosylate, aclarubicin, epirubicin hydrochloride, camptothecin, autumine, 5-fluorouracil, and gemcitabine.
In order to achieve the second objective, the solution of the invention is:
a method for preparing the nucleic acid microneedle comprises the following steps:
(1) mixing nucleic acid and water to prepare stock solution gel;
(2) adding the stock solution gel into a microneedle mould, and fully filling the stock solution gel into the microneedle mould by a vacuumizing or centrifuging method;
(3) and removing the micro-needle mold after drying and curing to obtain the nucleic acid micro-needle.
In a preferred embodiment of the present invention, in step (1), the content of the nucleic acid in the stock solution gel is 0.5 to 60% by weight.
In the preferred embodiment of the present invention, in step (2), the vacuum is applied at a negative pressure of (-120) - (-60) kPa for a period of 5-60 min.
In the preferred embodiment of the present invention, in step (2), the rotation speed of centrifugation is 1000-.
In a preferred embodiment of the present invention, in the step (3), the microneedles are cured in one or more selected from the group consisting of thermosetting and freeze-drying curing.
The method of preparing the microneedles includes a 3D printing method and a thermal drawing method in addition to the above-described inverse mold method.
In order to achieve the third object, the solution of the invention is:
the application of the nucleic acid microneedle in medical cosmetic plastic, subcutaneous tumor and skin disease treatment is disclosed.
The skin diseases include, but are not limited to, abnormal scars, psoriasis and the like.
Due to the adoption of the scheme, the invention has the beneficial effects that:
the micro-needle takes nucleic acid as a matrix material, is a gene therapy means based on nucleic acid, and can be loaded with trace drugs to break through the obstruction of the skin cuticle so that the drugs are locally released on the skin; in addition, the nucleic acid microneedle prepared by the reverse mold method has excellent mechanical property, is not easy to break, can smoothly penetrate into the skin, thereby achieving the painless administration effect, and further can be used for medical cosmetology, subcutaneous tumors, abnormal scars, psoriasis and other diseases.
Second, the microneedle material of the present invention is preferably a naturally extracted nucleic acid, and a crosslinked nucleic acid obtained by crosslinking the naturally extracted nucleic acid and the artificial nucleic acid with a crosslinking agent, and the microneedle does not cause an allergic reaction, a local tissue reaction, or a systemic toxic reaction after penetrating into the skin, and thus the microneedle should have good biocompatibility.
Drawings
Fig. 1 is a flowchart of the preparation of nucleic acid microneedles according to the present invention.
Fig. 2 is a topographical view of the nucleic acid microneedles in example 1 of the present invention.
Detailed Description
The invention provides a nucleic acid micro-needle and a preparation method and application thereof.
< nucleic acid microneedles >
The nucleic acid micro-needle of the invention comprises a substrate and a needle body on the substrate, wherein the material of the substrate comprises but is not limited to nucleic acid, hyaluronic acid, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, sodium carboxymethylcellulose, pullulan and the like; the needle body is made of nucleic acid. In addition, alginic acid, chitosan, polymethyl vinyl ether-maleic acid and the like can be mostly adopted as the soluble microneedle matrix.
In practice, the nucleic acid is selected from more than one of natural nucleic acids, artificial nucleic acids and cross-linked nucleic acids.
The natural nucleic acid comprises at least one of DNA or RNA of animal tissue, plant tissue, microorganism; artificial nucleic acids include in vitro synthesis of DNA.
The crosslinked nucleic acid includes nucleic acids synthesized between natural nucleic acids using a crosslinking agent, nucleic acids synthesized between artificial nucleic acids using a crosslinking agent, and nucleic acids synthesized between natural nucleic acids and artificial nucleic acids using a crosslinking agent.
The cross-linking agent is selected from more than one of diethylene glycol diacrylate (DEGDA), polyethylene glycol diacrylate (PEGDA), metal salt and cisplatin.
The metal salt includes, but is not limited to, zinc sulfate, zinc nitrate, zinc chloride, zinc bromide, ferrous sulfate, ferrous nitrate, ferrous chloride, ferrous bromide, cuprous sulfate, cuprous nitrate, cuprous chloride, cuprous bromide, cupric sulfate, cupric nitrate, cupric chloride, cupric bromide, magnesium sulfate, magnesium nitrate, magnesium chloride, magnesium bromide, calcium nitrate, calcium chloride, calcium bromide, barium nitrate, barium chloride, barium bromide, manganese nitrate, manganese chloride, manganese bromide, and the like.
