CN115475256B - Small-size hyperbranched zwitterionic nanomicelle capable of crossing blood brain barrier and application thereof - Google Patents
Small-size hyperbranched zwitterionic nanomicelle capable of crossing blood brain barrier and application thereof Download PDFInfo
- Publication number
- CN115475256B CN115475256B CN202211354291.5A CN202211354291A CN115475256B CN 115475256 B CN115475256 B CN 115475256B CN 202211354291 A CN202211354291 A CN 202211354291A CN 115475256 B CN115475256 B CN 115475256B
- Authority
- CN
- China
- Prior art keywords
- zwitterionic
- hyperbranched
- micelle
- compound
- brain barrier
- 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
- 230000008499 blood brain barrier function Effects 0.000 title claims abstract description 33
- 210000001218 blood-brain barrier Anatomy 0.000 title claims abstract description 29
- 239000000693 micelle Substances 0.000 claims abstract description 81
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 229920000515 polycarbonate Polymers 0.000 claims abstract description 25
- 239000004417 polycarbonate Substances 0.000 claims abstract description 25
- 150000005676 cyclic carbonates Chemical class 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims abstract description 10
- 239000000178 monomer Substances 0.000 claims abstract description 9
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 mercapto alcohol compound Chemical class 0.000 claims abstract description 8
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000007112 amidation reaction Methods 0.000 claims abstract description 5
- 230000000149 penetrating effect Effects 0.000 claims abstract description 5
- 238000006845 Michael addition reaction Methods 0.000 claims abstract description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000003999 initiator Substances 0.000 claims description 4
- 229920005862 polyol Polymers 0.000 claims description 3
- 150000003077 polyols Chemical class 0.000 claims description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 2
- QXJQHYBHAIHNGG-UHFFFAOYSA-N trimethylolethane Chemical compound OCC(C)(CO)CO QXJQHYBHAIHNGG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002105 nanoparticle Substances 0.000 abstract description 8
- 102000004169 proteins and genes Human genes 0.000 abstract description 5
- 108090000623 proteins and genes Proteins 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000017531 blood circulation Effects 0.000 abstract description 4
- 230000004048 modification Effects 0.000 abstract description 4
- 238000012986 modification Methods 0.000 abstract description 4
- 238000001179 sorption measurement Methods 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 238000007348 radical reaction Methods 0.000 abstract 1
- 150000003254 radicals Chemical class 0.000 abstract 1
- 238000001338 self-assembly Methods 0.000 abstract 1
- 229920000728 polyester Polymers 0.000 description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 208000005017 glioblastoma Diseases 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 3
- 229960003237 betaine Drugs 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 101001094083 Homo sapiens Sodium- and chloride-dependent betaine transporter Proteins 0.000 description 2
- 102100035259 Sodium- and chloride-dependent betaine transporter Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000013553 cell monolayer Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000009210 therapy by ultrasound Methods 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003373 anti-fouling effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 208000030224 brain astrocytoma Diseases 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- LNUDKRYFAFELDF-UHFFFAOYSA-N carbonic acid;prop-2-enoic acid Chemical compound OC(O)=O.OC(=O)C=C LNUDKRYFAFELDF-UHFFFAOYSA-N 0.000 description 1
- NKCVNYJQLIWBHK-UHFFFAOYSA-N carbonodiperoxoic acid Chemical compound OOC(=O)OO NKCVNYJQLIWBHK-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000000635 electron micrograph Methods 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229920000587 hyperbranched polymer Polymers 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 210000004925 microvascular endothelial cell Anatomy 0.000 description 1
- 238000004848 nephelometry Methods 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6907—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G64/00—Macromolecular compounds obtained by reactions forming a carbonic ester link in the main chain of the macromolecule
- C08G64/20—General preparatory processes
- C08G64/30—General preparatory processes using carbonates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G64/00—Macromolecular compounds obtained by reactions forming a carbonic ester link in the main chain of the macromolecule
- C08G64/42—Chemical after-treatment
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Polymers & Plastics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nanotechnology (AREA)
- Dispersion Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
The invention discloses a small-size hyperbranched zwitterionic nanomicelle capable of penetrating through a blood brain barrier and application thereof, wherein a cyclic carbonate monomer and a mercapto alcohol compound are reacted to obtain hydroxylated cyclic carbonate, and ring-opening polymerization is carried out to obtain functional hyperbranched polycarbonate; the preparation method comprises the steps of reacting an acrylamide zwitterionic compound with a dimercapto compound to obtain a sulfhydrylated zwitterionic compound, carrying out Michael addition reaction on functional hyperbranched polycarbonate and the sulfhydrylated zwitterionic compound to obtain hyperbranched zwitterionic polycarbonate, obtaining stable nano-micelle by utilizing self-assembly and free radical reaction of double bonds, and finally modifying amino on a photosensitizer by reacting with hexamethylenediamine to carry out amidation reaction with the nano-micelle. The amphoteric ion ensures that the nano particles have good protein adsorption resistance and blood circulation time prolonging capability; the small size advantage and modification of the zwitterion enable the nanomicelle to cross the blood brain barrier and be deeply enriched at the tumor site.
