Mesoporous Fe3O4hydroxyapatite composite for targeted drug delivery

工业十水合四硼酸二钠的英文别称 (The English Alternative Name for Industrial Sodium Tetraborate Decahydrate)在化学领域中，工业十水合四硼酸二钠是一种重要的化合物，它在工业生产和实验室研究中都具有广泛的应用。

除了常见的名称外，它还有一些其他的英文别称，让我们一起来了解一下。

1. 起源与特性工业十水合四硼酸二钠，其化学式为Na2B4O7·10H2O，是一种无色晶体，通常呈矿物状或粉末状。

它溶解于水，在酸性条件下呈现出独特的化学性质，因此在许多工业领域中都被广泛使用。

2. 主要用途工业十水合四硼酸二钠在工业中的用途非常广泛，主要包括：a. 作为防腐剂和防腐蚀剂，常用于木材、纤维、皮革等材料的防腐处理；b. 用作焊接和钎焊时的助焊剂，有助于提高焊接表面的清洁度和润湿性；c. 作为清洁剂和去污剂，能有效去除油脂、污垢和细菌，常用于家庭清洁和工业清洗中。

3. 英文别称除了常见的名称“工业十水合四硼酸二钠”外，它在化学文献中还有一些其他的英文别称，例如：a. Sodium Tetraborate Decahydrateb. Borax Decahydratec. Sodium Borate Decahydrate4. 个人观点与理解对于工业十水合四硼酸二钠这一化合物，我个人的观点和理解是： a. 它的广泛用途和重要性不言而喻，无论是在日常生活中的清洁用品，还是在工业生产中的防腐处理，都发挥着重要作用；b. 除了常见的名称外，了解其英文别称有助于扩展化学知识，便于与国际上的化学专家和科研人员进行交流和合作；c. 在使用工业十水合四硼酸二钠时，需要谨慎处理，避免其对人体和环境造成不良影响。

