CN115227671B - 一种药物递送***及其制备方法和应用 - Google Patents
一种药物递送***及其制备方法和应用 Download PDFInfo
- Publication number
- CN115227671B CN115227671B CN202210823054.2A CN202210823054A CN115227671B CN 115227671 B CN115227671 B CN 115227671B CN 202210823054 A CN202210823054 A CN 202210823054A CN 115227671 B CN115227671 B CN 115227671B
- Authority
- CN
- China
- Prior art keywords
- drug delivery
- delivery system
- anesthetic
- mesoporous silica
- preparation
- 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.)
- Active
Links
- 238000012377 drug delivery Methods 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 102
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 51
- 238000003384 imaging method Methods 0.000 claims abstract description 31
- 210000003617 erythrocyte membrane Anatomy 0.000 claims abstract description 30
- 230000003444 anaesthetic effect Effects 0.000 claims abstract description 25
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 claims description 29
- 229960004288 levobupivacaine Drugs 0.000 claims description 29
- 229960004692 perflenapent Drugs 0.000 claims description 27
- NJCBUSHGCBERSK-UHFFFAOYSA-N perfluoropentane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F NJCBUSHGCBERSK-UHFFFAOYSA-N 0.000 claims description 27
- 208000002193 Pain Diseases 0.000 claims description 18
- 230000036407 pain Effects 0.000 claims description 18
- 239000012216 imaging agent Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 238000012285 ultrasound imaging Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000002105 nanoparticle Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000011148 porous material Substances 0.000 claims description 6
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000000502 dialysis Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 claims description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 2
- 229960004194 lidocaine Drugs 0.000 claims description 2
- 229960004919 procaine Drugs 0.000 claims description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 claims description 2
- 229960001549 ropivacaine Drugs 0.000 claims description 2
- 229960002372 tetracaine Drugs 0.000 claims description 2
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 claims description 2
- VTHOKNTVYKTUPI-UHFFFAOYSA-N triethoxy-[3-(3-triethoxysilylpropyltetrasulfanyl)propyl]silane Chemical compound CCO[Si](OCC)(OCC)CCCSSSSCCC[Si](OCC)(OCC)OCC VTHOKNTVYKTUPI-UHFFFAOYSA-N 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims 1
- 238000002604 ultrasonography Methods 0.000 abstract description 32