Description
Technical Field
The invention relates to a nano micelle material and application thereof, in particular to a small-size hyperbranched zwitterionic nano micelle capable of crossing a blood brain barrier and application thereof.
Background
Glioblastoma multiforme (GBM) is a central nervous system fatal tumor that cannot be effectively treated. Chemotherapy also plays an important role in the treatment of glioblastoma, but the efficacy is still low and side effects are often severe. Indeed, intensive research has demonstrated that functionalized nanoparticles can act as intelligent drug delivery systems to enhance the therapeutic effects and reduce side effects of GBM. However, nanotechnology-based GBM chemotherapy still faces several bottleneck challenges. First, the blood circulation time of most nano-drugs is not long enough at present because proteins are absorbed and rapidly cleared from the blood by the reticuloendothelial system (RES). Second, the blood-brain barrier is a physical transport barrier that tightly controls the entry and exit of substances into the brain, and it is difficult for nearly 98% of therapeutic drugs to pass through the blood-brain barrier.
Bionic zwitterionic has the same positive and negative charges, and is widely paid attention to as a substitute of polyethylene glycol due to the super-hydrophilicity and antifouling property. Compared with PEG, the zwitterion realizes stronger hydration through ion solvation, reduces nonspecific adsorption with biological media such as serum or blood platelet, generates resistance to bacterial or mammalian cell adhesion, and escapes from the immune response of the body. In addition, the zwitterionic has chemical diversity and ductility, and can be used for zwitterionic nano-drugs with stability, multifunction and structural diversity. This makes zwitterions a promising bio-inert and stealth material in terms of structure and surface modification of nanomedicines. Zwitterionic betaines are substrates for the carrier protein BGT-1, and BGT-1 is highly expressed on the blood brain barrier, thereby helping hyperbranched zwitterionic polycarbonates to cross the blood brain barrier.
Size is an important parameter affecting the passage of nanoparticles across the blood brain barrier. In one model study, the effect of size on blood brain barrier penetration was explored, and materials of different sizes 60, 30 and 10nm were prepared by the nano-precipitation method. In the rat brain stroke model, 30 and 10nm NPs successfully penetrated the impaired blood brain barrier, while 60nm NPs exhibited minimal extravasation. Etame et al observed that the transmittance of PEG nanoparticles in an in vitro blood brain barrier penetration experiment was size dependent, with particle sizes of 4-24nm. NPs with smaller particle sizes are easier to cross the blood brain barrier.
Disclosure of Invention
The invention aims to: the invention provides a small-size hyperbranched zwitterionic nanomicelle capable of crossing the photosensitizer bonding of a blood brain barrier and application thereof.
The technical scheme is as follows: the small-size hyperbranched zwitterionic nanomicelle capable of penetrating through a blood brain barrier disclosed by the invention is prepared by reacting a cyclic carbonate monomer with a mercapto alcohol compound to generate hydroxylated cyclic carbonate, and then performing ring-opening polymerization to obtain functional hyperbranched polycarbonate; reacting an acrylamide zwitterionic compound with a dimercapto compound to obtain a sulfhydrylated zwitterionic compound, and then carrying out Michael addition reaction on the functional hyperbranched polycarbonate and the sulfhydrylated zwitterionic compound to obtain the hyperbranched zwitterionic polycarbonate; the photosensitizer reacts with hexamethylenediamine to obtain an amino-modified photosensitizer, and then the amino-modified photosensitizer is bonded with hyperbranched zwitterionic polycarbonate micelle through amidation reaction to obtain the hyperbranched zwitterionic polycarbonate micelle bonded with the photosensitizer, namely the small-size hyperbranched zwitterionic nano micelle penetrating through the blood brain barrier.