总结回顾文章中我们对工业十水合四硼酸二钠的英文别称进行了全面、深入的探讨，并结合其起源、特性和主要用途进行了介绍。

我们也共享了个人对这一化合物的观点和理解，希望能够为读者提供全面、深刻和灵活的化学知识。

1. 3-亚苯基四（2，6-二甲基苯基）酯的简介3-亚苯基四（2，6-二甲基苯基）酯是一种化学物质，也称为TDBP。

它是一种有机化合物，具有特定的分子结构和化学性质。

由于其特殊的结构和性质，3-亚苯基四（2，6-二甲基苯基）酯在化工、医药和其他领域具有广泛的应用价值。

2. 3-亚苯基四（2，6-二甲基苯基）酯的物理性质3-亚苯基四（2，6-二甲基苯基）酯是一种白色至浅黄色的结晶固体，具有特殊的气味。

其化学分子式为C19H19O4，摩尔质量约为307.35 g/mol。

该物质的熔点约为92-95°C，沸点约为340°C。

3-亚苯基四（2，6-二甲基苯基）酯是一种易溶于有机溶剂的化合物，对水的溶解度较低。

3. 3-亚苯基四（2，6-二甲基苯基）酯的化学性质3-亚苯基四（2，6-二甲基苯基）酯是一种有机酯化合物，具有较强的稳定性和惰性。

它在常温下较不容易发生化学反应，对氧、酸、碱等具有一定的抵抗能力。

然而，当遇到高温、光照、或者特定催化剂的作用时，3-亚苯基四（2，6-二甲基苯基）酯可能会发生酯交换、酯水解等反应，生成其他化合物。

4. 3-亚苯基四（2，6-二甲基苯基）酯的应用由于其特殊的结构和性质，3-亚苯基四（2，6-二甲基苯基）酯在许多领域均有广泛的应用。

在化工领域，它常用作溶剂、润滑剂、抗氧化剂等。

在医药领域，3-亚苯基四（2，6-二甲基苯基）酯也可作为药物的原料或添加剂。

它在染料、香料、塑料、橡胶等产业中也有一定的应用。

5. 3-亚苯基四（2，6-二甲基苯基）酯的制备方法目前，制备3-亚苯基四（2，6-二甲基苯基）酯的方法较多，常见的方法包括酯化反应、酸催化等。

通过合理选择合成原料、催化剂以及反应条件，可以高效地合成出高纯度的3-亚苯基四（2，6-二甲基苯基）酯。

6. 3-亚苯基四（2，6-二甲基苯基）酯的安全性评估在使用3-亚苯基四（2，6-二甲基苯基）酯时，需要注意其安全性问题。

羟基四甲基哌啶氮氧自由基
羟基四甲基哌啶氮氧自由基（英文缩写：PTIO）是一种广泛应用于生物学和化学领域，用于检测自由基等化学物质的试剂。

它是一种富含氮氧的有机分子，具有强烈的抗氧化作用，可靠地捕获许多高能自由基。

PTIO分子的结构是一个羟基四甲基哌啶环，其中甲基取代环的四个位置。

该分子带有一个氮原子和一个氧原子，氮原子通过共价键连接到环上一个碳原子上。

羟基四甲基哌啶环的结构中有一个稳定的六元环，其中一个MNO桥键将氮原子与羟基四甲基哌啶环的环上一个碳原子连接起来。

PTIO分子在离子色谱、HPLC和其他色谱技术中常常用作标准，以用于检测和测量自由基等化学物质。

此外，它还被广泛地用于生物学中的细胞研究和体外实验中，以评估自由基产生和氧化应激等过程中的各种反应。

PTIO可以与具有自由基反应活性的化合物（如NO、亚硝酸或一氧化氮等）发生转化，从而表现出其强大的捕获和中和自由基和其他氧化活性物质的能力。

具体来说，当PTIO遇到氧化化合物时，它会从化合物中夺取氢原子，而形成PTI自身的稳定自由基。

除此之外，PTIO也可以用于评估抗氧化剂的活性。

在这种应用中，PTIO被称为超氧化物自由基供体，其可以释放自由基来模拟氧化应激情况，从而选择性地对抗氧化剂进行测定和评估。

β-hydroxybutyrate，也称为3-羟基丁酸，是一种重要的生物体内代谢产物，化学式为C4H8O3。

它是一种重要的酮体，通常在糖原枯竭时由肝脏合成，并在饥饿状态或长期低碳水化合物饮食时作为能量来源被大量产生。

β-hydroxybutyrate还被用作体内细胞膜的活性物质和一些甲酰基转移反应的底物。

1. β-hydroxybutyrate的生物合成β-hydroxybutyrate的生物合成主要发生在肝脏中。

当血糖水平较低时，胰岛素分泌减少，脂肪细胞开始分解脂肪并释放游离脂肪酸，这些脂肪酸被肝脏摄取并在线粒体内经过β氧化反应生成乙酰辅酶A。

乙酰辅酶A进一步发生生物合成反应，生成β-hydroxybutyrate。

β-hydroxybutyrate随着血液流向体内其他组织，被运用为重要的能源供应物质。

2. β-hydroxybutyrate的作用机制β-hydroxybutyrate在细胞中具有多种作用机制。

它可以通过改变细胞内的氧化还原平衡，调节细胞动力学。

β-hydroxybutyrate还能够抑制一些特定的蛋白酶，影响细胞内的信号传导通路。

研究还表明，β-hydroxybutyrate还能够影响基因表达，并通过调节某些转录因子来影响细胞的功能。

3. β-hydroxybutyrate在疾病中的作用除了在正常新陈代谢过程中起着重要作用外，β-hydroxybutyrate在一些疾病中也具有重要作用。

在糖尿病患者中，β-hydroxybutyrate 的水平会显著升高，因为他们无法有效利用血糖来产生能量，而转而依赖脂肪酸代谢来产生β-hydroxybutyrate作为能量来源。

一些神经退行性疾病也与β-hydroxybutyrate的水平变化有关，研究显示在一些情况下，β-hydroxybutyrate可以通过调节能量代谢、减缓氧化应激和抑制炎症反应来保护神经细胞免受损害。

4. 个人观点和总结β-hydroxybutyrate是一个多方面作用的分子，它在维持正常生物体代谢稳定性和应对一些疾病方面都有着重要作用。

羟乙基乙二胺三亚甲基膦酸分子式羟乙基乙二胺三亚甲基膦酸，又简称为HEDP，是一种广泛应用于工业和农业领域的多功能有机磷酸盐。

其分子式为C9H21NO9P3，化学结构中包含了氧原子、氮原子、碳原子、氢原子和磷原子，具有多种功能和应用。

首先，我们来了解一下羟乙基乙二胺三亚甲基膦酸的化学结构。

它的结构中有两个羟乙基基团(-CH2CH2OH)和一个乙二胺基团(-NHCH2CH2NH2)，它们通过三个亚甲基膦酸基团(-PO3H2)连接在一起。

这种结构使得HEDP具有许多特殊的化学性质和应用性能。

HEDP是一种无色至微黄色的液体，可溶于水和一些有机溶剂。

其溶液呈微酸性，pH值一般为2~3之间。

它具有良好的螯合性，能够与金属离子形成稳定的络合物，从而起到缓蚀、防锈、螯合剂等多种功能。

同时，HEDP还具有良好的碱度缓冲性能，能够在酸性和碱性环境中保持较稳定的pH值，起到缓冲作用。

HEDP广泛应用于工业领域的水处理、金属表面处理、洗涤剂、纺织品印染、造纸、油田开采等领域。

在水处理中，它可用作螯合剂和阻垢剂，能够有效地抑制水中的钙、镁等金属离子的沉积，防止水垢的形成。

在金属表面处理中，HEDP可以作为钝化剂和缓蚀剂，为金属表面提供一层保护膜，防止金属腐蚀。

在洗涤剂和纺织品印染中，HEDP作为助剂能够增强清洗和染色效果。

在造纸过程中，HEDP可以作为络合剂和抗垢剂，提高纸张质量和生产效率。

在油田开采中，HEDP可以用作缓蚀剂和阻垢剂，防止管道和设备的堵塞和腐蚀。

另外，HEDP还具有良好的生物降解性，对环境友好。

在农业领域，HEDP可以用作水稻土壤改良剂，提高土壤的抗盐碱性，促进植物生长。

同时，HEDP还可以用作食品添加剂，用于矿物质的补充和保鲜。

由于其多功能性和环境友好性，HEDP受到了广泛的应用和研究。

总结起来，羟乙基乙二胺三亚甲基膦酸（HEDP）是一种多功能有机磷酸盐，具有良好的螯合性、缓冲性和生物降解性。

它在工业和农业领域有着广泛的应用，如水处理、金属表面处理、洗涤剂、纺织品印染、造纸和油田开采等。

三羟甲基氨基甲烷化学式
分子式：C4H11NO3
分子量：121.14
英文名称：TRIS；Tris-base；THAM；Tris(hydrosymenthyl)-aminomethande；Trometamol；
2-Amino-2-(hydroxymethyl)-1,3-propanediol；Tromethamine
其他名称：缓血酸铵；三（羟甲基）氨基甲烷；2-氨基-2-(羟甲基)-1,3-丙二醇；氨丁三醇；三甲醇氨基甲烷；氨基丁三醇；三羟基甲基氨基甲烷
CAS号：77-86-1
C4H11NO3=121.14
级别：GR
含量：≥99.9%
熔点：168～171℃
PH：10.0～10.8
重金属：≤5ppm
氯化物：≤3ppm
灼烧残渣：≤0.05%
性状(以下信息仅供参考)：白色结晶或结晶性粉末。