- 239000003589 local anesthetic agent Substances 0.000 abstract description 13
- 230000007704 transition Effects 0.000 abstract description 10
- 230000004044 response Effects 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- 230000010354 integration Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 32
- 101000979288 Homo sapiens Negative elongation factor E Proteins 0.000 description 27
- 102100023070 Negative elongation factor E Human genes 0.000 description 27
- 229940079593 drug Drugs 0.000 description 26
- 239000000243 solution Substances 0.000 description 15
- 210000003743 erythrocyte Anatomy 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 239000007789 gas Substances 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 210000002683 foot Anatomy 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- 238000007726 management method Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 230000005540 biological transmission Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 208000004550 Postoperative Pain Diseases 0.000 description 6
- 230000036592 analgesia Effects 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 238000001000 micrograph Methods 0.000 description 5
- 238000011002 quantification Methods 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 230000001960 triggered effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 239000003193 general anesthetic agent Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229960005015 local anesthetics Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000001217 buttock Anatomy 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000012154 double-distilled water Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 210000003497 sciatic nerve Anatomy 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 229920000153 Povidone-iodine Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000002607 contrast-enhanced ultrasound Methods 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 208000022119 inability to concentrate Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000012782 phase change material Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960001621 povidone-iodine Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5176—Compounds of unknown constitution, e.g. material from plants or animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/18—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/62—Submicrometer sized, i.e. from 0.1-1 micrometer
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/12—Surface area
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/16—Pore diameter