As preferable:
the cyclic carbonate monomer is selected from compounds with the following structures:
wherein R 1 is selected from H or CH 3
The mercapto alcohol compound is selected from compounds with the following structures:
Wherein R 2 is selected from C2-C4 alkyl or C4-C8 aryl.
The ring-opening polymerization may be carried out using a hydroxylated cyclic carbonate (preferably in a molar ratio of 20% -100%) as an initiator for the ring-opening polymerization, or may be carried out by stepwise obtaining the hydroxylated cyclic carbonate and then carrying out ring-opening polymerization with other cyclic carbonate monomers, or may be carried out by adding other polyol molecules as a co-initiator.
Further preferred is: the polyalcohol molecules are selected from trimethylolethane, glycerol or pentaerythritol, etc.
The acrylamide zwitterionic compound is selected from compounds shown in the following structures:
the dimercapto compound is selected from compounds shown in the following structure:
wherein n=1-50.
The molar percentage of the zwitterionic units on the hyperbranched polymer is 0-80%.
The photosensitizer is selected from compounds shown in the following structures:
Preferably, the preparation method of the nanogel comprises the following steps:
(1) The preparation method comprises the steps of reacting a cyclic carbonate monomer with a thiol compound in a certain proportion by using chloroform as a solvent for 4-6 hours to obtain an intermediate product of hydroxylated cyclic carbonate, continuously adding a catalyst (DBU or Sn (Oct) 2) into a reaction mixture to initiate ring-opening polymerization, and transferring to a temperature of 40-60 ℃ for reacting for 18-24 hours to obtain the functional hyperbranched polycarbonate.
(2) The acrylamide zwitterionic compound reacts with dimercapto compound to obtain the corresponding sulfhydryl carboxylic acid betaine.
(3) Dissolving hyperbranched polycarbonate with dimethylformamide and methanol, adding sulfhydryl carboxylic acid betaine and a catalyst triethylamine, and reacting at room temperature overnight to obtain the functional hyperbranched zwitterionic polymer.
(4) The nanoparticle preparation is divided into four types. The solvent exchange method comprises the following specific steps: dissolving the material in an organic solvent, then dropwise adding deionized water into the organic solvent under ultrasonic conditions, and finally removing the organic solvent by dialysis; the ultrasonic water-soluble method comprises the following specific steps: under the ultrasonic condition, deionized water is added into the material, and the nano micelle can be obtained after ultrasonic treatment for a certain time; ultrasonic water-soluble and photo-crosslinking preparation, which comprises the following specific steps: under the ultrasonic condition, deionized water is added into the material, a photoinitiator is added into the solution after ultrasonic treatment is carried out for a certain time, and the solution is irradiated for a period of time under a specific ultraviolet wavelength after deoxidization to crosslink; the preparation method of the nano precipitation method comprises the following specific steps: dissolving the material in high-purity water, then dripping the dissolved material into acetone under stirring, finally adding a photoinitiator into the solution, and irradiating the solution for a period of time under a specific ultraviolet wavelength after deoxidization to crosslink the solution.
(5) The zwitterionic hyperbranched polycarbonate bonded with the photosensitizer is obtained by amidation reaction of the amino grafted photosensitizer and the zwitterionic polycarbonate micelle.
The invention relates to application of a small-size hyperbranched zwitterionic nano-micelle capable of penetrating through a blood brain barrier in preparing an anti-brain tumor drug.
The small-size hyperbranched zwitterionic nanomicelle capable of crossing the blood brain barrier is applied to the treatment of glioblastoma multiforme.
The hyperbranched zwitterionic nanomicelle can be used as a drug carrier, especially an anti-tumor drug carrier, can cross the blood brain barrier, has low cytotoxicity, has good blood compatibility and reduces immunogenicity.