25℃时溶解度(mg/ml)：水550、乙二醇79.1、甲醇26、无水乙醇14.6、95%乙醇22.0、N，N-二甲基甲胺14、戊醇2.6、丙醇2.0、乙酸乙酯0.5、橄榄油0.4、环己烷0.1、氯仿0.05、四氯化碳<0.05。

水溶液在空气中不吸收二氧化碳，0.1mol/L水溶液pH10.4。

对铜、铝有腐蚀作用。

用途：本品仅供科研，不得用于其它用途。

(以下用途仅供参考)生物缓冲剂，缓冲范围pH7.0-9.0。

酸性气体吸收剂。

酸量滴定法基准物质。

电流滴定法测定蛋白质中的巯基。

纸上电泳分离血清蛋白。

淀粉平板电泳分离毒素。

保存：RT。

硫代甘油和盐酸羟胺螯合镁离子
硫代甘油是一种有机化合物，也称为硫代甘油醚，化学式为
C3H8O3S。

它是一种硫代醚化合物，通常用作医药和化妆品中的成分。

盐酸羟胺是一种无机化合物，化学式为NH2OH·HCl，是羟胺的盐酸
盐形式。

螯合是指两个或多个原子或离子通过化学键结合在一起形
成一个配合物的过程。

镁离子是镁的带电离子形式，化学式为Mg2+，在生物体内起着重要的作用。

当硫代甘油和盐酸羟胺螯合镁离子时，可能会发生一系列化学
反应。

首先，硫代甘油中的硫原子可能与镁离子形成配合物，形成
硫代甘油镁配合物。

盐酸羟胺中的羟胺分子也可能与镁离子形成配
合物。

这些配合物的形成可能会导致化学性质的改变，例如溶解度、稳定性和生物活性的增强。

从化学角度来看，螯合反应可能会影响配合物的稳定性和溶解度，从而改变其在生物体内的活性和生物利用度。

此外，螯合反应
还可能影响镁离子在生物体内的分布和代谢途径，从而影响其生物
学功能。

总的来说，硫代甘油和盐酸羟胺螯合镁离子可能会导致配合物
的形成，从而影响其化学性质和生物活性。

这些变化可能对药物或化妆品的性能和效果产生影响，因此在相关领域中需要进一步研究和探讨。

Mesoporous silica nanotubes coated with multilayered polyelectrolytes for pH-controlled drug releaseYun-Jie Yang a,b ,Xia Tao a,*,Qian Hou a ,Yi Ma a,b ,Xuan-Li Chen a,b ,Jian-Feng Chen b,*a Key Lab for Nanomaterials of the Ministry of Education,Beijing University of Chemical Technology,Bei San Huan Dong Road 15,Beijing 100029,People’s Republic of ChinabResearch Center of the Ministry of Education for High Gravity Engineering and Technology,Beijing University of Chemical Technology,Beijing 100029,People’s Republic of Chinaa r t i c l e i n f o Article history:Received 21September 2009Received in revised form 10February 2010Accepted 24February 2010Available online 1March 2010Keywords:Mesoporous silica nanotubes Polyelectrolytes pH-responsive Controlled release Doxorubicina b s t r a c tTwo kinds of inorganic/organic hybrid composites based on mesoporous silica nanotubes (MSNTs)and pH-responsive polyelectrolytes have been developed as pH-controlled drug delivery systems via the layer by layer self-assembly technique.One system was based on alternatively loading poly(allylamine hydro-chloride)and sodium poly(styrene sulfonate)onto as-prepared MSNTs to load and release the positively charged drug doxorubicin.The other system was synthesized by alternately coating sodium alginate and chitosan onto amine-functionalized MSNTs,which were used as vehicles for the loading and release of the negatively charged model drug sodium fluorescein.Controlled release of the drug molecules from these delivery systems was achieved by changing the pH value of the release medium.The results of in vitro cell cytotoxicity assays indicated that the cell killing efficacy of the loaded doxorubicin against human fibrosarcoma (HT-1080)and human breast adenocarcinoma (MCF-7)cells was pH dependent.Thus,these hybrid composites could be potentially applicable as pH-controlled drug delivery systems.Ó2010Acta Materialia Inc.Published by Elsevier Ltd.All rights reserved.1.IntroductionIn recent years much work has focused on controlled drug re-lease from polymeric materials in response to specific stimuli,such as electric [1]or magnetic [2]fields,exposure to ultrasound [3],light [4],enzymes [5],saccharides [6]or antigens [7]and changes in pH [8],temperature [9]or redox state [10].Since the human body exhibits variations in pH along the gastrointestinal tract from the stomach (pH 1.0–3.0),to the small intestine (pH 6.5–7.0),to the colon (pH 7.0–8.0)[11]and also in some specific areas like tumoral tissues (pH 6.5–7.2)and subcellular compartments,such as endo-somes/lysosomes (pH 5.0–5.5)[12],one very important system group is those sensitive to the pH of their surroundings.In this con-text pH-sensitive polyelectrolyte polymers have been found or de-signed as new drug carriers for controlled delivery [13,14].These polymers contain relatively ionizable groups at levels ranging from a few mol.to 100%of the repeating units.They undergo controlla-ble volume changes in response to small variations in pH of the external environment,which facilitate drug delivery control.To date,pH-sensitive polyelectrolyte polymers based on hollow microcapsules prepared by the layer by layer (LBL)self-assembly of polyelectrolytes on colloidal particles have been extensively investigated [15–23].Möhwald and co-workers prepared hollowpoly(allylamine hydrochloride)and sodium poly(styrene sulfo-nate)(PAH/PSS)microcapsules and confirmed the controlled encapsulation and release of several kinds of species,such as dyes [18],enzymes [19],dextran [20]and DNA [21],from the capsules by changing the pH of the release ing the same method Ye et al.achieved the pH-controlled encapsulation and release of insulin from hollow alginate (ALG)and chitosan (CHI)microcap-sules [22].Caruso and co-workers prepared poly(L -lysine)and poly(L -glycolic acid)microcapsules by sequentially coating meso-porous silica spheres and accomplished the controlled encapsula-tion and release of catalase [23].However,these hollow capsules are not mechanically strong and easily collapse in the course of drying and the removal of colloidal templates [24].Therefore,some smart inorganic/organic composites have been developing for pH-controlled drug delivery [24,25].Sukhorukov and co-workers syn-thesized pH-sensitive YF 3/polycyclic aromatic hydrocarbon (PAH),Fe 3O 4/PAH and hydroxyapatite/PAH composite capsules and dem-onstrated the controllable encapsulation and release of dextran molecules [25].Zhu et ed hollow mesoporous silica spheres as a container for drug molecules and PAH/PSS multilayer coatings as a pH-responsive switch [24].It is encouraging that with these smart composites they not only achieved pH-controlled encapsula-tion and release of drug molecules,but also enhanced the mechan-ical strength of the polyelectrolyte capsules.Especially in the latter research,the drug storage capacity was greatly increased by mesoporous silica materials as drug vehicles.As is well known,mesoporous silica materials are ideal drug supports due to their1742-7061/$-see front matter Ó2010Acta Materialia Inc.Published by Elsevier Ltd.All rights reserved.doi:10.1016/j.actbio.2010.02.042*Corresponding authors.Tel.:+861064456466;fax:+861064434784.E-mail addresses:taoxia@ (X.Tao),chenjf@ (J.