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physics & Mathematics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Radiology & Medical Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Optics & Photonics (AREA)
- Inorganic Chemistry (AREA)
- Anesthesiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acoustics & Sound (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Zoology (AREA)
- Emergency Medicine (AREA)
- Botany (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及生物技术领域,具体公开了一种药物递送***及其制备方法和应用。所述药物递送***包括壳‑核结构,红细胞膜作为壳层,树突状介孔二氧化硅作为内核,所述树突状介孔二氧化硅装载有***物和/或超声成像制剂。本发明将红细胞膜和树突状介孔二氧化硅联合,装载***物和超声成像制剂,通过液气相变技术提高***物的超声响应性,超声辐照激发液态氟碳发生液气相变,增强局麻药物在肿瘤局部的释放性能,同时产生的气体可在超声下观察到成像信号,为***物递送提供影像学信息,实现超声成像与局麻药物递送一体化。
Description
技术领域
本发明涉及生物技术领域,尤其是一种药物递送***及其制备方法和应用。
背景技术
目前,术后10-50%的患者存在术后疼痛,持续的术后疼痛与延迟出院相关,从而严重降低了生活质量。因此,持续性术后疼痛的管理对于以患者为中心的临床诊疗至关重要。尽管多种***物(如局部麻醉剂、环氧合酶抑制剂和阿片类药物)可以在手术期间和术后不久控制疼痛,但即使在局限性疼痛情况下,阿片类药物仍然是术后疼痛管理的主要手段。但是阿片类药物副作用明显,包括恶心、皮肤瘙痒、便秘、成瘾、耐受性差、注意力无法集中等,过量服用甚至致命。尽管局部麻醉剂可用于缓解术后疼痛,但作用时间有限,过量使用会产生严重的心血管或神经疾病等副作用。此外,不能调整镇痛强度以满足患者的需求。尽管通过导管持续输注局部麻醉剂可以提供长期镇痛,但不建议抗凝患者使用。因此,有必要开发一种新型***物进行高效术后疼痛管理。
为了解决局麻药物可控释放的难题,已有学者利用激光辐照控制疼痛管理。但是近红外激光触发的按需镇痛***存在穿透深度低的难题,因此只能用于浅表部分镇痛,临床价值受限。与近红外激光触发的按需镇痛***相比,超声波在组织穿透深度方面具有优势,且超声设备和超声技术已广泛应用于各种临床和理疗场景中。但是现有超声响应体系存在三方面问题:第一,现有超声响应体系需要更高的超声刺激强度,这可能对机体造成一定程度的损伤。第二,纳米药物在体内会迅速被机体免疫***清除,造成药物在体内无法长时间发挥作用。第三,纳米药物在体内缺乏影像学监控手段。为了解决以上难题,超声微泡在超声辐照下产生的空化效应可能增强局部***物的药物递送,增强药物对超声辐照的敏感性,从而降低临床上超声的应用强度,降低副损伤。改善药物输送的机制主要归因于惰性空化效应和间隙流体流量的增加。此外,然而,在生理条件下,这些微泡是不稳定的,单次注射的半衰期短,无法长期控制药物释放。虽然大多数研究都使用微泡来辅助疾病治疗,但目前尚不清楚如何将这些技术结合起来进行有效的疼痛管理。
发明内容
本发明提供一种药物递送***及其制备方法和应用,解决了以下三个技术问题:1)纳米药物在体内会迅速被机体免疫***清除,造成药物在体内无法长时间发挥作用;2)现有超声响应体系需要较高的超声刺激强度,这可能对机体造成一定程度的损伤;3)***物在体内缺乏影像学监控手段。本发明提供的药物递送***通过红细胞膜修饰提高了其在生物体内的稳定性,避免免疫***快速清除,延长其在体内的存留时间。此外,本发明通过液气相变技术提高***物的超声响应性,超声辐照激发液态氟碳发生液气相变,增强局麻药物在肿瘤局部的释放性能,同时产生的气体可在超声下观察到成像信号,为***物递送提供影像学信息。
为实现上述目的,本发明采取的技术方案为:
本发明提供了一种药物递送***,所述药物递送***包括壳-核结构,红细胞膜作为壳层,树突状介孔二氧化硅作为内核,所述树突状介孔二氧化硅装载有***物和/或超声成像制剂。
红细胞膜工程化是一种仿生策略,可以延长血液滞留时间,减少非特异性巨噬细胞的摄取。红细胞膜保留了天然红细胞表面的多种组分(例如CD47、各种膜蛋白、酸性唾液酸和聚糖),可以有效地使其附属物或内部内容物具有延长的血液滞留时间和免疫逃避能力。这种细胞膜封装技术可以使内部纳米材料半衰期显著延长,尚未应用于疼痛管理领域。
树枝状介孔二氧化硅具有高载药量的特点,可作为药物载体装载***物和/或超声成像制剂,用于临床术后镇痛及解决疼痛管理相关需求。但是树枝状介孔二氧化硅在生物体内会激起免疫反应,而迅速被机体清除,不利于其在体内长时间停留,严重制约了镇痛疗效。本申请的发明人经过大量研究及试验发现,以红细胞膜作为壳层,旨在提高其在体内的存留时间,使得树突状介孔二氧化硅在体内可以长时间停留,促进镇痛疗效的实现;并且红细胞囊泡有利于防止装载药物的渗漏。现有超声响应性局麻药物递送***虽然可发生超声响应性释药,但无法提供超声成像数据。此外,超声响应性释放过程依赖于高强度超声触发,非特异性超声辐照可能带来不必要的副损伤,限制其临床应用。本研究通过装载超声成像制剂,在超声辐照下发生液气相变,生成的气体既可以增强超声响应性释药的敏感性,又可以产生超声成像信号,实现超声成像与局麻药物递送一体化的药物递送***。