The beneficial effects are that: compared with the prior art, the invention has the following advantages:
The amphoteric ion ensures that the nano particles have good protein adsorption resistance and blood circulation time prolonging capability; the small size advantage and modification of the zwitterion enable the nanomicelle to cross the blood brain barrier and be deeply enriched at the tumor site. The crosslinked nanoparticle micelle of the invention improves the stability of the drug. The amphoteric ion ensures that the nano particles have good protein adsorption resistance, immunogenicity reduction and blood circulation time prolonging capabilities; zwitterionic modifications and small size advantages enable nanomicelles to cross the blood brain barrier.
Drawings
FIG. 1 shows the hydrogen nuclear magnetic pattern of the hyperbranched zwitterionic polyester HP-HAC 10％-CB60％-AC30％ in example 1;
FIG. 2 shows a hydrogen nuclear magnetic resonance spectrum of an amino group grafted photosensitizer in example 2;
FIG. 3 a hydrogen nuclear magnetic resonance spectrum of a zwitterionic polycarbonate micelle grafted with a photosensitizer of example 3;
FIG. 4 an electron micrograph of the bonded photosensitizer hyperbranched zwitterionic polyester micelles HP-HAC 10％-CB60％-AC30％ -IR780 micelles in example 3;
FIG. 5 an ultraviolet full spectrum of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle in example 3;
FIG. 6 stability of the bonded photosensitizer hyperbranched zwitterionic polyester micelles HP-HAC 10％-CB60％-AC30％ -IR780 micelles in example 4;
FIG. 7 photo-thermal curve of the bonded photosensitizer hyperbranched zwitterionic polyester micelles HP-HAC 10％-CB60％-AC30％ -IR780 micelles in example 5;
FIG. 8 cytotoxicity of the bonded photosensitizer hyperbranched zwitterionic polyester micelles HP-HAC 10％-CB60％-AC30％ -IR780 micelles in example 6;
FIG. 9 proportion of hyperbranched zwitterionic polyester micelles HP-HAC 10％-CB60％-AC30％ of the material in example 7 that penetrate the in vitro BBB model.
Detailed Description
Example 1 HP Synthesis of HAC 10％-CB60％-AC30％
(1) Synthesis of hydroxylated carbonate HAC
Acrylic acid carbonate AC (2 g,10 mmol) was dissolved in dichloromethane, mercaptoethanol (0.82 g,10.50 mmol) and catalytic amount of triethylamine were added under nitrogen protection and reacted at room temperature for 4-6h. After the reaction is finished, the reaction liquid is dripped into sufficient amount of glacial ethyl ether to be precipitated and separated out, and the precipitate is dried under reduced pressure to obtain the colorless oily compound hydroxyl carbonate HAC.
(2) Synthesis of hyperbranched polycarbonate HP-HAC
In a glove box, 400mg of the hydroxy carbonate HAC monomer is dissolved in chloroform, the chloroform is added into a sealed reactor, then a catalyst 1, 8-diazabicyclo undec-7-ene (DBU) is added, the reactor is sealed, then the reactor is transferred out of the glove box and placed into an oil bath at 40-60 ℃ for reaction overnight, glacial acetic acid is used for stopping the reaction after the reaction is finished, precipitation is carried out in glacial diethyl ether, the supernatant is removed, and the oily viscous liquid at the bottom is collected and dried in vacuum to obtain the product.
(3) Synthesis of hyperbranched zwitterionic polycarbonates HP-HAC 10％-CB60％-AC30％
The hyperbranched polycarbonate HP-HAC with acrylic ester and sulfhydryl carboxylic acid betaine undergo Michael addition reaction under the catalysis of triethylamine to obtain the multifunctional biodegradable hyperbranched polycarbonate zwitterionic polymer. The nuclear magnetic diagram is shown in figure 1.
EXAMPLE 2 Synthesis of amino-modified photosensitizer IR780-NH 2
100Mg of photosensitizer IR780 and 26.73mg of hexamethylenediamine are mixed in N, N-dimethylformamide, a catalytic amount of triethylamine is added, then stirring is continued for 8-10h under the protection of nitrogen at 80-100 ℃, the solvent is distilled off in vacuo, the crude product is purified by silica gel and dried in vacuo. The nuclear magnetic diagram is shown in figure 2.