-F.Chen).Acta Biomaterialia 6(2010)3092–3100Contents lists available at ScienceDirectActa Biomaterialiajournal homepage:/locate/actabiomatnon-toxic and biocompatible nature,adjustable pore size and high specific surface area with abundant Si–OH bonds[26,27].These materials have been found to have promising applications for some oral drug formulations[28–30]and as implantable matrices for the regeneration of bone tissues[31].Several research groups have re-ported the design of stimuli-responsive controlled drug delivery systems based on mesoporous silica materials.As examples,Fujiw-ara and co-workers successfully realized photo-controlled revers-ible release of drug molecules from coumarin-modified MCM-41 [32].Lin and co-workers prepared a series of stimuli-responsive controlled delivery systems by capping removable CdS[33], Fe3O4[34]or gold[35]nanoparticles in the channel of mesoporous silica spheres.In addition,thermo-responsive[36],glucose-responsive[37],enzyme-responsive[38]and dual stimuli-respon-sive[39]controlled drug delivery systems have also been devel-oped on the basis of mesoporous silica materials with various morphologies,such as SiO2–Au nanoshells,mesoporous silica nan-ospheres and MCM-41nanoparticles.Recently,our group has successfully synthesized a novel kind of mesoporous silica nanotubes(MSNTs)with a very spacious hollow core and a tubular shell with a mesoporous framework,as well as a tunable pore size distribution and shell thickness[40].This mate-rial has been studied as a carrier to load and release various active species,such as drugs[41],enzymes[42]and so on.However,the cargo-loaded tube material suffers from the drawback of uncon-trolled release of active species from the carrier upon being ex-posed to external surroundings such as various pH media.Here we attempt to introduce polyelectrolytes onto the surface of the preformed silica tubes as a pH switch in the hope of obtaining no-vel pH-responsive MSNTs.In view of this,two kinds of inorganic/ organic composites based on MSNTs and polyelectrolytes,includ-ing the synthetic pair PAH/PSS and the natural pair ALG/CHI,were developed for pH-controlled drug delivery.The PAH/PSS pair is the most researched polyelectrolyte and presents very good pH-responsiveness[18–21].ALG and CHI are biocompatible and biode-gradable polysaccharides and,more importantly,they are very economical,because they can be obtained from brown algae and crustacea,respectively,which are both widespread in nature [22].pH-controlled release of model drugs,including doxorubicin hydrochloride(DOX)and sodiumfluorescein(FLU),from these composites has been investigated in detail.In addition,in vitro cell cytotoxicity assays of the loaded DOX against tumoral cells were carried out in different pH culture media.The fabricated pH-responsive MSNTs are anticipated to be applicable as oral drug for-mulations for local drug delivery or implantable matrices in the treatment of bone disease.2.Experimental2.1.MaterialsPAH(M w70,000)and PSS(M w70,000)were obtained from Al-drich.ALG(M w12,000–80,000)was obtained from Sigma,Canada. CHI(M w30,000)was obtained from Primex Biochemicals,Norway. DOX(M w580,p K a=6.5[43])was purchased from Meiji Pharma-ceuticals,China.FLU(M w376,p K a1=4.3,p K a2=6.4[44])was ob-tained from Sinopharm Chemical Reagent,China.For reference, the chemical structures and charges of PAH,PSS,CHI,ALG,DOX and FLU are shown in Fig.1.3-Aminopropyltriethoxysilane(APTS) was purchased from Fluka,Japan.Humanfibrosarcoma(HT-1080) and human breast adenocarcinoma(MCF-7)cells were from the ATCC.All other chemicals used in the experiments were obtained from commercial sources as analytical reagents without further purifilipore water with a resistivity of18.2M X cm was used throughout the study.2.2.Polyelectrolyte multilayer coatingMSNTs were fabricated according to the procedure in a previous report[41].PAH/PSS multilayer coating was accomplished as fol-lows.An aliquot of25ml of PAH(2mg mlÀ1in0.5M NaCl)was Fig.1.Chemical structures of PAH,PSS,CHI,ALG,DOX and FLU.Y.-J.Yang et al./Acta Biomaterialia6(2010)3092–31003093added to a suspension of MSNTs(2.0wt.%,25ml),pH7.5and stir-red for30min at room temperature.The suspension was then kept at353K for4h.The resulting particles were recovered by three re-peated centrifugation(4000rpm for3min)/washing/redispersion cycles with dilute aqueous NaCl.Then,oppositely charged PSS (25ml,2mg mlÀ1in0.5M NaCl)was added,stirred for2h,centri-fuged,washed and redispersed in NaCl ing a similar coating process as for thefirst PSS layer,other PAH and PSS layers were alternately deposited on the MSNTs.Finally,MSNTs coated with four bilayers of PAH/PSS were obtained,denoted PAH/PSS-MSNTs.Before coating with ALG/CHI multilayers the MSNTs werefirst modified with APTS to produce NH2-MSNTs[41].CHI was dis-solved in0.5M NaCl solution and the pH adjusted to3.0.Then 25ml of ALG solution(2mg mlÀ1in0.5M NaCl)was added to the suspension of NH2-MSNTs(2.0wt.