The nucleic acid is selected from more than one of deoxyribonucleic acid, ribonucleic acid and nucleic acid analogue. The nucleic acid is mainly composed of phosphoric acid, pentose and a base, the nucleic acid in which pentose is deoxyribose is called deoxyribonucleic acid, the nucleic acid in which pentose is ribose is called ribonucleic acid, and the nucleic acid analogue means that at least one of the phosphoric acid, pentose and base in the nucleic acid is replaced by some other substance.
In practice, the nucleic acid analogue is selected from more than one of a peptide nucleic acid and a threose nucleic acid.
The radius of the needle body can be 1-400 μm, preferably 10-100 μm; the height may be 100-3000 μm, preferably 100-1000 μm, more preferably 700 μm; the pitch of adjacent pins may be 1-2000. mu.m, preferably 300-1000. mu.m, more preferably 900. mu.m.
The shape of the needle body includes, but is not limited to, conical, pyramidal, bullet-nose, and multi-pointed star-cone shapes, etc.
In addition, the needle body can be loaded with trace amount of medicine, the medicine content is 0-1g, and the needle body can also be unloaded with no medicine; the nucleic acid microneedle loaded with the drug uses the drug and the nucleic acid as a treatment means, and the nucleic acid microneedle not loaded with the drug uses the nucleic acid as a treatment means.
Specifically, the drugs include, but are not limited to, cisplatin, bendamustine, doxorubicin hydrochloride, daunorubicin, gemcitabine, cidentamine, cytarabine, methotrexate, pemetrexed, hydroxyurea, 10-hydroxycamptothecin, irinotecan, paclitaxel, vincristine, erlotinib hydrochloride, sorafenib tosylate, aclarubicin, epirubicin hydrochloride, camptothecin, autumine, 5-fluorouracil, gemcitabine, and the like.
< method for producing nucleic acid microneedles >
As shown in fig. 1, the method for preparing a nucleic acid microneedle (back-mold method) of the present invention comprises the steps of:
(1) mixing nucleic acid and water to prepare stock solution gel;
(2) adding the stock solution gel into a microneedle mould, and fully filling the stock solution gel into the microneedle mould by a vacuumizing or centrifuging method;
(3) and removing the micro-needle mold after drying and curing to obtain the nucleic acid micro-needle.
Wherein, in the step (1), the content of the nucleic acid in the stock solution gel may be 0.5 to 60% by weight, preferably 5 to 30% by weight.
In step (2), the negative pressure of the vacuum may be (-120) - (-60) kPa, preferably (-120) - (-80) kPa; the time can be 5-60min, preferably 30-60 min.
In step (2), the rotation speed of centrifugation may be 1000-; the time period may be 3-30min, preferably 3-20min, more preferably 12 min.
In step (3), the microneedle is cured by a method including, but not limited to, heat curing, freeze-drying curing, and the like.
< application of nucleic acid microneedles >
The nucleic acid micro-needle can be applied to medical cosmetic plastic, subcutaneous tumor and dermatosis treatment.
Specifically, skin diseases include, but are not limited to, abnormal scars and psoriasis, among others.
The present invention will be further described with reference to the following examples.
Example 1:
the method for preparing the nucleic acid microneedle of the present embodiment includes the steps of:
(1) extracting deoxyribonucleotide of blue algae to prepare powder, weighing 0.24g of powder, adding the powder into 3.76mL of deionized water, and uniformly stirring to obtain stock solution gel with the content of 6 wt%;
(2) adding 0.2g of stock solution gel into a micro-needle mold containing polydimethylsiloxane with a 10 x 10 conical hole array (namely 10 x 10 refers to the conical hole array, 10 rows are provided, 10 holes are formed in each row, and 100 conical holes are formed in total), wherein the hole depth is 700 mu m, and the hole spacing is 900 mu m, and centrifuging at 4000rpm for 12min to fully fill the stock solution gel into the micro-needle mold;
(3) drying for 48h at 4 ℃, and demoulding to obtain the nucleic acid microneedle.
The morphology of the prepared nucleic acid microneedles was observed with a microscope, and the results are shown in fig. 2. The height of the needle bodies of the micro-needle is consistent to 700 mu m, the distance between the adjacent needle bodies is 900 mu m, the diameter of the bottom of the micro-needle is 300 mu m, and the micro-needle has a sharp needle point and can smoothly penetrate into the skin of an experimental animal (mouse).