EXAMPLE 3 preparation of the bonded photosensitizer hyperbranched zwitterionic polyesters HP-HAC 10％-CB60％-AC30％ -IR780
(1) Preparation of hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ micelle
Purified water was added to 2mg of hyperbranched zwitterionic polycarbonate HP-HAC 10％-CB60％-AC30％ polymer under ultrasound conditions, and sonicated for half an hour. A catalytic amount of photoinitiator was then added to the micelle solution and nitrogen was bubbled into the solution to exclude air and cross-linked under UV irradiation.
(2) Preparation of bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle
100Mg of hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ micelle, 6.2mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 4.6mg of N-hydroxysuccinimide (NHS) are thoroughly mixed in high-purity water and stirred continuously at room temperature for 4-6h. And then stirring the solution and an amino-decorated photosensitizer IR780-NH 2 for reaction, and dialyzing to obtain the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle. The nuclear magnetic diagram is shown in fig. 3, and the electron microscope diagram is shown in fig. 4. The ultraviolet full spectrum chart of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle is shown in figure 5.
As shown in FIG. 4, the size of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle is about 10 nm.
As shown in FIG. 5, the absorption wavelength of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 at 650nm is exactly consistent with the maximum absorption wavelength of the amino-modified photosensitizer IR780-NH 2, indicating that the hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ micelle is successfully bonded with the amino-modified photosensitizer IR780-NH 2.
EXAMPLE 4 stability of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle
The increase in absorbance (indicating aggregation) was monitored at 500nm by an ultraviolet-visible spectrophotometer and the stability of the bound photosensitizer hyperbranched zwitterionic polyester micelles HP-HAC 10％-CB60％-AC30％ -IR780 micelles was evaluated by nephelometry. The bound photosensitizer hyperbranched zwitterionic polyester micelles HP-HAC 10％-CB60％-AC30％ -IR780 micelles were dispersed in buffer at a final concentration of 1wt% and absorbance was recorded by adding protein (10% FBS in PBS) at 37 ℃. As shown in FIG. 6, the absorbance of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle is unchanged with the change of time, which indicates that the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle has good stability.
EXAMPLE 5 photo-thermal Effect of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle
The photo-thermal effect of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle, the amino-modified photosensitizer IR780-NH 2 and PBS under the irradiation of near infrared laser is shown in figure 7. As shown in the graph, the temperature of the hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 bonded with the photosensitizer within 5min can reach 42 ℃, the photo-thermal stability of the hyperbranched zwitterionic polyester micelle is far better than that of the photosensitizer IR780-NH 2 modified with amino, and the PBS group has almost no temperature rise.
Example 6 cytotoxicity experiment (MTT) of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle
The cytotoxicity experiment of the hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ micelle adopts an MTT method. Human brain astrocytoma cells were used in the cytotoxicity test. Human brain astrocyte tumor cells were cultured in DMEM medium containing 10% serum at 37 ℃ under 5% carbon dioxide, with a cell density of 3500 cells/well. After 12 hours, 10. Mu.L of hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ micelle (0.5 mg/mL) and the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle (the concentration of the amino-modified photosensitizer IR780-NH 2 is 1.5. Mu.g/mL) were added, the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle was divided into two groups, one group was subjected to 660nm laser irradiation after 24 hours of incubation with cells, then incubated for 24 hours, and the other group was not subjected to light irradiation. After 48h, 10. Mu.L MTT (5 mg/mL) was added. The culture was continued for 4 hours, the medium was removed, 100. Mu. LDMSO was added to each well, and absorbance was measured at 490nm with an ELISA reader after complete dissolution of the purple crystals. As shown in FIG. 8, the survival rate of U87MG cells is still more than 90% at the micelle concentration of 0.5MG/mL, and the hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ micelle is proved to have no cytotoxicity basically. Under the condition of no illumination, the cell survival rate of the bonded photosensitizer hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ -IR780 micelle is about 90%, and the cell survival rate is greatly reduced to about 45% after illumination, which indicates that cytotoxicity is caused by temperature rise.
Example 7 in vitro BBB penetration experiment of hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ micelle
Human brain microvascular endothelial cells (bEnd.3) were cultured in DMEM medium containing 10% serum at 37℃under 5% carbon dioxide. To establish the BBB model in vitro, bend.3 cells (5×104/well) were seeded in the trans-well plate upper chamber and 800 μl of DMEM medium containing 10% serum was added to the lower chamber. The medium was refreshed every two days. Transendothelial resistance (TEER) instruments are used to monitor the tightness of cell monolayers. In vitro BBB penetration experiments were performed when bEnd.3 cell monolayers TEER values were greater than 200Ω.cm 2. The hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ nano micelle is bonded with Cy5-NH 2 through amidation reaction, and the fluorescence proportion passing through the nano micelle is measured at 1h, 2h, 4h, 6h, 8h, 12h and 24h, so that the transmittance of the material is determined.