作为本发明所述药物递送***的优选实施方式,所述***物为水溶性或油溶性的局部***物,优选地,所述***物为所述***物为左旋布比卡因、利多卡因、普鲁卡因、丁卡因和罗哌卡因中的至少一种。***物不仅限于上述药物,还包括了本领域中常用的麻醉剂。
***物选择上述组分时,可针对多种疼痛场景进行疼痛管理。
作为本发明所述药物递送***的优选实施方式,所述超声成像制剂为疏水性和疏油性的超声成像制剂,优选地,所述超声成像制剂为全氟戊烷,当超声成像制剂不是疏水性和疏油性时,其可能存在激发相变困难的问题,因此,全氟戊烷为最佳选择。全氟戊烷在药物递送***中的浓度为20-200μL。
与传统的超声微泡相比,全氟戊烷(PFP)是一种在体内稳定的“液-气”相变材料。超声辐照可以引发相转变,并将液相PFP转化为气相,从而增强药物传递过程,并可为临床提供超声影像学信息。
作为本发明所述药物递送***的优选实施方式,所述树突状介孔二氧化硅的表面积为500-700m2g-1,平均孔径为3-20nm;优选地,所述树突状介孔二氧化硅的表面积为553.449m2g-1,平均孔径为18nm。
树突状介孔二氧化硅是一类具有较大载药量的药物载体,可装载多种水溶性及油溶性局部***物,也适合装载兼具有疏水性和疏油性的超声成像制剂全氟戊烷。本发明将多种性质药物同时装载于树突状介孔二氧化硅中,可作为超声响应性制剂应用于临床实践中。
传统二氧化硅孔径小(2-3nm),树突状二氧化硅孔径更大,本研究所合成的树突状二氧化硅比表面积相对传统介孔二氧化硅孔径更大,载药量更多,进而使得更佳的发挥镇痛的效果。
作为本发明所述药物递送***的优选实施方式,所述树突状介孔二氧化硅的制备方法包括以下步骤:
将十六烷基三甲基氯化铵和三乙醇胺溶解在水中形成混合物,在混合物中添加正硅酸乙酯和双[3-(三乙氧基硅)丙基]四硫化物,搅拌,洗涤,清除残余反应物,然后使用含有乙醇的盐酸溶液回流提取产物,获得树突状介孔二氧化硅。
其树突状介孔二氧化硅合成方法简便,红细胞容易从各种生物体内轻松获取,两者的生物相容性较高,成本较为低廉。
本发明还提供了一种上述的药物递送***的制备方法,将树突状介孔二氧化硅分散在***物水溶液中搅拌,然后再添加超声成像制剂继续搅拌,离心,收集装载有***物和超声成像制剂的纳米颗粒,将红细胞膜包被装载有***物和超声成像制剂的纳米颗粒,透析,浸入PBS溶液中,获得药物递送***。
优选地,***物在麻药药物水溶液中的浓度为2-10mg/ml。
优选地,超声成像制剂的浓度为20-200μL。
作为本发明所述药物递送***的制备方法的优选实施方式,所述透析的截留分子量为3500-8000Da。
此外,本发明提供了上述药物递送***在制备用于治疗疼痛的试剂中的用途。
本发明提供了一种药物组合物,所述药物组合物包括上述的药物递送***。
本发明提供了上述药物组合物在制备用于治疗疼痛的试剂中的用途。
与现有技术相比,本发明具有以下有益效果:
本发明提供了一种装载局部***物和全氟戊烷的药物递送***及其制备方法和应用,所述药物递送***包括壳-核结构,红细胞膜作为壳层,树突状介孔二氧化硅作为内核,以红细胞膜作为壳层时,提高了其在生物体内的稳定性,避免免疫***快速清除,延长其在体内的存留时间,使得树突状介孔二氧化硅在体内可以长时间停留,促进镇痛疗效的实现;并且红细胞有利于防止装载药物的渗漏。本发明将红细胞膜和树突状介孔二氧化硅联合,装载***物和超声成像制剂,通过液气相变技术提高***物的超声响应性,超声辐照激发液态氟碳发生液气相变,增强局麻药物在肿瘤局部的释放性能,同时产生的气体可在超声下观察到成像信号,为***物递送提供影像学信息,实现超声成像与局麻药物递送一体化。
附图说明
图1为树突状介孔二氧化硅透射电子显微镜图(200nm);
图2为树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电子显微镜图(200nm);
图3为红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电子显微镜图(200nm);
图4为红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的SDS-PAGE图;
图5为红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电镜元素成分分析图;
图6为药物递送***RDBP和RDB的超声响应性释药图;
图7为药物递送***RDBP和RDB的无超声释药图;
图8为药物递送***RDBP和RDB的超声响应性释药定量图;
图9为药物递送***RDBP在超声辐照后的超声基波和谐波成像图;
图10为药物递送***RDBP的B-Mode基波超声定量图;
图11为药物递送***RDBP的造影模式谐波超声定量图;
图12为药物递送***RDBP的生物安全性评估图;
图13为药物递送***RDBP的超声辐照安全性评估图;
图14为实施例4中PBS处理组、RDBP处理组、DBP处理组和左旋布比卡因处理组测试小鼠抬脚的阈值刺激强度图;
图15为实施例4中RDBP处理组、RDBP+超声辐照处理组和DBP+超声辐照处理组测试小鼠抬脚的阈值刺激强度图;
图16为实施例4中PBS处理组、PBS+超声辐照组和RDP组测试小鼠抬脚的阈值刺激强度图;
图17为普通介孔二氧化硅与树突状二氧化硅比较载PFP成像比较图;
图18为实施例5中RDBP+US处理组、RDBP处理组、PBS处理组的超声成像观察液气相变图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点,下面将结合附图和具体实施例对本发明作进一步说明。
在以下实施例中,所使用的实验方法如无特殊说明,均为常规方法,所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
缩写:
全氟戊烷(PFP);红细胞膜(red blood cell membrane,RBCM);树突状介孔二氧化硅纳米颗粒(DMSN);左旋布比卡因(bupi)。
