【作者】 陈伟；

【导师】 鲁希华；

【作者基本信息】 东华大学 ， 化学工程与技术， 2021， 硕士

【摘要】 热致物理交联纳米水凝胶可以随温度变化从流动性良好的溶液状态（sol）转变为不可流动的固态/半固态状态（gel）,这种原位溶胶-凝胶（sol-gel）转变特性使其在药物输送和组织工程领域具有独特的应用前景。作为一类典型的温敏性水凝胶,聚（N-异丙基丙烯酰胺）（PNIPAM）在高于其相变温度（Phase transition temperature,Tp,32～34℃）时由于剧烈的相转变行为无法实现溶胶-凝胶转变。目前,基于PNIPAM（PNIPAM-based）组装的热致交联水凝胶可以通过引入官能团和设计结构实现溶胶-凝胶转变。然而,它们大多通过嵌段、接枝、无规聚合和互穿等方法制备,具有制备工艺复杂、容易引入高分子催化剂和链转移剂、合成成本较高、凝胶化浓度较高、需要额外的添加剂或温度响应性变差等缺点。由于PNIPAM-based纳米水凝胶体系通常需要在疏水性和亲水性之间取得微妙的平衡才能实现溶胶-凝胶转变,因此,开发一种合成步骤简单、临界凝胶化浓度较低且不添加额外的盐或其他添加剂的方法制备PNIPAM-based热致物理交联纳米水凝胶对推进其在生物领域的实际应用具有一定的意义和挑战性。本论文采用乳液沉淀聚合法,以N-异丙基丙烯酰胺（NIPAM）为基本温度响应型单体,引入不同的疏水性单体制备PNIPAM-based热致物理交联纳米水凝胶。具体内容如下:（1）利用乳液沉淀聚合法,将疏水性单体N-苯乙基丙烯酰胺（PEAA）、N-苯基丙烯酰胺（PAA）和N-环己基丙烯酰胺（CHAA）分别与NIPAM共聚,得到P（NIPAM-co-PEAA）（PNPE）、P（NIPAM-co-PAA）（PNPA）和P（NIPAM-co-CHAA）（PNCH）温敏性共聚纳米水凝胶。通过动态光散射（DLS）、流变学、变温1H NMR和变温FT-IR对PNPE、PNPA和PNCH纳米水凝胶进行表征。结果表明,三种纳米水凝胶具有缓慢的相转变行为,这种缓慢的相变行为避免了纳米水凝胶的剧烈收缩、崩塌和宏观相分离行为,使纳米水凝胶在相变温度以上保持相互接触,发生相分离前可以相互缠结,建立物理疏水域作为交联点“撑起”水凝胶网络,从而实现热诱导的溶胶-凝胶转变。而缓慢的相转变行为与引入凝胶网络中侧链的N-苯基、N-苯乙基和N-环己基密切相关,大分子链发生收缩或旋转时,侧链基团带来的空间位阻和疏水效应阻碍其运动,在一定程度上防止了颗粒受热后的瞬间收缩。侧基的空间位阻和疏水作用不同,N-苯基>N-苯乙基>N-环己基,PNPA纳米水凝胶较PNPE和PNCH纳米水凝胶具有更低的凝胶化温度和更缓慢的相转变行为。（2）变温¹H NMR、变温FT-IR光谱、微扰相关移动窗口（PCMW）和二维红外相关光谱（2Dcos）表明,PNPE、PNPA、PNCH和PNIPAM纳米水凝胶具有相同的基团受温度扰动脱水顺序。随着温度升高,纳米水凝胶中的氢键最敏感,C=O···D-O-D氢键中的水分子脱离,形成新氢键（C=O···D-N）。当疏水性增强时,侧链上的-CH₃基团脱水,并形成疏水缔合作用,随后是主链上的-CH₂基团脱水。此外,三种纳米水凝胶均具有良好的可注射性能和生物相容性,这表明PNPE、PNPA、PNCH纳米水凝胶能用于生物医学领域,在组织工程、药物负载等需要低毒性和良好生物相容性要求的领域具有广阔的应用前景。更多还原

