CN105457026A - Polyaniline-base injectable photo-thermal hydrogel - Google Patents
Polyaniline-base injectable photo-thermal hydrogel Download PDFInfo
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 48
- NPKSPKHJBVJUKB-UHFFFAOYSA-N N-phenylglycine Chemical compound OC(=O)CNC1=CC=CC=C1 NPKSPKHJBVJUKB-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 19
- 238000007626 photothermal therapy Methods 0.000 claims abstract description 19
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 12
- 238000002512 chemotherapy Methods 0.000 claims abstract description 11
- 238000000799 fluorescence microscopy Methods 0.000 claims abstract description 6
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims abstract description 5
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims abstract description 5
- 229910002056 binary alloy Inorganic materials 0.000 claims abstract description 4
- 238000003384 imaging method Methods 0.000 claims abstract description 4
- 229920000767 polyaniline Polymers 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 229920001427 mPEG Polymers 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 9
- 238000002560 therapeutic procedure Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000000178 monomer Substances 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- 229920003169 water-soluble polymer Polymers 0.000 claims description 7
- CCMKPCBRNXKTKV-UHFFFAOYSA-N 1-hydroxy-5-sulfanylidenepyrrolidin-2-one Chemical compound ON1C(=O)CCC1=S CCMKPCBRNXKTKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- -1 polyoxyethylene Polymers 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 4
- 230000003252 repetitive effect Effects 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003937 drug carrier Substances 0.000 abstract description 2
- 238000002428 photodynamic therapy Methods 0.000 abstract 2
- 229920000642 polymer Polymers 0.000 abstract 2
- 229940044683 chemotherapy drug Drugs 0.000 abstract 1
- 229920000858 Cyclodextrin Polymers 0.000 description 9
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 8
- VAZSKTXWXKYQJF-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)OOS([O-])=O VAZSKTXWXKYQJF-UHFFFAOYSA-N 0.000 description 5
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 4
- 229930195573 Amycin Natural products 0.000 description 4
- XCJYREBRNVKWGJ-UHFFFAOYSA-N copper(II) phthalocyanine Chemical compound [Cu+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 XCJYREBRNVKWGJ-UHFFFAOYSA-N 0.000 description 4
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 4
- 229940043267 rhodamine b Drugs 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 229920002521 macromolecule Polymers 0.000 description 3
- 238000001338 self-assembly Methods 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 150000001408 amides Chemical group 0.000 description 2
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- 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 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
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- 238000004132 cross linking Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- JACPFCQFVIAGDN-UHFFFAOYSA-M sipc iv Chemical compound [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].C=1C=CC=C(C(N=C2[N-]C(C3=CC=CC=C32)=N2)=N3)C=1C3=CC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 JACPFCQFVIAGDN-UHFFFAOYSA-M 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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Abstract
The invention discloses polyaniline-base injectable photo-thermal hydrogel which is binary-system hydrogel composed of alpha-cyclodextrin and a water-soluble high-polymer photo-thermal material. The water-soluble high-polymer photo-thermal material is polyethylene glycol grafted poly-N-phenylglycine comprising a main chain and a side chain, and the main chain is poly-N-phenylglycine (PPG) while the side chain is polyethylene glycol (PEG). The hydrogel has good photothermal conversion capability and can be used for photothermal therapy, meanwhile, the hydrogel can load chemotherapy drugs, photodynamic reagents and fluorescence imaging reagents to respectively obtain a photo-thermal hydrogel carry system which has chemotherapy, photodynamic therapy and imaging functions and is a biocompatible multifunctional photo-thermal response-type carrier hydrogel system, and the hydrogel has broad application prospect in drug carriers, photocontrol drug release, photothermal therapy, photodynamic therapy, tissue engineering and the like.
Description
Technical field
The present invention relates to photo-thermal therapy reagent, belong to biology medical material technical field.Be specifically related to class polyaniline injectable photo-thermal hydrogel, also relate to and its preparation method and application simultaneously.
Background technology
Photo-thermal therapy is under laser irradiates, and utilizes the material with photo-thermal converting function, absorbs near infrared light, converts luminous energy to heat energy, produces high heat, thus kills a kind of method that sick cell reaches therapeutic effect.It has the features such as accurate, efficient, controlled, noinvasive, side effect be low.Current photo-thermal therapy normally optothermal material is prepared into targeted nano granule or aqueogel is treated.And relative to targeted nano granule, photo-thermal aqueogel can realize the treatment of original position fixed point, and can repetitive therapy, this aggressiveness for cancer is strong, and the characteristic of easily recurrence is very effective.Photo-thermal hydrogel or the carrier of medicine controlled releasing can realize the Synergistic treatment of photo-thermal therapy and chemotherapy simultaneously.
Poly-N-phenylglycine is a kind of macromolecule of class polyaniline structure, is with the difference of polyaniline, with carboxyl functional group on its side chain, can carry out chemical modification modification.And polyaniline finds that it is by after realizing water solublity with the fatty acid of Pegylation is coated, can be used for the photo-thermal ablation of cancerous cell by Korea S professor Huh in 2011.(Yang, J.Choi, D.Bang, E.Kim, E.-K.Lim, H.Park, J.-S.Suh, K.Lee, K.-H.Yoo, E.-K.Kim, Y.-M.Huh, S.Haam.Angew.Chem.Int.Ed.2011, 50, studies have reported that with F127 (J.Zhou 441-444.) successively, Z.G.Lu, X.J.Zhu, X.J.Wang, Y.Liao, Z.F.Ma, F.Y.Li.Biomaterials2013, 34, 9584-9592.) and hyaluronic acid (B.-P.Jiang, L.Zhang, Y.Zhu, X.-C.Shen, S.-C.Ji, X.-Y.Tan, L.Cheng, H.Liang.J.Mater.Chem.B, 2015, 3, 3767-3776) etc. non-covalent compound obtains water-soluble polyaniline nanoparticle and carries out photo-thermal therapy.And rarely have the report being prepared into photo-thermal aqueogel.
Cyclodextrin is a kind of cyclic oligosaccharide, and it is hydrophobic that it has inner chamber, the structure that exocoel is hydrophilic, can with the self assembly of macromolecule generation Subjective and Objective.1994 by Japanese Scientists Harada Late Cambrian when PEG molecular weight is greater than 2000, can assemble with α-CD and form accurate poly-rotaxane hydrogel, after this lot of documents report cyclodextrin and line style, combed, star-like, tree-shaped macromolecule generation Subjective and Objective self assembly, forms that cyclodextrin is accurate gathers rotaxane supermolecule (CD-PPR) hydrogel.CD-PPR hydrogel has shear-sensitive and temperature sensitive dual intelligent response usually, is widely used in medicine controlled releasing research.But yet there are no the research report poly-for cyclodextrin standard rotaxane hydrogel being used for photo-thermal therapy.
Summary of the invention
The object of this invention is to provide a kind of class polyaniline injectable photo-thermal hydrogel, it shows good photo-thermal temperature rise effect under near infrared light, and energy load cancer therapy drug, the Synergistic treatment of photo-thermal therapy and chemotherapy can be realized.
In the present invention, described class polyaniline injectable photo-thermal hydrogel, it is comprise the binary system hydrogel that alpha-cyclodextrin and water soluble polymer optothermal material form; Described water soluble polymer optothermal material is that Polyethylene Glycol grafting gathers N-phenylglycine, comprises main chain and side chain, and described main chain is poly-N-phenylglycine (PPG), and described side chain is Polyethylene Glycol (PEG).
The invention still further relates to the preparation method of described class polyaniline injectable photo-thermal hydrogel, comprise the steps:
(1) preparation of poly-N-phenylglycine: N-phenylglycine monomer (PG), Ammonium persulfate. (APS) are dissolved in acid solution respectively, control temperature is 0-5 DEG C, slowly ammonium persulfate solution is dripped in monomer solution, dropwise, reaction 2-10h, rise to room temperature reaction 12-36h afterwards, filter and wash, dry, namely obtain dark green solid is poly-N-phenylglycine (PPG);
(2) Polyethylene Glycol grafting gathers the preparation of N-phenylglycine: will gather N-phenylglycine, methoxy poly (ethylene glycol) amine solvent in dimethyl sulfoxide, under 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide and N-hydroxy thiosuccinimide exist, 40-60 DEG C of reaction 12-36h, namely purification lyophilizing afterwards obtains Polyethylene Glycol grafting and gathers N-phenylglycine (i.e. graft PPG-g-PEG);
(3) Polyethylene Glycol grafting is gathered N-phenylglycine and alpha-cyclodextrin is mixed with aqueous solution respectively, by the enclose mol ratio n (CH of polyoxyethylene segment and α-CD
2cH
2o): k (α-CD)=1-4:1, by both mix homogeneously, room temperature leaves standstill, and obtains described class polyaniline photo-thermal hydrogel.
Further in step (1), the addition of described N-phenylglycine monomer and Ammonium persulfate. is equimolar amounts, and described acid solution is the H of 0.1-0.5M
2sO
4the HCl aqueous solution of aqueous solution or 0.5-2M, the time of described reaction is react 3-8h, room temperature reaction 20-30h at 0-5 DEG C.
Further, in step (1), described washing is for using distillation washing three times; Described drying is at 40-60 DEG C of vacuum drying 48-96h.
In step (2), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) and N-hydroxy thiosuccinimide (NHS) are condensing agent, when condensing agent exists, there is amide condensed reaction in poly-N-phenylglycine and methoxy poly (ethylene glycol) amine.In step (2), poly-N-phenylglycine is dissolved in dimethyl sulfoxide, adds 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide and N-hydroxy thiosuccinimide, stir 2h, add methoxy poly (ethylene glycol) amine afterwards.
In step (2), the rate of charge of described poly-N-phenylglycine and methoxy poly (ethylene glycol) amine is: the repetitive of poly-N-phenylglycine: methoxy poly (ethylene glycol) amine mol ratio=1:1-1.5, is preferably 1:1.2.
As optimization, in step (2), the control of amide condensed reaction is 50 DEG C of reaction 20-30h.
Further, in step (2), described purification comprises: distilling under reduced pressure removing dimethyl sulfoxide, be dissolved in afterwards in deionized water, first cross and filter insoluble matter, then to dialyse in deionized water 5-10 days with the bag filter that molecular cut off is 8000-14000, remove unreacted methoxy poly (ethylene glycol) amine.
The present invention carries out enclose in step (3) and is cross-linked, and wherein polyoxyethylene segment refers to that Polyethylene Glycol grafting gathers the EG unit in N-phenylglycine molecule, i.e. CH
2cH
2o quantity, enclose mol ratio n (CH
2cH
2o): in k (α-CD), the unit of n, k is mole; Wherein said standing time temperature be 5-35 DEG C, time of repose is 1min-90h.
The invention still further relates to the application of described class polyaniline photo-thermal hydrogel, specifically comprise the medicine that adds and there is chemotherapy effect and obtain having chemotherapy and photo-thermal therapy function medicine, add optical dynamic therapy medicine or reagent and obtain having the medicine of optical dynamic therapy and photo-thermal therapy function or add the reagent of fluorescence imaging function and obtain having the medicine of imaging function and photo-thermal therapy function.
The described medicine with chemotherapy effect comprises: the water solublity such as amycin, camptothecine chemotherapeutics.
Described optical dynamic therapy medicine or reagent comprise: the water solublity light power reagent such as tetrasulfonic acid base C.I. Pigment Blue 15, tetramino silicon phthalocyanine.
The reagent of described fluorescence imaging function comprises: the organic nir dye of the water solublity such as Cyanine5.5, rhodamine B.
In class polyaniline injectable photo-thermal hydrogel binary system of the present invention, skeleton (PPG-g-PEG) is that a kind of novel water soluble polymer optothermal material Polyethylene Glycol grafting gathers N-phenylglycine, its main chain is poly-N-phenylglycine (PPG), it is a kind of structure of class polyaniline, there is photothermal deformation performance, near infrared light can be absorbed, realize photo-thermal therapy, its side chain PEG mono-aspect improves the water solublity of PPG, with α-CD, Subjective and Objective self assembly can occur forms " tunnel-like " crystallization as physical crosslinking point on the other hand, be built into accurate poly-rotaxane hydrogel.Can Gel-sol transition be there is in this kind of hydrogel under intensification, shear action, it is a kind of injectable multiple response intelligent aqueous gel capable, can also load chemotherapeutics, light power reagent and fluorescence imaging reagent, obtain the photo-thermal hydrogel carrier systems with chemotherapy, optical dynamic therapy, imaging function respectively, be a kind of bio-compatible multifunctional light thermal response-type delivery aquogel system, and play Synergistic treatment in photo-thermal therapy and chemotherapy.Hydrogel of the present invention has wide practical use in pharmaceutical carrier, light-operated drug release, photo-thermal therapy, optical dynamic therapy, organizational project etc.
In addition, the preparation method of photo-thermal hydrogel of the present invention is easy, reaction condition is gentle, be easy to control.
Detailed description of the invention
Be described principle of the present invention and feature below in conjunction with embodiment, example, only for explaining the present invention, is not intended to limit scope of the present invention.
Preparation embodiment 1
(1) preparation of poly-N-phenylglycine:
Monomer N-phenylglycine (0.30g, 2mmol) and oxidant Ammonium persulfate. (0.46g, 2mmol) are dissolved in respectively the H of 0.1M
2sO
4in, ice bath, maintenance temperature is 0-5 DEG C, drips oxidant ammonium persulfate solution in monomer solution, and time for adding is 2h.Dropwise, ice bath continues reaction 5h, rises to room temperature reaction 24h.Stopped reaction.Filter and use distillation washing three times.50 DEG C of vacuum drying 48h, obtain dark green solid, are poly-N-phenylglycine (PPG).
(2) Polyethylene Glycol grafting gathers the preparation of N-phenylglycine:
By PPG (0.010g, repetitive PG is 0.065mmol) be dissolved in 5mlDMSO, add 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (0.025g, 0.13mmol) with N-hydroxy thiosuccinimide (0.015g, 0.13mmol), stir-activating 2h, add the methoxy poly (ethylene glycol) amine (0.39g that molecular weight is 5000 afterwards, 0.078mmol), 50 DEG C of condensation reaction 24h, stopped reaction, distilling under reduced pressure removing DMSO.Crude product is dissolved in 20ml water, crosses and filter insoluble matter.Dialyse in deionized water 7 days with the bag filter that molecular cut off is 8000-14000.Namely lyophilizing obtains PPG-g-PEG water soluble polymer optothermal material.
(3) getting above-mentioned PPG-g-PEG water soluble polymer optothermal material 0.0028g is dissolved in 0.1ml water, getting 0.03g α-CD is dissolved in 0.2ml water, both is mixed, stirs, room temperature leaves standstill 0.5h, and the standard obtaining cyclodextrin and PPG-g-PEG compound gathers rotaxane photo-thermal hydrogel.
The sample bottle that the photo-thermal hydrogel prepared is housed is inverted 2min, and in bottle there is not any flowing in material, proves to define the standard be composited based on cyclodextrin and PPG-g-PEG graft in the present invention and gather rotaxane supermolecule photo-thermal hydrogel.
Preparation embodiment 2
Be with above-mentioned preparation embodiment 1 difference, in the preparation process of (1) poly-N-phenylglycine, by the H of 0.1M
2sO
4change the HCl aqueous solution of 1M into.Result is obtained poly-N-phenylglycine equally smoothly, and final certification also form the standard be composited based on cyclodextrin and PPG-g-PEG graft in the present invention gathers rotaxane supermolecule photo-thermal hydrogel.
Testing example
Experimental technique is as follows:
The PPG-g-PEG graft preparing (2) gained in embodiment 1 is mixed with the aqueous solution of 28mg/ml, irradiates with 808nm laser (1-2W, spot diameter 5mm), with the change with light application time of the temperature of infrared thermography recording solution.
The class polyaniline photo-thermal hydrogel of step (3) gained in embodiment 1 will be prepared, irradiate with 808nm laser (1-2W, spot diameter 5mm), with the change with light application time of the temperature of infrared thermography record gel.
Along with the prolongation of light application time, PPG-g-PEG graft and the temperature of hydrogel be composited with cyclodextrin thereof raise gradually, after irradiating 10min, the temperature of PPG-g-PEG graft is increased to 53 DEG C, and the temperature of the supramolecular hydrogel of PPG-g-PEG and cyclodextrin compound is increased to 57 DEG C.Prove that photo-thermal therapy class polyaniline injection aquagel of the present invention has good photo-thermal temperature rise effect.
Application Example
According to the step of preparation embodiment 1, in step (3), getting PPG-g-PEG graft 0.0028g is dissolved in 0.1ml water, getting 0.03g α-CD is dissolved in 0.2ml water, both are mixed, adds 0.3mg amycin, stir, room temperature leaves standstill 0.5h, obtains the class polyaniline photo-thermal hydrogel of load amycin medicine.The class polyaniline photo-thermal hydrogel of this load amycin medicine belongs to the photo-thermal hydrogel carrier systems with anticancer chemotherapy function.
According to the step of preparation embodiment 1, in step (3), getting PPG-g-PEG graft 0.0028g is dissolved in 0.1ml water, getting 0.03g α-CD is dissolved in 0.2ml water, both are mixed, adds 0.3mg tetrasulfonic acid base C.I. Pigment Blue 15, stir, room temperature leaves standstill 0.5h, obtains the class polyaniline photo-thermal hydrogel of load tetrasulfonic acid base C.I. Pigment Blue 15.The class polyaniline photo-thermal hydrogel of this load tetrasulfonic acid base C.I. Pigment Blue 15 belongs to the photo-thermal hydrogel carrier systems with optical dynamic therapy function.