红细胞膜包被的DMSN-bupi-PFP(简称RDBP);红细胞膜包被的DMSN-bupi(简称RDB);装载全氟戊烷的树突状介孔二氧化硅纳米颗粒(DMSN-PFP)、装载左旋布比卡因的树突状介孔二氧化硅纳米颗粒(DMSN bupi,简称DB)。、红细胞裂解液的配方为:10ml原液1号+10ml原液2号,加双蒸水定容至100ml。
原液1号:10g葡萄糖+0.6g磷酸二氢钾+3.58g磷酸氢二钠(7H2O)+20ml5g/L酚红溶液,加双蒸水定容至1 000ml。
原液2号:1.86g氯化钙(2H2O)+4.0g氯化钾+80g氯化钠+1.04g氯化镁+2.0g硫酸镁(7H2O),加双蒸水定容至1 000ml。
实施例1、一种装载左旋布比卡因和全氟戊烷的药物递送***及其制备方法
1、树突状介孔二氧化硅的合成:在95℃下搅拌,并将2g十六烷基三甲基氯化铵和三乙醇胺溶解在20毫升水中。20分钟后,逐滴添加1g正硅酸乙酯和1.3g双[3-(三乙氧基硅)丙基]四硫化物并将混合物再搅拌4小时。将产物离心并用乙醇和水洗涤多次,以清除残余反应物。在78℃条件下,使用乙醇的盐酸溶液(10%v/v)回流提取产物两次,持续12小时,以去除十六烷基三甲基氯化铵。上述制备的树突状介孔二氧化硅透射电子显微镜图像如图1所示。氮气吸附实验表面树突状二氧化硅比表面积为553.449m2g-1,采用BJH理论分析,其平均孔径约为18nm。
2、红细胞膜囊泡的合成:从小鼠的眶后丛中采集小鼠全血,并收集在EDTA抗凝管中以避免凝血。然后用预冷的PBS溶液(pH=7.4)稀释全血,离心以收集红细胞(800g,4℃,20min)。用1倍PBS(pH=7.4)洗涤红细胞3次,将获得的红细胞在冰浴条件下使用红细胞裂解液处理5min,15000rpm离心30min收集红细胞膜。将红细胞膜超声处理2min,得到红细胞膜囊泡,将所得的红细胞膜囊泡储存在4℃中以备进一步使用。
3、一种药物递送***的制备方法,包括以下步骤:
将树突状介孔二氧化硅(10mg)分散在5mL左旋布比卡因水溶液(2-10mg/mL,优选为10mg/mL)中,并在室温下搅拌12小时,然后添加20-200μL(优选为200μL)全氟戊烷,并在冰浴中再搅拌12小时。将溶液在12000rpm下离心10分钟,以收集装载全氟戊烷和左旋布比卡因的纳米颗粒(DMSN-bupi-PFP,简称DBP)。收集上清液以确定左旋布比卡因的确切装载剂量。
以下方程式用于计算载药效率:载药效率=1-左旋布比卡因上清液量/左旋布比卡因总量。树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电子显微镜图像如图2所示。
将红细胞膜包被的DMSN-bupi-PFP(简称RDBP)与红细胞膜包被的DMSN-bupi(简称RDB)包裹在透析袋(截留分子量3500Da)中,并浸入PBS溶液(20mL)中,最终获得装载左旋布比卡因和全氟戊烷的药物递送***及装载左旋布比卡因的药物递送***。红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电子显微镜图像如图3所示。
采用SDS-PAGE证实红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷后保留了红细胞膜,结果如图4所示。
红细胞膜包裹树突状介孔二氧化硅装载左旋布比卡因及全氟戊烷的透射电镜元素成分分析(参考图5),数据显示所合成的药物递送***含有介孔二氧化硅(Si、O元素),左旋布比卡因(C、O、N元素)和全氟戊烷(C、F元素)的特征性元素。
实施例2、药物递送***的超声响应性体外释药研究
将上述获得的药物递送***(RDBP和RDB)研究左旋布比卡因的体外释放。在本研究中,超声辐照强度为0.6W cm-2,未使用超声辐照作为对照。在超声触发药物释放实验选择的时间内,在涂有超声偶联剂(医用超声耦合剂,广工牌,0.25L装)后对试管进行超声处理(0.6W cm-2,1MHz,15min),在37℃孵育下摇动所有试管。在指定时间,收集释放的样品(5mL)测定紫外-可见光吸收光谱,确定释放的左旋布比卡因的量。
当有超声辐照时,药物递送***RDBP和RDB的超声响应性释药图如图6所示,箭头代表超声辐照时间点。
当未使用超声辐照时,药物递送***RDBP和RDB的释药图如图7所示。
药物递送***RDBP和RDB的超声响应性释药定量图(*p<0.05认为有统计学差异)如图8所示。
药物递送***RDBP在超声辐照后的超声基波和谐波成像如图9所示。
药物递送***RDBP的B-Mode基波超声定量图和造影模式谐波超声定量图分别如图10-11所示。
实施例3、药物递送***的细胞毒性评估
采用标准CCK-8法评估RDBP的细胞毒性。在96孔板中种植处于对数生长期的HUVEC细胞,并于37℃下在5%CO2环境中培养。在HUVEC细胞培养基中添加不同浓度(0、50、100、200、400、600、800和1000μg mL-1)的RDBP。然后移除HUVEC细胞培养基,培养24或48h后,用CCK-8检测试剂盒(日本Dojindo,100μL,10%)替换培养基,并将细胞再培养2小时。最后,使用微孔板阅读器在450nm处测量HUVEC细胞的存活率。为了评估超声触发左旋布比卡因释放的安全性,在HUVEC细胞中添加不同浓度(0、50、100、200、300、400、500和600μg mL-1)的RDBP,并与HUVEC细胞一起培养4小时。之后,用PBS洗涤细胞三次,以去除孔板中游离的RDBP,将细胞暴露于超声辐照(0.6W cm-2,1MHz,2min,占空比50%)后。使用CCK-8检测试剂盒替换培养基并孵育2小时,并使用微孔板读取器测定HUVEC细胞的活性。
药物递送***RDBP的生物安全性评估和超声辐照安全性评估如图12-13所示。
实施例4、构建小鼠切口疼痛模型
建立小鼠切口疼痛模型的步骤:按照文献所报道(G.J.Bennett,Y.K.Xie,Pain1988,33,87.)的方案创建小鼠切口疼痛模型。用2%异氟醚麻醉小鼠,在用10%聚维酮碘溶液清洁左臀部区域后,从臀部的近端边缘进行纵向切口(2mm)。做纵向切口后将底部肌肉提起,暴露坐骨神经,在切口中心用4-0尼龙线缝合皮肤后涂抹抗生素软膏预防感染。
