温度响应的酶催化核交联胶束
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摘要
以聚4-乙酰氧基苯乙烯P(4-ASt)和N-异丙基丙烯酰胺(NIPAm)为单体,通过可逆加成-断裂链转移聚合(RAFT)合成了结构明确窄相对分子质量分布(M_w/M_n=1.28)的两嵌段共聚物P(4-ASt-b-NIPAm)。通过水合肼将P(4-ASt-b-NIPAm)中的P(4-ASt)嵌段上的乙酰基团选择性水解后得到聚(4-乙烯基苯酚-b-N-异丙基丙烯酰胺)两嵌段共聚物P(4-VPh-b-NIPAm)。采用~1HNMR、FTIR和GPC对P(4-VPh-b-NIPAm)结构进行了表征,利用荧光光谱、透光率法和DLS研究了其水溶液的聚集行为和温度响应性。结果表明,P(4-VPh-b-NIPAm)在水中可自组装形成以P(4-VPh)为核、PNIPAm为壳的胶束,其临界胶束浓度(CMC)为0.015 g/L,室温下平均粒径约为137 nm,低临界溶解温度(LCST)为31.2℃。以辣根过氧化物酶(HRP)催化交联P(4-VPh)核制备了平均粒径约为119 nm的核交联胶束,TEM显示干态核交联胶束为球形,粒径为60～100 nm。核交联胶束水溶液具有良好的热稳定性和温度响应性,其相转变温度为32～36℃,LCST约为34.9℃,随温度升高平均粒径从25℃的119 nm减小至37℃的92.9 nm。
Diblock copolymer P(4-ASt-b-NIPAm) with well-defined structure and narrow molecular-weight distribution(M_w/M_n=1.28) was synthesized by reversible addition-fragmentation transfer(RAFT)polymerization using poly(4-acetoxystyrene) P(4-ASt) and N-isopropylacrylamide(NIPAm) as monomers.The acetyl groups in the chain of P(4-ASt-b-NIPAm) were selectively hydrolyzed by hydrazine hydrate to obtain diblock copolymer P(4-VPh-b-NIPAm). Copolymer P(4-VPh-b-NIPAm) was characterized by ~1HNMR, FTIR and GPC. The aggregation behavior and temperature response of P(4-VPh-b-NIPAm)aqueous solution were studied by fluorescence spectrum, transmittance method and DLS. The results showed that copolymer P(VPh-b-NIPAm) could self-assemble into micelles using P(4-VPh) as core and PNIPAm as shell in aqueous solution and the critical micelle concentration(CMC) was 0.015 g/L. The average particle size was about 137 nm at room temperature and the lower critical solution temperature(LCST) was 31.2 ℃. Horseradish peroxidase(HRP) catalyzed cross-linking of P(4-VPh) core to prepare core-crosslinked micelles with an average particle size of 119 nm. TEM showed that dry core-crosslinked micelles were spherical with particle size of 60～100 nm. The aqueous solution of core-crosslinked micelles had good stability and temperature response. Its phase transition temperature ranged from 32 ℃ to 36 ℃and its LCST was about 34.9 ℃. The average diameter of core-crosslinked micelles decreased from119 nm to 92.9 nm with increasing temperature from 25 ℃ to 37 ℃.
Diblock copolymer P(4-ASt-b-NIPAm) with well-defined structure and narrow molecular-weight distribution(M_w/M_n=1.28) was synthesized by reversible addition-fragmentation transfer(RAFT)polymerization using poly(4-acetoxystyrene) P(4-ASt) and N-isopropylacrylamide(NIPAm) as monomers.The acetyl groups in the chain of P(4-ASt-b-NIPAm) were selectively hydrolyzed by hydrazine hydrate to obtain diblock copolymer P(4-VPh-b-NIPAm). Copolymer P(4-VPh-b-NIPAm) was characterized by ~1HNMR, FTIR and GPC. The aggregation behavior and temperature response of P(4-VPh-b-NIPAm)aqueous solution were studied by fluorescence spectrum, transmittance method and DLS. The results showed that copolymer P(VPh-b-NIPAm) could self-assemble into micelles using P(4-VPh) as core and PNIPAm as shell in aqueous solution and the critical micelle concentration(CMC) was 0.015 g/L. The average particle size was about 137 nm at room temperature and the lower critical solution temperature(LCST) was 31.2 ℃. Horseradish peroxidase(HRP) catalyzed cross-linking of P(4-VPh) core to prepare core-crosslinked micelles with an average particle size of 119 nm. TEM showed that dry core-crosslinked micelles were spherical with particle size of 60～100 nm. The aqueous solution of core-crosslinked micelles had good stability and temperature response. Its phase transition temperature ranged from 32 ℃ to 36 ℃and its LCST was about 34.9 ℃. The average diameter of core-crosslinked micelles decreased from119 nm to 92.9 nm with increasing temperature from 25 ℃ to 37 ℃.