According to the step of preparation embodiment 1, in step (3), getting PPG-g-PEG graft 0.0028g is dissolved in 0.1ml water, getting 0.03g α-CD is dissolved in 0.2ml water, both are mixed, adds 0.3mg rhodamine B, stir, room temperature leaves standstill 0.5h, obtains the class polyaniline photo-thermal hydrogel of load rhodamine B.The class polyaniline photo-thermal hydrogel of this load rhodamine B belongs to the photo-thermal hydrogel carrier systems with fluorescence imaging function.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. class polyaniline injectable photo-thermal hydrogel, it is comprise the binary system hydrogel that alpha-cyclodextrin and water soluble polymer optothermal material form; Described water soluble polymer optothermal material is that Polyethylene Glycol grafting gathers N-phenylglycine, comprises main chain and side chain, and described main chain is poly-N-phenylglycine, and described side chain is Polyethylene Glycol.
2. the preparation method of class polyaniline injectable photo-thermal hydrogel according to claim 1, comprises the steps:
(1) preparation of poly-N-phenylglycine: N-phenylglycine monomer, Ammonium persulfate. are dissolved in acid solution respectively, control temperature is 0-5 DEG C, slowly ammonium persulfate solution is dripped in monomer solution, dropwise, reaction 2-10h, rise to room temperature reaction 12-36h afterwards, filter and wash, dry, namely obtain dark green solid is poly-N-phenylglycine;
(2) Polyethylene Glycol grafting gathers the preparation of N-phenylglycine: will gather N-phenylglycine, methoxy poly (ethylene glycol) amine solvent in dimethyl sulfoxide, under 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide and N-hydroxy thiosuccinimide exist, 40-60 DEG C of reaction 12-36h, namely purification lyophilizing afterwards obtains Polyethylene Glycol grafting and gathers N-phenylglycine;
(3) Polyethylene Glycol grafting is gathered N-phenylglycine and alpha-cyclodextrin is mixed with aqueous solution respectively, by the enclose mol ratio n (CH of polyoxyethylene segment and α-CD
2cH
2o): k (α-CD)=1-4:1, by both mix homogeneously, room temperature leaves standstill, and obtains described class polyaniline photo-thermal hydrogel.
3. preparation method according to claim 2, is characterized in that: in step (1), and the addition of described N-phenylglycine monomer and Ammonium persulfate. is equimolar amounts, and described acid solution is the H of 0.1-0.5M
2sO
4the HCl aqueous solution of aqueous solution or 0.5-2M, the time of described reaction is react 3-8h, room temperature reaction 20-30h at 0-5 DEG C.
4. preparation method according to claim 2, is characterized in that: in step (1), and described washing is for using distillation washing three times; Described drying is at 40-60 DEG C of vacuum drying 48-96h.
5. preparation method according to claim 2, it is characterized in that: in step (2), poly-N-phenylglycine is dissolved in dimethyl sulfoxide, add 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide and N-hydroxy thiosuccinimide, stir 2h, add methoxy poly (ethylene glycol) amine afterwards.
6. preparation method according to claim 2, it is characterized in that: in step (2), the rate of charge of described poly-N-phenylglycine and methoxy poly (ethylene glycol) amine is: the repetitive of poly-N-phenylglycine: methoxy poly (ethylene glycol) amine mol ratio=1:1-1.5.
7. preparation method according to claim 2, is characterized in that: in step (2), 50 DEG C of reaction 20-30h.
8. preparation method according to claim 2, it is characterized in that: in step (2), described purification comprises: distilling under reduced pressure removing dimethyl sulfoxide, be dissolved in afterwards in deionized water, first cross and filter insoluble matter, then to dialyse in deionized water 5-10 days with the bag filter that molecular cut off is 8000-14000.
9. preparation method according to claim 2, is characterized in that: in step (3), and described dwell temperature is 5-35 DEG C, and time of repose is 1min-90h.
10. the application of class polyaniline photo-thermal hydrogel according to claim 1, comprise the medicine that adds and there is chemotherapy effect and obtain having chemotherapy and photo-thermal therapy function medicine, add optical dynamic therapy medicine or reagent and obtain having the medicine of optical dynamic therapy and photo-thermal therapy function or add the reagent of fluorescence imaging function and obtain having the medicine of imaging function and photo-thermal therapy function.
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CN108047462A (en) * | 2017-12-30 | 2018-05-18 | 广西师范大学 | Preparation method and applications based on poly- N-phenylglycine-polyethylene glycol hydrogel |
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