%,25ml)and stirred for 2h at room temperature.The resulting particles were recovered by three repeated centrifugation(4000rpm for3min)/washing/ redispersion cycles with dilute aqueous NaCl.Then,oppositely charged CHI(25ml,2mg mlÀ1in0.5M NaCl)was added,stirred for2h and then centrifuged,washed and redispersed.The process for producing thefirst ALG/CHI bilayer coating was repeated three times.Four bilayers of ALG/CHI were coated on the NH2-MSNTs, denoted ALG/CHI-NH2-MSNTs.The prepared samples were dried in vacuum at308K for further characterization.2.3.Characterization instrumentsThe morphology and structure of the prepared samples were characterized by transmission electron microscopy(TEM)at an accelerating voltage of200keV(Hitachi H-800).Nitrogen adsorp-tion–desorption isotherms were measured in an ASAP2010surface area analyzer(Micromeritics),in which the samples($0.2g)were first out-gassed under vacuum at373K overnight and the mea-surements were then carried out at77K.The pore size distribution (PSD)and the average pore size(D pore)were determined from the N2desorption branch of the nitrogen isotherms by the Barret–Joy-ner–Halenda method[45]and the surface area was calculated by the Brunauer–Emmett–Teller(BET)method[46].Fourier transform infrared(FTIR)spectroscopy was performed with a Bruker Vector-22infrared spectrometer using the KBr pellet method and the data were processed using the accessory software supplied with the spectrometer.The concentrations of the DOX and FLU solutions were determined with a Shimadzu UV2501spectrometer.f poten-tials were measured with a Malven Zetasizer-3000HS at a concen-tration of0.05g lÀ1.Confocal laser scanning microscopy(CLSM) images were taken with an Olympus FV500.2.4.pH-controlled drug storagePositively charged DOX and negatively charged FLU(see Fig.1) were selected as model drugs.A typical procedure for loading DOX was as follows.An aliquot of0.2g of PAH/PSS-MSNTs was added to 20ml of DOX solution(1.0mg mlÀ1)at298K and then the solution was adjusted to pH2.0with1M HCl.The suspension was stirred for10h in the dark,followed by adjustment to pH8.0with 0.2M NaOH and further stirring for2h.The drug-loaded particles ware separated from this solution by centrifugation(4000rpm) and washed with dilute NaOH solution(pH8.0).The supernatant was collected to determine the drug loading by UV–vis spectros-copy at a wavelength of480nm.A similar process with different pH adjustment was performed for the loading of FLU in ALG/CHI-NH2-MSNTs(see Scheme1).FLU loading was determined by UV–vis spectroscopy at a wavelength of488nm.For comparison,the loading of DOX and FLU in MSNTs was also performed.In this work the drug-loading value(mg g carrierÀ1)was equals to the drug-loading efficiency when the unit of efficiency was per cent.CLSM images were taken directly in the washing solution after comple-tion of drug loading into the carriers.2.5.In vitro pH-controlled drug releaseA typical in vitro drug release experiment was performed as fol-lows.An aliquot of2ml of drug-loaded composite suspendedinScheme1.Experimental process for the coating of a polyelectrolyte multilayer on MSNTs and NH2-MSNTs and subsequent pH-controlled encapsulation and release of the model drugs DOX and FLU.3094Y.-J.Yang et al./Acta Biomaterialia6(2010)3092–3100solution(10mg mlÀ1)was poured in a dialysis bag(cut-off molec-ular weight7000Da)and the bag was placed in50ml of50mM buffer of the required pH(pH1.2,hydrochloric acid;pH4.0and 5.2,acetate buffer;pH6.8,7.4and8.0,phosphate buffer)(see Scheme1).The release medium was stirred at100rpm and 310K.At predetermined sampling times4ml of medium was re-moved and replaced with the same volume of fresh buffer.The amount of DOX or FLU in the medium was determined by UV-spectroscopy(DOX,480nm for all pH values;FLU,437,440,473, 488,489and490nm for pH 1.2, 4.0, 5.2, 6.8,7.4and8.0, respectively).2.6.pH-dependent cell cytotoxicityTwo kinds of drug-sensitive cells,human breast adenocarci-noma(MCF-7)and humanfibrosarcoma(HT-1080),were main-tained in DMEM(high glucose)medium in a humidified incubator at310K and under a5%CO2atmosphere.Before testing the cells were harvested with0.25%(w/v)trypsin–0.03%(w/v)EDTA solution and seeded in a96-well plate ($6Â102cells wellÀ1)for48h.Free DOX or equivalent DOX-loaded samples in RPMI1640medium(pH7.4or6.8),adjusted with1M HCl or NaOH,were prepared immediately before use and then added to the96-well plate from which medium had been removed at different DOX concentrations.After treatment for48h,50l l of MTT solution(2mg lÀ1)was added to each well and then incubated for4h.The medium was removed and di-methyl sulfoxide(150l l)was added to each well and incubated for10min.The absorbance of each well was determined with a microplate reader(Bio-Rad-318)at a wavelength of570nm.Cell viability was calculated by dividing the number of live cells (after being treated with DOX or DOX-loaded micelles)by the number of live cells(existing in drug-free culture medium)at each pH value after48h incubation.2.7.Statistical analysisQuantitative data are expressed as means±standard deviation from at least three independent experiments.Statistical compari-sons were carried out using the one-way Student’s t-test or ANOVA test with P<0.05significance.These tests were performed using SPSS software(version13).3.Results and discussion3.1.Characterization of samplesFig.2A shows a TEM micrograph of MSNTs with a length of 6–10l m and a diameter in the range400–600nm.From the TEM image of NH2-MSNTs(Fig.2B)it can be seen that the sam-ples retained the same morphology as the as prepared MSNTs after modification with APTS.A TEM micrograph of MSNTs coated with PAH/PSS multilayers is presented in Fig.2C.It can be observed that the thickness of the silica shell was$60nm and a PAH/PSS multilayer coating with a thickness of$12nm existed on the outer surface of the MSNTs.The thickness of the four bilayer PAH/PSS coating was analogous to a value re-ported previously[26].Similar results for the thickness of the ALG/CHI multilayer assembled on NH2-MSNTs can be determined from the TEM micrograph of Fig.2D.Electrophoresis measurements can be employed to monitor whether the polyelectrolyte multilayer is deposited on the silica particles.Fig.3A shows f potentials as a function of polyelectrolyte layer number for negatively charged MSNTs coated with PAH and PSS.An initial value of approximatelyÀ33.4mV corresponds to as prepared MSNTs particles.The subsequent alternation in f potentials observed with each coating step strongly suggests the growth of a polyelectrolyte multilayer on the surface of MSNTs. Similarly,the plot of f potentials versus the assembled layernum-Fig.2.TEM images of(A)MSNTs,(B)NH2-MSNTs,(C)PAH/PSS-MSNTs and(D)ALG/CHI-NH2-MSNTs.Y.