Example 2:
the method for preparing the nucleic acid microneedle of the present embodiment includes the steps of:
(1) weighing 0.32g of commercial salmon testis DNA, adding into 3.68mL of deionized water, and uniformly stirring to obtain stock solution gel with the content of 8 wt%;
(2) adding 0.2g of stock solution gel into a micro-needle mold of polydimethylsiloxane in the bullet-shaped hole array, and centrifuging at 4000rpm for 12min to fully fill the stock solution gel into the micro-needle mold;
(3) drying for 48h at 4 ℃, and demoulding to obtain the nucleic acid microneedle.
The nucleic acid microneedles of the present embodiments are also capable of piercing the skin to form microchannels.
Example 3:
the method for preparing the nucleic acid microneedle of the present embodiment includes the steps of:
(1) and establishing a reaction system by using an amplification primer and an artificially synthesized plasmid DNA as a template and using a rolling circle amplification kit to carry out in-vitro amplification.
(2) After the amplification is finished, adding absolute ethyl alcohol into the solution obtained in the step (1) to precipitate the DNA, and drying the DNA;
(3) adding the dried 20mg of DNA into deionized water to prepare 6 wt% DNA stock solution gel;
(4) adding 10 mu L of cross-linking agent PEGDA into the stock solution gel, fully and uniformly mixing, immediately adding into a micro-needle mold of polydimethylsiloxane in a bullet-shaped hole array, and centrifuging at 4000rpm for 12min to fully fill the stock solution gel into the micro-needle mold;
(5) drying for 48h at 4 ℃, and demoulding to obtain the nucleic acid microneedle.
Wherein in the step (1), the sequence of the amplification primer is as follows: 5'-ATGGCCTGAGTCTAGAGCTC-3' are provided.
The sequence of the artificially synthesized plasmid DNA is as follows:
plus strand (5 '-3'): 4756nt
CCATGCATTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCGCTAGCGCTACCGGACTCAGATCTCGAGCTCAAGCTTCGAATTCTGCAGTCGACGGTACCGCGGGCCCGGGATCCACCGGTCGCCACCATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAAAGCGGCCGCGACTCTAGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATTGTTGTTGTTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCGGATCCACGCGCCCTGTAGCGGCGCATTAAGCGCGGCGGGTGTGGTGGTTACGCGCAGCGTGACCGCTACACTTGCCAGCGCCCTAGCGCCCGCTCCTTTCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTCTAAATCGGGGGCTCCCTTTAGGGTTCCGATTTAGTGCTTTACGGCACCTCGACCCCAAAAAACTTGATTTGGGTGATGGTTCACGTAGTGGGCCATCGCCCTGATAGACGGTTTTTCGCCCTTTGACGTTGGAGTCCACGTTCTTTAATAGTGGACTCTTGTTCCAAACTGGTTTAACACTCAGAATTCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGACGCGCCCTGTAGCGGCGCATTAAGCGCGGCGGGTGTGGTGGTTACGCGCAGCGTGACCGCTACACTTGCCAGCGCCCTAGCGCCCGCTCCTTTCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTCTAAATCGGGGGCTCCCTTTAGGGTTCCGATTTAGTGCTTTACGGCACCTCGACCCCAAAAAACTTGATTTGGGTGATGGTTCACGTAGTGGGCCATCGCCCTGATAGACGGTTTTTCGCCCTTTGACGTTGGAGTCCACGTTCTTTAATAGTGGACTCTTGTTCCAAACTGGAACAACACTCAACCCTATCTCGGGCTATTCTTTTGATTTATAAGGGATTTTGCCGATTTCGGGGTA。
Negative strand (5 '-3'): 4756nt
TACCCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGCCCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCAAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCATATGGTGCACTCTCAGTACAATCTGCTCTGATGCCGCATAGTTAAGCCAGCCCCGACACCCGCCAACACCCGCTGACGCGCCCTGACGGGCTTGTCTGCTCCCGGCATCCGCTTACAGACAAGCTGTGACCGTCTCCGGGAGCTGCATGTGTCAGAGGTTTTCACCGTCATCACCGAAACGCGCGAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAATGTCATGATAATAATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGTATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCTCAACAGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTATTGACGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTACTCACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAACGATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGTAGCAATGGCAACAACGTTGCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAGACCAAGTTTACTCATATATACTTTAGATTGATTTAAAACTTCATTTTTAATTTAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGCCTTTGAGTGAGCTGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGAGTCAGTGAGCGAGGAAGCGGAAGAGCGCCCAATACGCAAACCGCCTCTCCCCGCGCGTTGGCCGATTCATTAATGCAGCTGGCACGACAGGTTTCCCGACTGGAAAGCGGGCAGTGAGCGCAACGCAATTAATGTGAGTTAGCTCACTCATTAGGCACCCCAGGCTTTACACTTTATGCTTCCGGCTCGTATGTTGTGTGGAATTGTGAGCGGATAACAATTTCACACAGGAAACAGCTATGACCATGATTACGAATTCTGAGTGTTAAACCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCAAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTGGATCCGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAAAGCAAGTAAAACCTCTACAAATGTGGTATGGCTGATTATGATCTAGAGTCGCGGCCGCTTTACTTGTACAGCTCGTCCATGCCGAGAGTGATCCCGGCGGCGGTCACGAACTCCAGCAGGACCATGTGATCGCGCTTCTCGTTGGGGTCTTTGCTCAGGGCGGACTGGGTGCTCAGGTAGTGGTTGTCGGGCAGCAGCACGGGGCCGTCGCCGATGGGGGTGTTCTGCTGGTAGTGGTCGGCGAGCTGCACGCTGCCGTCCTCGATGTTGTGGCGGATCTTGAAGTTCACCTTGATGCCGTTCTTCTGCTTGTCGGCCATGATATAGACGTTGTGGCTGTTGTAGTTGTACTCCAGCTTGTGCCCCAGGATGTTGCCGTCCTCCTTGAAGTCGATGCCCTTCAGCTCGATGCGGTTCACCAGGGTGTCGCCCTCGAACTTCACCTCGGCGCGGGTCTTGTAGTTGCCGTCGTCCTTGAAGAAGATGGTGCGCTCCTGGACGTAGCCTTCGGGCATGGCGGACTTGAAGAAGTCGTGCTGCTTCATGTGGTCGGGGTAGCGGCTGAAGCACTGCACGCCGTAGGTCAGGGTGGTCACGAGGGTGGGCCAGGGCACGGGCAGCTTGCCGGTGGTGCAGATGAACTTCAGGGTCAGCTTGCCGTAGGTGGCATCGCCCTCGCCCTCGCCGGACACGCTGAACTTGTGGCCGTTTACGTCGCCGTCCAGCTCGACCAGGATGGGCACCACCCCGGTGAACAGCTCCTCGCCCTTGCTCACCATGGTGGCGACCGGTGGATCCCGGGCCCGCGGTACCGTCGACTGCAGAATTCGAAGCTTGAGCTCGAGATCTGAGTCCGGTAGCGCTAGCGGATCTGACGGTTCACTAAACCAGCTCTGCTTATATAGACCTCCCACCGTACACGCCTACCGCCCATTTGCGTCAATGGGGCGGAGTTGTTACGACATTTTGGAAAGTCCCGTTGATTTTGGTGCCAAAACAAACTCCCATTGACGTCAATGGGGTGGAGACTTGGAAATCCCCGTGAGTCAAACCGCTATCCACGCCCATTGATGTACTGCCAAAACCGCATCACCATGGTAATAGCGATGACTAATACGTAGATGTACTGCCAAGTAGGAAAGTCCCATAAGGTCATGTACTGGGCATAATGCCAGGCGGGCCATTTACCGTCATTGACGTCAATAGGGGGCGTACTTGGCATATGATACACTTGATGTACTGCCAAGTGGGCAGTTTACCGTAAATACTCCACCCATTGACGTCAATGGAAAGTCCCTATTGGCGTTACTATGGGAACATACGTCATTATTGACGTCAATGGGCGGGGGTCGTTGGGCGGTCAGCCAGGCGGGCCATTTACCGTAAGTTATGTAACGCGGAACTCCATATATGGGCTATGAACTAATGACCCCGTAATTGATTACTATTAATAACTAATGCATGG。
The components of the reaction system in the step (1) comprise:
the nucleic acid microneedle of this example had a sharp needle tip, and was pressed against the skin of the back of a mouse with a thumb, and was found to be capable of piercing the skin to form a microchannel.
< experiment >
The following experiment was performed using the nucleic acid microneedles prepared in example 1:
wiping and disinfecting the back area of an experimental animal (mouse) by using disinfecting alcohol, pressing the nucleic acid microneedle in the embodiment 1 by using a thumb to pierce the skin of the mouse, taking down the nucleic acid microneedle after pressing for 30 seconds, and observing the appearance and the state of the skin of the mouse at the acting part of the microneedle, so that a 10 x 10 microchannel array can be obviously observed and formed. After 1 hour of continuous observation, it was found that the micro channel array was naturally healed, and the skin where the nucleic acid microneedles were used was not found to have redness and swelling.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments and the generic principles defined herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments. Those skilled in the art should appreciate that many modifications and variations are possible in light of the above teaching without departing from the scope of the invention.