【Abstract】 Physical crosslinked thermogelable nanogels can rapidly change from a well-fluidized solution（sol）to a nonflowable solid/semisolid state（gel）with changes in temperature,and this in situ sol-gel transition characteristic makes them have unique application prospects in the field of drug delivery and tissue engineering.As a typical thermosensitive hydrogel,pure poly（N-isopropylacrylamide）（PNIPAM）is unable to achieve the sol-gel transition due to the violent phase transition behavior above the phase transition temperature（Tp,32～34℃）.At present,the majority of PNIPAM-based thermogelable nanogels are focused on block,grafted or branched polymers,which undergo a complex preparation process,use macromolecular catalysts and initiators that increase the cost of synthesis,may affect the purity of the polymers and increase the toxicity.Random or interpenetrated polymers require a high polymer concentration or additional salts,and may reduce the temperature responsiveness.Since PNIPAM-based nanogels usually need to strike a delicate balance between hydrophobicity and hydrophilicity to achieve a sol-gel transition,it is meaningful but challenging to develop a method to prepare PNIPAM-based thermogelable nanogels with simple synthesis steps,a low critical gelation concentration and no additional salt or other additives to promote their practical applications in the biological field.In this paper,PNIPAM-based thermogelable nanogels were prepared by emulsion precipita-tion polymerization using N-isopropylacrylamide（NIPAM）as the basic temperature-responsive monomer and introducing different hydrophobic monomers.The details are as follows:（1）Hydrophobic monomers N-phenylethylacrylamide（PEAA）,N-phenylacrylamide（PAA）and N-cyclohexylacrylamide（CHAA）were copolymerized with NIPAM by emulsion precipitation polymerization to obtain P（NIPAM-co-PEAA）（PNPE）,P（NIPAM-co-PAA）（PNPA）and P（NIPAM-co-CHAA）（PNCH）thermosensitive nanogels.PNPE,PNPA and PNCH nanogels were investigated by dynamic light scattering（DLS）,rheology,variable temperature¹H NMR and variable tempera-ture FT-IR.The results showed that the three kinds of nanogels have slow phase transition behavior,which avoided the violent shrinkage,collapse and macroscopic phase separation behavior of the nanogels so that the nanogels remained in contact with each other above the Tp and could entan-gle with each other before phase separation occurred.The physical crosslinking hydrophobic area was established as the cross-linking point to“prop up”the hydrogel network,thus achieving a ther-mal sol-gel transition.The slow phase transition behavior was attributed to the introduction of side chains N-phenyl,N-phenylethyl and N-cyclohexyl in the gel network.The existence of hydrophobic groups brought large steric hindrance and hydrophobic interactions,which increased the rigidity of the molecular chain.When the macromolecular chain rotated or shrank around this rigid group,the motion of the chain segment was hindered by the large steric hindrance,which prevented the instan-taneous shrinkage of the particles after heating to a certain extent.Due to the difference in steric hindrance and hydrophobicity caused by side groups,N-phenyl>N-phenylethyl>N-cyclohexyl,PNPA nanogels have a lower gelation temperature and slower phase transition behavior than PNPE and PNCH nanogels.（2）Variable temperature¹H NMR and FT-IR spectra,perturbation correlation moving win-dow（PCMW）and two-dimensional correlation spectroscopy（2Dcos）indicated that PNPE,PNPA,PNCH and PNIPAM nanogels have the same dehydration order caused by temperature disturbance.With an increase in temperature around the phase transition,the C=O···D-O-D hydrogen bonds of the nanogels were the most sensitive to dehydration,forming new hydrogen bonds of C=O···D-N.Furthermore,as hydrophobicity increased,the-CH₃ groups in the side chain dehydrated and formed hydrophobic associations,followed by the-CH₂ group on the main chain.In addition,the three kinds of nanogels have good injectability and biocompatibility,which indicated that PNPE,PNPA and PNCH nanogels can be used in biomedical fields and have broad application prospects in tissue engineering,drug loading and other fields requiring low toxicity and good biocompatibility.更多还原