-J.Yang et al./Acta Biomaterialia6(2010)3092–31003095ber,shown in Fig.3B,confirms alternating deposition of ALG and CHI layers on NH 2-MSNTs particles.Fig.4shows the FTIR spectra of all produced silica samples.The Si–OH band at 953cm À1presented in Fig.4a almost disappears in Fig.4b,indicating a decrease in silanol groups on the surface of MSNTs after modification with APTS.The absorption band at $2927cm À1in Fig.4b–d can be attributed to C–Hx stretching vibrations of aminopropyl groups on NH 2-MSNTs or alkyl groups on polyelectrolytes.As reported,the absorption band at 1635cm À1is assigned to Si–OH vibrations or N–H bending (scis-soring)vibrations [15].Apparently,the band at 1635cm À1in Fig.4a and b can be assigned to the Si–OH vibrations.However,the intensities of the band at 1635cm À1in Fig.4c and d are much greater than those in Fig.4a and b,which may be due to an enhancement of N–H bending vibrations of the deposited PAH or CHI.In addition,the band at 1524cm À1corresponding to N–H bending (wagging)vibrations in NH þ3[15]was also found in Fig.4c and d.These observations on N–H bending could prove suc-cessful deposition of PAH or CHI on the silica particles.The peaks at 1498and 1456cm À1are related to stretching of the benzene ring of PSS.The bands at 1173cm À1in Fig.4c and 1414cm À1in Fig.4d can be attributed to the stretching of SO À3groups of PSSand COO Àgroups of ALG,respectively [47,16].These findings con-firm the successful deposition of PSS and ALG layers on the silica particles.The nitrogen adsorption–desorption isotherms and PSD data for the fabricated silica particles are presented in Fig.5.These typical type IV isotherms are characteristic of mesoporous materials [41].The inset PSD graph reveals that all the samples had broad pore size distributions.The probability of small pores ranging from 2to 10nm decreased dramatically after the deposition of PAH/PSS or ALG/CHI multilayers.These observations imply that the polymer molecules diffused into pores and were adsorbed onto the pore walls during the deposition process.The physico-chemical param-eters of the fabricated silica materials before and after coating with polyelectrolytes are summarized in Table 1.3.2.Drug loading and release studiesTwo fluorescent species,positively charged DOX and negatively charged FLU,were selected as model drugs.Fig.6presents CLSM images of DOX-loaded PAH/PSS-MSNTs and FLU-loaded ALG/CHI-NH 2-MSNTs.The silica nanotubes clearly exhibited bright redandFig. 3.f potentials as a function of polyelectrolyte layer number on MSNTs alternately coated with (A)PAH and PSS and (B)NH 2-MSNTs alternately coated with ALG and CHI (means ±standard deviation,n =3).Fig.4.FTIR spectra of (a)MSNT,(b)NH 2-MSNTs,(c)PAH/PSS-MSNTs and (d)ALG/CHI-NH 2-MSNTs.Fig. 5.Nitrogen adsorption–desorption isotherms and (inset)PSD data for the produced silica samples.Table 1Physico-chemical parameters and drug-loading efficiency of the fabricated silica materials.SampleS BET(m 2g À1)V Pore(cm 3g À1)D Pore (nm)Drug-loading efficiency (%)DOXFLU MSNTs6380.788.281.7±3.648.9±2.9NH 2-MSNTs 2850.578.7––PAH/PSS-MSNTs860.4219.189.4±4.89.6±1.4ALG/CHI-NH 2-MSNTs1390.6319.6–20.5±2.1Drug-loading efficiencies are expressed as means ±standard deviation (n =3).3096Y.-J.Yang et al./Acta Biomaterialia 6(2010)3092–3100green fluorescence originating from the loaded DOX and FLU.This observation indicates successful pH-controlled encapsulation of DOX and FLU inside these carriers.Moreover,the drug-loading capacities of the fabricated silica materials were quantitatively measured and are listed in Table 1.From Table 1one can see that PAH/PSS-MSNTs has a higher drug-loading efficiency for positively charged DOX (89.4±4.8%)than that of MSNTs (81.7±3.6%),even though both the surface area and pore volume of PAH/PSS-MSNTs are lower than those of MSNTs.The probable reasons for the en-hanced drug storage capacity of DOX in PAH/PSS-MSNTs are:(i)electrostatic adsorption of DOX by the strongly negatively charged PSS outmost layer (see Fig.3A);(ii)drug storage in the porous PAH/PSS coating [20].However,after deposition of the PAH/PSS multi-layer on MSNTs the storage efficiency for negatively charged FLU was significantly reduced (from 48.9±2.9to 9.6±1.4%).Electro-static repulsion between FLU and the negatively charged outer-most PSS layer of the tube material,together with the decreased surface area and pore volume after coating,may be considered the main explanation for this result.To obtain a material with both a good loading capacity for negatively charged drugs and pH-responsiveness we designed and synthesized a novel inorganic/or-ganic composite by first amine functionalizing MSNTs with APTS and subsequently coating the amine-functionalized MSNTs with a biocompatible and biodegradable ALG/CHI multilayer (see Scheme 1).As expected,the storage efficiency for FLU in ALG/CHI-NH 2-MSNTs could reach up to 20.5±2.1%,which was double the storage efficiency for FLU in the PAH/PSS-MSNTs composite.This observation indicates that the composite of ALG/CHI-NH 2-MSNTs should facilitate the loading of negatively charged drugs.Fig.7shows the release of DOX molecules from PAH/PSS-MSNTs in solutions of different pH value over a period of 48h.It can be clearly seen that the release of DOX increased with decreas-ing pH from 8.0to 1.2.The delivery system exhibited only 17%DOX release at pH 8.0over 48h,but >95%at pH 1.2within 16h.These findings on the release of DOX from PAH/PSS-MSNTs can basically be explained as follows.The multilayer coating on MSNTs is made up of a strong polyelectrolyte (PSS,p K a 2.0[48])with a degree of ionization independent of the environmental conditions and a weak polyelectrolyte (PAH,p K a 9.0[48])where the degree of ion-ization depends on pH [49].At neutral pH positive and negativeside groups (NH þ3and SO À3)of the polyelectrolytes will roughly charge compensate.With decreasing pH the amino groups of PAH gradually become charged and,simultaneously,counterions are attracted to the multilayer to compensate for the net excess charge of PAH,which leads to an increase osmotic pressure [50].Subsequently,water molecules will diffuse into the multilayer from the bulk solution,driven by this osmotic pressure difference.As a result,the multilayer will gradually start to swell and develop a porous architecture [20]or local defects [51]that facilitate the permeation of drug molecules.Apart from this,increasing electro-static repulsion between the drug molecules and PAH/PSS-MSNTs particles might be another important factor in the accelerated re-lease of DOX with decreasing pH.Moreover,DOX-loaded PAH/PSS-MSNTs were passed through different pH value buffers to ver-ify their potential application in pH-controlled drug delivery.From Fig.8it can be seen that DOX release was <15%in the solution at pH 8.0over a period of 12h;adjusting the pH of the solution to 1.2resulted in a rapid release of DOX molecules.Thus,PAH/PSS-coated MSNTs could be considered to be applicable in pH-con-trolled release of drug molecules.In contrast to the release of DOX from PAH/PSS-MSNTs,the re-lease of FLU from ALG/CHI-NH 2-MSNTs decreased with decreasing pH from 8.0to 4.0(see Fig.9).This delivery system exhibited al-most 84%FLU release at pH 8.0over 6.5h,but <38%at pH 4.0.A possible explanation for the differences in the release of DOX and FLU could be the different functional groups on the PAH/PSS and ALG/CHI pairs and the different charges on the DOX and FLU mol-ecules (see Fig.1).It has been reported that the p K a values of the mannuronic acid and guluronic acid units of the ALG chain are 3.4and 3.7,respectively,and that the p K a value of chitosan is 6.3[52].Therefore,at pH 8.0the amino groups of CHI are mostlyun-Fig.6.Confocal laser scanning microscopy images of (A)DOX-loaded PAH/PSS-MSNTs and (B)FLU-loaded ALG/CHI-NH 2-MSNTs.Fig.7.Percentage release of DOX from PAH/PSS-MSNTs in different pH media (means ±standard deviation,n =3).Y.-J.Yang et al./Acta Biomaterialia 6(2010)3092–31003097ionized and the carboxylate groups on ALG are mainly in the form COO À.In this case counterions (K +,Na +,etc.)would diffuse into the multilayered coating to compensate for the net excess charge of ALG,which would result in osmotic swelling of the multilayer and a porous architecture [53,54].This architecture,together with electrostatic repulsion between COO Àgroups of the FLU molecules and the ALG layers [22],would facilitate the release of FLU from ALG/CHI-NH 2-MSNTs at pH 8.0.With a gradual decrease in pH from 8.0to 4.0the amino groups on CHI would become progres-sively ionized ðNH þ3Þ.Thus,the presence of both COO Àand NH þ3groups along the polymer backbone could increasingly enhance electrostatic interaction in the ALG/CHI multilayer [55],which would inevitably lead to poor permeability of the multilayer.At lower pH values,especially at pH 1.2,hydrogen bonds between ALG and CHI [56,57],as well as between FLU and ALG/CHI-NH 2-MSNTs,would develop and hinder the release of FLU molecules in view of the fact:(i)the carboxylate groups on ALG and FLU are mostly in the form COOH;(ii)the amino groups on CHI and NH 2-MSNTs are almost completely ionized.Swelling of the multi-layer due to the excess NH þ3groups on CHI would be restrained to some extent by hydrogen bonds within the polyelectrolyte mul-tilayer [56,57].However,electrostatic repulsion between posi-tively charged FLU molecules and the excess NH þ3groups on ALG/CHI-NH 2-MSNTs could improve the release of drug molecules to some extent,because FLU is positively charged at pH 1.2[44].These factors cooperatively caused an intermediate rate and level of release of FLU at pH 1.2.Comparing Fig.7with Fig.9,one can see that the release of FLU reaches equilibrium more quickly than that of DOX.The probable reason is that the polysaccharides ALG and CHI have a stronger affinity for water than PAH/PSS and their matrices are highly hydrolyzed [58]and,hence,low molecular weight hydrophilic drugs could diffuse out more easily.The cytotoxicity of the loaded DOX against HT-1080and MCF-7cells in culture at pH 7.4and 6.8was assayed to further demon-strate the pH sensitivity of the hybrid composites (Fig.10).From Fig.10A one can see a higher cytotoxicity against HT-1080cells at the weakly acidic pH 6.8than that at the physiological pH 7.4at the DOX concentrations 50,100and 500ng ml À1(P <0.05).However,the cytotoxicity of free DOX to HT-1080cells showed no significant differences between culture at pH 7.4and pH 6.8for the same concentrations of DOX (P >0.05).This is presumably due to the greater release of DOX from PAH/PSS-MSNTs at pH 6.8than that at pH 7.4,as shown in Fig.7.Similar results on the pH-dependent cytotoxicity of loaded DOX against MCF-7cells can also be found in Fig.10B.Moreover,the blank composites without DOX showed no cytotoxicity against HT-1080and MCF-7cells in pH 7.4and 6.8culture media.These observations provide further evidence that these fabricated hybrid composites are pH-responsive and imply that the loaded DOX in the composites should showmoreFig.9.Percentage release of FLU from ALG/CHI-NH 2-MSNTs in different pH media (means ±standard deviation,n =3).Fig.8.pH-controlled release of DOX molecules from PAH/PSS-MSNTs(means ±standard deviation,n =3).Fig.10.Cytotoxicity of DOX-loaded PAH/PSS-MSNTs against (A)HT-1080and (B)MCF-7cells in culture at pH 7.4(DOXPEM 7.4)and pH 6.8(DOXPEM 6.8)as a function of DOX (or equivalent)concentration.Four control experiments [free DOX in culture at pH 7.4(DOX 7.4)and pH 6.8(DOX 6.8)and PAH/PSS-MSNTs in culture at pH 7.4(PEM 7.4)and pH 6.8(PEM 6.8)culture media]were conducted (means ±standard deviation,n =4).3098Y.-J.Yang et al./Acta Biomaterialia 6(2010)3092–3100。

对羟基苯甲酸的历史
羟基苯甲酸，化学式为C7H6O3，是一种有机化合物，是羧酸和苯酚的一种混合物。

它是一种白色粉末状固体，具有苯酚和羧酸的性质。

在工业上，它常用作制造染料、医药和
食品添加剂的原材料。

羟基苯甲酸的历史可以追溯到19世纪初。

1814年，法国化学家埃蒙德·佩尔热（Emmanuel Péligot）首次将苯酚和苯甲酸混合在一起进行实验，并发现了一种新的化合物。

他称之为“加酸苯酚”（acide oxybenzoïque）。

随后的几年中，化学家们对这种新化合物进行了系列的研究，他们发现，“加酸苯酚”能够溶于水，表现出了典型的羧酸性质，而且具有类似苯酚的一些性质，如氧化性、还原
性等。

在对“加酸苯酚”进行深入研究的过程中，人们意识到它的分子式为C7H6O3，将其命名为“苯羧酸酚”（oxybenzoic acid）。

1859年，芬兰化学家约翰·雅克斯·贝维（Johannes Jacobus Berzelius）提出了“苯羧酸酚”这个名称，并在研究过程中发现了
该化合物的萘红色卤素物质（naphthol red halogen compound），这成为了后来染料化学的重要进展。

随着对羟基苯甲酸的研究逐渐深入，人们发现它不仅仅可以用于染料的制造，还可以
用于医药、化妆品、食品等众多领域。

现在，羟基苯甲酸已成为一种常见的工业原料，是
许多产品的必须组成部分。

同时，人们也在不断地探索和挖掘这种化合物的新用途和潜
力。