As shown in FIG. 9, the hyperbranched zwitterionic polyester micelle HP-HAC 10％-CB60％-AC30％ micelle can penetrate 34.17% at 24h and can well penetrate an in vitro blood brain barrier model.
Claims (5)
1. A small-size hyperbranched zwitterionic nanomicelle capable of crossing a blood brain barrier is characterized in that a cyclic carbonate monomer and a mercapto alcohol compound react to generate a hydroxylated cyclic carbonate, and then ring-opening polymerization is carried out to obtain a functional hyperbranched polycarbonate; reacting an acrylamide zwitterionic compound with a dimercapto compound to obtain a sulfhydrylated zwitterionic compound, and then carrying out Michael addition reaction on the functional hyperbranched polycarbonate and the sulfhydrylated zwitterionic compound to obtain the hyperbranched zwitterionic polycarbonate; the photosensitizer reacts with hexamethylenediamine to obtain an amino-modified photosensitizer, and then the amino-modified photosensitizer is bonded with hyperbranched zwitterionic polycarbonate micelle through amidation reaction to obtain a hyperbranched zwitterionic polycarbonate micelle bonded with the photosensitizer, namely a small-size hyperbranched zwitterionic nano micelle capable of penetrating through a blood brain barrier; the size of the nano micelle is 10nm;
the cyclic carbonate monomer is selected from compounds with the following structures: Wherein R 1 is selected from H or CH 3;
The mercapto alcohol compound is selected from compounds with the following structures: Wherein R 2 is selected from C2-C4 alkyl or C4-C8 aryl;
The acrylamide zwitterionic compound is selected from compounds shown in the following structures: 、/> Or (b) ；
The dimercapto compound is selected from compounds shown in the following structure:、/> Or/> Wherein n=1-50;
The photosensitizer compound is selected from compounds shown in the following structures: 。
2. The small-sized hyperbranched zwitterionic nanomicelles capable of crossing the blood-brain barrier according to claim 1, wherein the ring-opening polymerization uses a hydroxylated cyclic carbonate as an initiator of the ring-opening polymerization, or the hydroxylated cyclic carbonate is obtained step by step and then ring-opening polymerization is performed on other cyclic carbonate monomers, or other polyol molecules are added as co-initiators.
3. The small-sized hyperbranched zwitterionic nanomicelle that can cross the blood-brain barrier according to claim 2 wherein the polyol molecules are selected from trimethylolethane, glycerol or pentaerythritol.
4. The small-sized hyperbranched zwitterionic nanomicelle capable of crossing the blood brain barrier according to claim 1, wherein the molar percentage of zwitterionic units on the hyperbranched polycarbonate is 60-80%.
5. Use of the small-sized hyperbranched zwitterionic nanomicelle capable of crossing the blood brain barrier according to any one of claims 1-4 in the preparation of an anti-brain tumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211354291.5A CN115475256B (en) | 2022-10-31 | 2022-10-31 | Small-size hyperbranched zwitterionic nanomicelle capable of crossing blood brain barrier and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211354291.5A CN115475256B (en) | 2022-10-31 | 2022-10-31 | Small-size hyperbranched zwitterionic nanomicelle capable of crossing blood brain barrier and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115475256A CN115475256A (en) | 2022-12-16 |
| CN115475256B true CN115475256B (en) | 2024-06-21 |
Family
ID=84396699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211354291.5A Active CN115475256B (en) | 2022-10-31 | 2022-10-31 | Small-size hyperbranched zwitterionic nanomicelle capable of crossing blood brain barrier and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115475256B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303397A (en) * | 2020-03-05 | 2020-06-19 | 中国药科大学 | Biodegradable hyperbranched zwitterionic polycarbonate and application thereof |
| CN114748639A (en) * | 2022-03-28 | 2022-07-15 | 华中科技大学 | Photosensitizer-hydroxyalkyl starch-polypeptide coupled amphiphilic macromolecular compound, nano drug delivery system and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105968373B (en) * | 2016-05-16 | 2019-09-20 | 四川大学 | One kind is containing zwitterionic multiple antitumor carrier micelle of acid-sensitive and its preparation method and application |
| CN114533671A (en) * | 2022-02-25 | 2022-05-27 | 中国药科大学 | Preparation method and application of biodegradable hyperbranched polycarbonate shell-core polymer micelle |
| CN114767655B (en) * | 2022-04-19 | 2023-09-22 | 中国药科大学 | Zwitterionic functionalized biodegradable oral nano medicine carrying system and application |
-
2022
- 2022-10-31 CN CN202211354291.5A patent/CN115475256B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303397A (en) * | 2020-03-05 | 2020-06-19 | 中国药科大学 | Biodegradable hyperbranched zwitterionic polycarbonate and application thereof |
| CN114748639A (en) * | 2022-03-28 | 2022-07-15 | 华中科技大学 | Photosensitizer-hydroxyalkyl starch-polypeptide coupled amphiphilic macromolecular compound, nano drug delivery system and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 神经胶质瘤治疗方法进展;熊学辉等;《福建医药杂志》;第33卷(第4期);第145-147页，尤其是第146页右栏第2段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115475256A (en) | 2022-12-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Karakoti et al. | PEGylated inorganic nanoparticles | |
| CN107550921B (en) | Nanoparticle-polymer injectable composite hydrogel double-drug-loading system and preparation method thereof | |
| CN111303397B (en) | Biodegradable hyperbranched zwitterionic polycarbonate and application thereof | |
| CN106589355B (en) | Non-viral gene transfection carrier material of the one kind based on cationic helical polypeptide | |
| CN103319388B (en) | Bi-functional polyethylene glycol derivative and preparation method thereof | |
| CN101474411B (en) | Anti-tumor prodrug using novel amphipathic hyperbranched polyesters as carrier and preparation method | |
| CN101791408A (en) | Cationic polymer gene vector having low cytotoxicity and high transfection efficiency, preparation method and use thereof | |
| Zhang et al. | A BiOCl nanodevice for pancreatic tumor imaging and mitochondria-targeted therapy | |
| Khakpour et al. | Graphene-based nanomaterials for stimuli-sensitive controlled delivery of therapeutic molecules | |
| Mehmood et al. | Green synthesis of zwitterion-functionalized nano-octahedral ceria for enhanced intracellular delivery and cancer therapy | |
| CN106397758B (en) | It is a kind of that there is multiple response high molecular nanometer carrier and its synthetic method and the application for passing rapidly through cell membrane characteristics | |
| CN115475256B (en) | Small-size hyperbranched zwitterionic nanomicelle capable of crossing blood brain barrier and application thereof | |
| Cai et al. | Metal–Organic Frameworks as Intelligent Drug Nanocarriers for Cancer Therapy | |
| Cui et al. | Thermo-and light-responsive polymer-coated magnetic nanoparticles as potential drug carriers | |
| CN113082206B (en) | Macromolecule nitric oxide donor modified up-conversion nanoparticle, preparation method and application | |
| CN108743971B (en) | Preparation method and application of drug-loaded polypyrrole nanoparticles | |
| CN111110630B (en) | Blood brain barrier crossing drug delivery system and preparation method and application thereof | |
| CN108014850A (en) | A kind of preparation method and applications of tetracarboxylic phenyl porphyrin supermolecule photochemical catalyst | |
| Kankala | Organic-or Inorganic-based Nanomaterials: Opportunities and Challenges in the Selection for Biomedicines | |
| CN111423571B (en) | Biodegradable zwitterionic polycarbonate and application thereof | |
| Deepagan et al. | Amphiphilic polysialic acid derivatives: synthesis, characterization, and in-vitro cytotoxicity | |
| CN101381454A (en) | Preparation method of ion type temperature-responsive hyperbranched polyether and/or polyester ether | |
| CN101129339A (en) | Method of producing nano magnetic chitosan composite particle for photodynamic medicament carrier | |
| Kim et al. | Preparation and characterizations of self-assembled PEGylated gelatin nanoparticles | |
| CN110859966A (en) | Oxidation-reduction responsive hyperbranched poly-prodrug nano-micelle and preparation method and application thereof |
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 |