Claims (10)
1. A nucleic acid microneedle comprising a substrate and a needle body on the substrate, characterized in that: the material of the substrate is selected from more than one of nucleic acid, hyaluronic acid, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, sodium carboxymethylcellulose and amylopectin;
the needle body is made of nucleic acid.
2. A nucleic acid microneedle according to claim 1, characterized in that: the nucleic acid is selected from more than one of natural nucleic acid, artificial nucleic acid and cross-linked nucleic acid.
3. A nucleic acid microneedle according to claim 2, characterized in that: the natural nucleic acid comprises at least one of animal tissue, plant tissue, DNA or RNA of a microorganism;
preferably, the artificial nucleic acid comprises in vitro synthetic DNA.
4. A nucleic acid microneedle according to claim 2, characterized in that: the cross-linked nucleic acid comprises nucleic acid synthesized by adopting a cross-linking agent among natural nucleic acid, nucleic acid synthesized by adopting a cross-linking agent among artificial nucleic acid, and nucleic acid synthesized by adopting a cross-linking agent among natural nucleic acid and artificial nucleic acid; and/or the presence of a gas in the gas,
the cross-linking agent is selected from more than one of diethylene glycol diacrylate, polyethylene glycol diacrylate, metal salt and cisplatin; and/or the presence of a gas in the gas,
the metal salt is selected from more than one of zinc sulfate, zinc nitrate, zinc chloride, zinc bromide, ferrous sulfate, ferrous nitrate, ferrous chloride, ferrous bromide, cuprous sulfate, cuprous nitrate, cuprous chloride, cuprous bromide, copper sulfate, cupric nitrate, cupric chloride, cupric bromide, magnesium sulfate, magnesium nitrate, magnesium chloride, magnesium bromide, calcium nitrate, calcium chloride, calcium bromide, barium nitrate, barium chloride, barium bromide, manganese nitrate, manganese chloride and manganese bromide.
5. A nucleic acid microneedle according to claim 1, characterized in that: the nucleic acid is selected from more than one of deoxyribonucleic acid, ribonucleic acid and nucleic acid analogues.
6. A nucleic acid microneedle according to claim 5, characterized in that: the nucleic acid analogue is selected from more than one of peptide nucleic acid and threose nucleic acid.
7. A nucleic acid microneedle according to claim 1, characterized in that: the radius of the needle bodies is 1-400 mu m, the height is 100-3000 mu m, and the distance between the adjacent needle bodies is 1-2000 mu m; and/or the presence of a gas in the gas,
the shape of the needle body is selected from more than one of conical shape, pyramid shape, bullet shape and multi-angle star cone shape; and/or the presence of a gas in the gas,
the needle body is loaded with 0-1g of medicine; and/or the presence of a gas in the gas,
the drug is selected from more than one of cisplatin, bendamustine, doxorubicin hydrochloride, daunorubicin, gemcitabine, cidentamine, cytarabine, methotrexate, pemetrexed, hydroxyurea, 10-hydroxycamptothecin, irinotecan, paclitaxel, vincristine, erlotinib hydrochloride, sorafenib tosylate, aclarubicin, epirubicin hydrochloride, camptothecin, autumine, 5-fluorouracil and gemcitabine.
8. A method for producing a nucleic acid microneedle according to claim 1, characterized in that: which comprises the following steps:
(1) mixing nucleic acid and water to prepare stock solution gel;
(2) adding the stock solution gel into a microneedle mould, and fully filling the stock solution gel into the microneedle mould by a vacuumizing or centrifuging method;
(3) and drying and curing, and demolding to obtain the nucleic acid microneedle.
9. The method of claim 8, wherein: in the step (1), the content of nucleic acid in the stock solution gel is 0.5-60 wt%; and/or the presence of a gas in the gas,
in the step (2), the vacuum pumping is performed under the negative pressure of (-120) - (-60) kPa for 5-60 min; and/or the presence of a gas in the gas,
in the step (2), the rotation speed of the centrifugation is 1000-20000rpm, and the time is 3-30 min; and/or the presence of a gas in the gas,
in the step (3), the microneedle is cured by at least one selected from the group consisting of heat curing and freeze-drying curing.
10. Use of the nucleic acid microneedle of claim 1 for cosmetic reshaping, treatment of subcutaneous tumors, and skin diseases.
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