体内机械性痛觉超敏的测量:为了测量小鼠对非伤害性机械刺激的反应,使用足底触觉计)进行了体内机械性痛觉超敏试验。小鼠在带有丝网地板的塑料笼中适应试验环境30分钟。随后,将探针压在小鼠后爪的鞋底上,力逐渐增加,直到小鼠缩回爪子。对两个后肢进行三次测试,并自动采用爪机械阈值,将平均值用于确定机械阈值(g)。
分组为PBS处理组、RDBP处理组、DBP处理组和左旋布比卡因处理组,切口部位局部注射,100μL,0.05mg左旋布比卡因或相同剂量其他组/每只小鼠,每组5只评估,测试小鼠抬脚的阈值刺激强度,结果如图14所示。
分组为RDBP处理组、RDBP+超声辐照处理组和DBP+超声辐照处理组,切口部位局部注射,100μL,0.05mg左旋布比卡因或相同剂量其他组/每只小鼠,每组5只评估,评估测试小鼠抬脚的阈值刺激强度,结果如图15所示。
分组为PBS处理组、PBS+超声辐照组和RDP组,切口部位局部注射,100μL,0.05mg左旋布比卡因或相同剂量其他组/每只小鼠,每组5只评估,评估测试小鼠抬脚的阈值刺激强度,结果如图16所示。
实施例5、体外给药和超声成像测试
超声成像测试:将DMSN-PFP溶液、RDBP溶液、DMSN bupi(DB)溶液、PBS溶液或左旋布比卡因溶液注射到小鼠体内。固定小鼠,暴露后腿进行超声波触发。然后,使用强度低的温和超声强度(0.6W cm-2,1MHz,2min,占空比50%)将药物在超声引导下直接输送到注射位置。在辐照后不同时间点分别对药物注射部位进行超声辐照,超声基波成像观察神经位置,谐波成像观察药物相变情况,如图18所示(画圈部位为坐骨神经),CEUS图像变亮说明已发生相变。
如图17所示,普通介孔二氧化硅与本研究的树突状二氧化硅比较载PFP成像比较图。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (6)
1.一种药物递送***,其特征在于,所述药物递送***包括壳-核结构,红细胞膜作为壳层,树突状介孔二氧化硅作为内核,所述树突状介孔二氧化硅装载有***物和超声成像制剂;所述***物为左旋布比卡因、利多卡因、普鲁卡因、丁卡因和罗哌卡因中的至少一种;所述超声成像制剂为全氟戊烷;
所述树突状介孔二氧化硅的表面积为500-700m2g-1,平均孔径为3-20nm;
所述树突状介孔二氧化硅的制备方法包括以下步骤:
将十六烷基三甲基氯化铵和三乙醇胺溶解在水中形成混合物,在混合物中添加正硅酸乙酯和双[3-(三乙氧基硅)丙基]四硫化物,搅拌,洗涤,清除残余反应物,然后使用含有乙醇的盐酸溶液回流提取产物,获得树突状介孔二氧化硅。
2.一种如权利要求1所述的药物递送***的制备方法,其特征在于,将树突状介孔二氧化硅分散在***物水溶液中搅拌,然后再添加超声成像制剂继续搅拌,离心,收集装载有***物和超声成像制剂的纳米颗粒,将红细胞膜包被装载有***物和超声成像制剂的纳米颗粒,透析,浸入PBS溶液中,获得药物递送***。
3.如权利要求2所述的药物递送***的制备方法,其特征在于,所述透析的截留分子量为3500-8000Da。
4.如权利要求1所述的药物递送***在制备用于治疗疼痛的试剂中的用途。
5.一种药物组合物,其特征在于,所述药物组合物包括如权利要求1所述的药物递送***。
6.如权利要求5所述的药物组合物在制备用于治疗疼痛的试剂中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210823054.2A CN115227671B (zh) | 2022-07-13 | 2022-07-13 | 一种药物递送***及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210823054.2A CN115227671B (zh) | 2022-07-13 | 2022-07-13 | 一种药物递送***及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115227671A CN115227671A (zh) | 2022-10-25 |
CN115227671B true CN115227671B (zh) | 2024-01-19 |
Family
ID=83673800
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210823054.2A Active CN115227671B (zh) | 2022-07-13 | 2022-07-13 | 一种药物递送***及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115227671B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116327985A (zh) * | 2023-02-21 | 2023-06-27 | 武汉工程大学 | 一种具有靶向超声造影成像功能的空心囊泡载药递送***及其制备方法与应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013052167A2 (en) * | 2011-06-02 | 2013-04-11 | The Regents Of The University Of California | Membrane encapsulated nanoparticles and method of use |
-
2022
- 2022-07-13 CN CN202210823054.2A patent/CN115227671B/zh active Active
Non-Patent Citations (3)
Title |
---|