引文
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[26]Chen L,Peng Z,Zeng Z,et al.Hairy polymeric nanocapsules with p H-responsive shell and thermoresponsive brushes:Tunable permeability for controlled release of water-soluble drugs[J].Journal of Polymer Science Part A:Polymer Chemistry,2014,52(15):2202-2216.
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[28]Peng Zhiping(彭志平),Liu Xinxing(刘新星),Tong Zhen(童真).Effect of hydrophobic blocks on the aggregate behavior of amphiphilic triblock copolymers in aqueous solution[J].Acta Polymerica Sinica(高分子学报),2009,(9):936-941.
[29]Choi B C,Choi S,Leckband D E.Poly(N-isopropyl acrylamide)brush topography:dependence on grafting conditions and temperature[J].Langmuir,2013,29(19):5841-5850.
[30]Wang H,Luo W,Chen J.Fabrication and characterization of thermoresponsive Fe3O4@PNIPAM hybrid nanomaterials by surfaceinitiated RAFT polymerization[J].Journal of Materials Science,2012,47(16):5918-5925.
[2]Biswas S,Kumari P,Lakhani P,et al.Recent advances in polymeric micelles for anti-cancer drug delivery[J].European Journal of Pharmaceutical Sciences,2016,83:184-202.
[3]Kuang H,Wu S,Meng F,et al.Core-crosslinked amphiphilic biodegradable copolymer based on the complementary multiple hydrogen bonds of nucleobases:synthesis,self-assembly and in vitro drug delivery[J].Journal of Materials Chemistry,2012,22(47):24832-24840.
[4]O'Reilly R K,Hawker C J,Wooley K L.Cross-linked block copolymer micelles:functional nanostructures of great potential and versatility[J].Chemical Society Reviews,2006,35(11):1068-1083.
[5]van Nostrum C F.Covalently cross-linked amphiphilic block copolymer micelles[J].Soft Matter,2011,7(7):3246-3259.
[6]Talelli M,Barz M,Rijcken C J F,et al.Core-crosslinked polymeric micelles:principles,preparation,biomedical applications and clinical translation[J].Nano Today,2015,10(1):93-117.
[7]Shuai X,Merdan T,Schaper A K,et al.Core-cross-linked polymeric micelles as paclitaxel carriers[J].Bioconjugate Chemistry,2004,15(3):441-448.
[8]Talelli M,Iman M,Varkouhi A K,et al.Core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin[J].Biomaterials 2010,31(30):7797-7804.
[9]PiogéS,Nesterenko A,Brotons G,et al.Core cross-linking of dynamic diblock copolymer micelles:quantitative wtudy of photopolymerization efficiency and micelle structure[J].Macromolecules,2011,44(3):594-603.
[10]Chen J,Ouyang J,Kong J,et al.Photo-cross-linked and pH-sensitive biodegradable micelles for doxorubicin delivery[J].ACS Applied Materials&Interfaces,2013,5(8):3108-3117.
[11]Dai Y,Chen X,Zhang X,et al.Recent developments in the area of click-crosslinked nanocarriers for drug delivery[J].Macromolecular Rapid Communications,2019,40(3):1800541.
[12]Gu Z,Wang X,Cheng R,et al.Hyaluronic acid shell and disulfide-crosslinked core micelles for in vivo targeted delivery of bortezomib for the treatment of multiple myeloma[J].Acta Biomaterialia,2018,80:288-295.
[13]Zhang H,Liu P.Bio-inspired keratin-based core-crosslinked micelles for pH and reduction dual-responsive triggered DOX delivery[J].International Journal of Biological Macromolecules,2019,123:1150-1156.
[14]Kawakita H,Hamamoto K,Ohto K,et al.Polyphenol polymerization by horseradish peroxidase for metal adsorption studies[J].Industrial&Engineering Chemistry Research,2009,48(9):4440-4444.
[15]Kawakita H,Nakano S,Hamamoto K,et al.Copper-ion adsorption and gold-ion reduction by polyphenols prepared by the enzymatic reaction of horseradish peroxidase[J].Journal of Applied Polymer Science,2010,118(1):247-252.
[16]Sakai S,Nakahata M.Horseradish peroxidase catalyzed hydrogelation for biomedical,biopharmaceutical,and biofabrication applications[J].Chemistry-An Asian Journal,2017,12(24):3098-3109.
[17]Lee F,Bae K H,Kurisawa M.Injectable hydrogel systems crosslinked by horseradish peroxidase[J].Biomedical Materials,2015,11(1):014101.
[18]Kim B Y,Park K M,Joung Y K,et al.Preparation and characterizations of in situ shell cross-linked 4-arm-poly(propylene oxide)-poly(ethylene oxide)micelles via enzyme-mediated reaction for controlled drug delivery[J].Journal of Bioactive and Compatible Polymers,2012,27(3):185-197.
[19]Zeng Z,She Y,Peng,Z,et al.Enzyme-mediated in situ formation of pH-sensitive nanogels for proteins delivery[J].RSC Advances,2016,6(10):8032-8042.
[20]Cho H,Kim J,Patil P,et al.Synthesis of succinylated poly(4-hydroxystyrene)and its application for negative-tone photoresist[J].Journal of Applied Polymer Science,2007,103(6):3560-3566.
[21]?těpánek M,HajduováJ,Procházka K,et al.Association of poly(4-hydroxystyrene)-block-poly(ethylene oxide)in aqueous solutions:block copolymer nanoparticles with intermixed blocks[J].Langmuir,2011,28(1):307-313.
[22]Matuszewska A,Uchman M,Adamczyk-Wo?niak A,et al.Glucoseresponsive hybrid nanoassemblies in aqueous solutions:ordered phenylboronic acid within intermixed poly(4-hydroxystyrene)-blockpoly(ethylene oxide)block copolymer[J].Biomacromolecules,2015,16(12):3731-3739.
[23]Kuo S W,Huang C F,Lu C H,et al.Syntheses and specific interactions of poly(?-caprolactone)-block-poly(vinyl phenol)copolymers obtained via a combination of ring-opening and atom-transfer radical polymerizations[J].Macromolecular Chemistry and Physics,2006,207(21):2006-2016.
[24]Khan H,Chen S,Zhou H,et al.Synthesis of multicompartment nanoparticles of ABC triblock copolymers through intramolecular interactions of two solvophilic blocks[J].Macromolecules,2017,50(7):2794-2802.
[25]Cau?t S I,Wooley K L.Kinetic investigation of the RAFTpolymerization of p-acetoxystyrene[J].Journal of Polymer Science Part A:Polymer Chemistry,2010,48(12):2517-2524.
[26]Chen L,Peng Z,Zeng Z,et al.Hairy polymeric nanocapsules with p H-responsive shell and thermoresponsive brushes:Tunable permeability for controlled release of water-soluble drugs[J].Journal of Polymer Science Part A:Polymer Chemistry,2014,52(15):2202-2216.
[27]Astafieva I,Zhong X F,Eisenberg A.Critical micellization phenomena in block polyelectrolyte solutions[J].Macromolecules,1993,26(26):7339-7352.
[28]Peng Zhiping(彭志平),Liu Xinxing(刘新星),Tong Zhen(童真).Effect of hydrophobic blocks on the aggregate behavior of amphiphilic triblock copolymers in aqueous solution[J].Acta Polymerica Sinica(高分子学报),2009,(9):936-941.
[29]Choi B C,Choi S,Leckband D E.Poly(N-isopropyl acrylamide)brush topography:dependence on grafting conditions and temperature[J].Langmuir,2013,29(19):5841-5850.
[30]Wang H,Luo W,Chen J.Fabrication and characterization of thermoresponsive Fe3O4@PNIPAM hybrid nanomaterials by surfaceinitiated RAFT polymerization[J].Journal of Materials Science,2012,47(16):5918-5925.
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