杜鑫 等.树枝状多孔二氧化硅纳米粒子的制备及其在先进载体中的应用.《化学进展》.2016,第28卷(第8期),第1131-1147页. * |
黄可.基于膜包裹的药物载体及其在白血病中的应用.《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑(月刊)》.2020,(第06期),第B016-822页. * |
黄可.基于膜包裹的药物载体及其在白血病中的应用.《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑(月刊)》.2020,(第第06期期),第B016-822页. * |
Also Published As
Publication number | Publication date |
---|---|
CN115227671A (zh) | 2022-10-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Zhou et al. | Modified ZIF-8 nanoparticles attenuate osteoarthritis by reprogramming the metabolic pathway of synovial macrophages | |
US4767402A (en) | Ultrasound enhancement of transdermal drug delivery | |
CN101589026B (zh) | 治疗脑神经胶质瘤的方法 | |
CN105641696B (zh) | 一种金钆复合纳米材料、制备方法及其用途 | |
Jung et al. | Ultrasound imaging and on-demand therapy of peripheral arterial diseases using H2O2-Activated bubble generating anti-inflammatory polymer particles | |
CN108653754B (zh) | 一种透明质酸靶向聚多巴胺包覆相变型液态氟碳纳米超声造影剂 | |
CN110743012A (zh) | 一种葡萄糖氧化酶修饰的介孔二氧化锰药物组合物的制备方法及应用 | |
CN115227671B (zh) | 一种药物递送***及其制备方法和应用 | |
JP3228941B2 (ja) | 臨床用のマイクロカプセル封入遺伝子操作微生物 | |
Feldmann et al. | Hydrocephalic dementia and spinal cord tumor: report of a case and review of the literature | |
WO2019050963A1 (en) | SONODYNAMIC THERAPY USING MICROBULLES AND METHODS AND SYSTEMS ULTRASOUNDED WITH PULSED WAVES | |
Qiao et al. | Artificial nano-red blood cells nanoplatform with lysosomal escape capability for ultrasound imaging-guided on-demand pain management | |
Song et al. | Moderate-intensity ultrasound-triggered on-demand analgesia nanoplatforms for postoperative pain management | |
CN116270728A (zh) | 一种具有内质网靶向的抗氧化功能纳米酶及其制备方法和应用 | |
CN113456587B (zh) | 一种靶向乳腺癌干细胞的谷胱甘肽响应型纳米药物载体制备及应用 | |
Bao et al. | Ultrasound-Triggered On-Demand Insulin Release for Diabetes Mellitus Treatment | |
CN113633789B (zh) | 一种集光声成像和包载药物一体化的液态金属纳米探针及其制备方法 | |
WHELAN et al. | Hepatic function in patients with hypoxaemia due to chronic pulmonary disease | |
CN102973513B (zh) | 智能纳米药物传递***和制备方法及应用 | |
Wang et al. | Neutrophil-targeted Mn3O4 nanozyme treats myocardial ischemia reperfusion injury by scavenging reactive oxygen species | |
Chen et al. | Ultrasound-Triggered on Demand Lidocaine Release Relieves Postoperative Pain | |
CN116919882A (zh) | 具有肿瘤微环境重塑功能的载药冰微针贴片及其制备方法 | |
RU2307658C2 (ru) | Способ стимуляции выработки простагландинов в организме | |
CN114225041A (zh) | 一种非对称结构纳米材料及其制备方法及其应用 | |
Xie et al. | Versatile Platforms of Microneedle Patches Loaded with Responsive Nanoparticles: Synthesis and Promising Biomedical Applications |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |