纳米多孔二氧化硅作为药物载体的研究进展

目的介绍几种纳米多孔二氧化硅作为药物载体的应用及最新发展动态。方法以国内外有代表性的文献资料31篇为依据,对介孔二氧化硅、二氧化硅气凝胶、微粉硅胶等几种多孔二氧化硅药物载体的结构特性、应用及发展动态进行分析、整理和归纳。结果纳米多孔二氧化硅作为药物载体,借助于其纳米孔道结构、形貌或孔道的控制及表面功能化修饰,可以实现药物的速释、缓释及pH或温度敏感释放。结论纳米多孔二氧化硅作为药物载体具有广阔的应用前景。     

介孔分子筛作为药物载体应用于缓/控释及靶向制剂的研究进展

目的:为介孔分子筛作为药物载体应用于缓/控释及靶向制剂提供参考。方法:"介孔分子筛""药物载体""缓释""控释""靶向""Mesoporous molecular sieves""Drug carrier""Sustained release""Controlled release""Targeting"等为关键词,组合查询1985年1月-2017年6月在中国知网、万方、维普、Pub Med、Web of Science等数据库中的相关文献,就介孔分子筛的分类及特点、对药物体外释放行为的影响、药物体外释放动力学机制、药物体内药物动力学及生物活性等研究进行综述。结果与结论:共检索到相关文献31 052篇,其中有效文献38篇。根据介观结构分类,介孔分子筛主要有2D结构的MCM-41,3D结构的MCM-48及无序、层状结构的HMS、MSU、TUD-1。MCM-41的相关研究较MCM-48、MSU及TUD-1多;HMS及介孔二氧化硅纳米粒子载药量大且可修饰性好;介孔分子筛的孔径尺寸、修饰分子、有序度和载药方法及模型药物固有特性等因素,均对药物体外释放行为产生影响;MCM-41及MCM-48的生物活性较好且COK-12以人为受试对象进行药动学评估时未见明显排斥反应。现有研究主要从结构修饰、嫁接、改变载药模式等方面进行缓/控释及靶向传递的研究。今后应着眼于提高模型药物多样性研究,评价介孔分子筛的体内毒性及生物相容性,构建修饰与掺杂型载体,以设计出适宜用于人体的多功能、多靶向、多重刺激响应、高载药量、低毒性的新型药物传递系统。     

智能响应型介孔二氧化硅抗肿瘤纳米递药系统的设计策略与研究应用

恶性肿瘤是危害人类健康的重大疾病,由于其微环境复杂多变,导致大多数抗肿瘤药物不能精准地到达病灶组织并可控释放。智能响应型纳米载体已成为抗肿瘤递药系统研究领域的热点。介孔二氧化硅作为一种优良的纳米材料,具有无毒、稳定、孔容孔径可调及表面易于功能化修饰等优势,凭借其对机体肿瘤微环境或生理变化的感知响应、实现递药系统在病灶组织定位释药或控制释药,使其成为智能响应型递药系统的理想载体。本文基于介孔二氧化硅的智能响应型递药系统的设计策略及研究应用展开综述,以期为抗肿瘤药物纳米制剂的研发提供参考。     

手性介孔二氧化硅载体对地西泮溶出行为的改善

目的建立接枝L-酒石酸的手性介孔二氧化硅的药物释放系统,提升地西泮的体外溶出度,考察手性介孔硅对地西泮的体外释放特点。方法将L-酒石酸接枝硅烷偶联剂制备手性共结构导向剂,以共缩聚法制备手性介孔硅载体。将疏水性药物地西泮载入载体孔道构建药物释放系统,利用不同pH值的释放介质中的体外溶出测试评估载体对药物释放的调控能力。结果载体内部的介观孔道促使药物晶体发生无定型化转变,药物体外释放的速度和程度较原料药均得到显著提升,30 min内释放量提升4.6～6.4倍,24 h内释放量提升1.39～1.78倍,药物从载体中的释放速度随着载体比例的增加而变快。结论手性介孔硅具有良好的药物装载结合和控制释放能力,可以有效提高地西泮的体外溶出,将进一步提高药物的生物利用度,有利于其临床应用。     

介孔二氧化硅载体对蛋白药物载药释药及提高酶降解稳定性的初步研究

目的根据模型蛋白的空间尺寸设计介孔二氧化硅载体,初步探索不同孔径载体对蛋白药物载药、释药及稳定性的保护作用。方法以表面活性剂P123为胶束模板,以正硅酸乙酯为硅源,制备介孔二氧化硅,利用透射电镜、氮气吸附-脱附等手段表征载体;以溶菌酶(lysozyme,LYS)和牛血清白蛋白(bovine serum albumin,BSA)为模型蛋白,采用SDS-PAGE电泳分析测定不同孔径载体对LYS和BSA酶降解的保护程度。结果制备出三种孔径(7、17、22 nm)介孔二氧化硅载体,三种载体对LYS和BSA的载药量均为40%左右,LYS和BSA在三种载体中的总释放度均随孔径的减小而减小,7 nm和17 nm载体分别对LYS和BSA的保护作用最强。结论介孔二氧化硅可用于高效装载蛋白药物并提高其稳定性,载体孔径尺寸越接近蛋白药物的大小,对其保护作用越强。     

介孔硅材料提高难溶性药物生物利用度的研究进展

介孔二氧化硅作为近年来比较热门的无机介孔载体材料,因其具有孔道排列规整、水热稳定性良好、生物相容性好,可以储存药物并保持药物的无定形态等特点,非常适合装载水难溶性药物。本文通过查阅国内外的相关文献,就难溶性药物口服生物利用度低的原因进行分析,并归纳总结了国内外关于介孔二氧化硅载体提高难溶性药物生物利用度方面的最新研究进展,为设计和制备具有特定结构和性能的介孔二氧化硅载体,提高难溶性药物的生物利用度及其临床应用提供参考。     

介孔二氧化硅纳米粒的研究进展

介孔二氧化硅纳米粒(MSNs)具有良好生物相容性、有序介孔结构、比表面积大、表面易修饰性等特点,在很多生物医药领域显示出了极大的应用前景,尤其是基于MSNs的纳米药物输送体系被广泛用于各种药物的递送。主要介绍MSNs和可降解MSNs的制备,同时介绍了MSNs膜包被及官能团修饰在缓释控释药物中的应用,最后探讨了MSNs递进到中空介孔二氧化硅纳米粒(HMSNs)的更大的应用前景。     

叶酸修饰长春新碱介孔二氧化硅脂质纳米粒的制备及体外释药研究

摘要：目的:制备叶酸修饰长春新碱介孔二氧化硅脂质纳米粒（FA-VCR-MSNs-LP）,对纳米粒进行质量评价并考察体外释药特性。方法:一步合成法制备氨基改性介孔二氧化硅纳米粒（NH2-MSNs）,浸渍吸附法载入长春新碱（VCR）,乙醇注入法制备叶酸修饰长春新碱介孔二氧化硅脂质纳米给药系统。利用透射电镜、小角粉末衍射仪、氮气吸脱附仪、红外光谱仪、激光粒度仪等考察其理化性质;高速离心法结合高效液相色谱（HPLC）测定其包封率及载药量;选用PBS（pH 7.4）作为释放介质,透析袋法考察其体外释药特性。结果:制备的FA-VCR-MSNs-LP透射电镜下外观呈圆形或类圆形,平均粒径为（178.5±8.5） nm,Zeta电位为（20.3±1.20） mV,包封率和载药量分别为（44.58±1.01）%（n=3）、（11.71±0.26）%（n=3）;脂质修饰包裹后改善介孔二氧化硅纳米给药系统的突释现象,并具有缓释特征。结论:制备的FA-VCR-MSNs-LP性质稳定,包封率和载药量较高、粒径较小,体外释药具有明显缓释特征,为后期肿瘤靶向性和毒性研究奠定基础。     

有序介孔硅胶提高难溶性药物白藜芦醇的溶出速率

本研究的目的是制备有序介孔硅胶并考察其作为难溶性药物载体的体外药物释放特点。以十六烷基三甲基溴化铵为模板合成了有序介孔硅胶, 以白藜芦醇为模型药物, 采用扫描电镜、透射电镜、N₂吸附-脱附、X-射线衍射和红外光谱对载药前后的有序介孔硅胶进行表征, 并考察药物体外释放行为。结果表明, 合成的有序介孔硅胶比表面积大、粒度均匀, 具有有序六方孔道结构, 载药后药物以无定形态或分子态存在, 释放速率明显提高。有序介孔硅胶有望成为新型的难溶性药物载体。     

介孔二氧化硅/乙基纤维素缓释骨架的制备与释放行为的研究

本文选取非诺贝特为模型药物,乙基纤维素为缓释材料,黄原胶作为调释剂,通过热熔挤出技术将介孔二氧化硅递药系统与缓控释技术结合,制备介孔二氧化硅/乙基纤维素缓释骨架,介孔二氧化硅SBA-15作为药物载体用以提高非诺贝特体外溶出速率。采用水热法合成SBA-15,以扫描电镜、透射电镜、N2吸附-脱吸附及小角衍射对其结构进行表征,结果显示,合成的SBA-15具有有序二维六方介孔结构以及较大比表面积、孔容和孔径。X射线衍射和差示扫描量热结果表明,非诺贝特经SBA-15吸附后以无定形或分子态存在,药物溶出速率明显提高。缓释骨架中药物释放受乙基纤维素黏度和黄原胶含量的影响。22%黄原胶含量的缓释骨架具有较好的缓释效果,体外释放呈一级动力学特征,以不规则释放为主。     

NMR cryoporometry characterisation studies of the relation between drug release profile and pore structural evolution of polymeric nanoparticles

PLGA/PLA polymeric nanoparticles could potentially enhance the effectiveness of convective delivery of drugs, such as carboplatin, to the brain, by enabling a more sustained dosage over a longer time than otherwise possible. However, the link between the controlled release nanoparticle synthesis route, and the subsequent drug release profile obtained, is not well-understood, which hinders design of synthesis routes and availability of suitable nanoparticles. In particular, despite pore structure evolution often forming a key aspect of past theories of the physical mechanism by which a particular drug release profile is obtained, these theories have not been independently tested and validated against pore structural information. Such validation is required for intelligent synthesis design, and NMR cryoporometry can supply the requisite information. Unlike conventional pore characterisation techniques, NMR cryoporometry permits the investigation of porous particles in the wet state. NMR cryoporometry has thus enabled the detailed study of the evolving, nanoscale structure of nanoparticles during drug release, and thus related pore structure to drug release profile in a way not done previously for nanoparticles. Nanoparticles with different types of carboplatin drug release profiles were compared, including burst release, and various forms of delayed release. ESEM and TEM images of these nanoparticles also provided supporting data showing the rapid initial evolution of some nanoparticles. Different stages, within a complex, varying drug release profile, were found to be associated with particular types of changes in the nanostructure which could be distinguished by NMR. For a core-coat nanoparticle formulation, the development of smaller nanopores, following an extended induction period with no structural change, was associated with the onset of substantial drug release. This information could be used to independently validate the rationale for a particular synthesis method. Hence, the specific reasons for the effectiveness of the synthesis route, for obtaining core-coat nanoparticles with delayed release, have been elucidated.     

Sustained release from mesoporous nanoparticles: evaluation of structural properties associated with release rate

We present here a detailed study of the controlled release of amino acid derived amphiphilic molecules from the internal pore structure of mesoporous nanoparticle drug delivery systems with different structural properties; namely cubic and hexagonal structures of various degrees of complexity. The internal pore surface of the nanomaterials presented has been functionalised with amine moieties through a one pot method. Release profiles obtained by Alternating Ionic Current measurements are interpreted in terms of specific structural and textural parameters of the porous nanoparticles such as pore geometry and connectivity. Results indicate that diffusion coefficients are lower by as much as four orders of magnitude in 2-dimensional structures in comparison to 3-dimensional mesoporous solids. A fast release in turn is observed from mesocaged materials AMS-9 and AMS-8 where the presence of structural defects is thought to lead to a slightly lower diffusion coefficient in the latter. Amount of pore wall functionalisation and number of binding sites on the model drug are found to have little effect on the drug release rate.     

Ordered mesoporous silica modified with lanthanum for ibuprofen loading and release behaviour

The ordered mesoporous silicas SBA-15 and KIT-6, modified with lanthanum, have been for the first time applied in investigation of ibuprofen adsorption and release. The materials of hexagonal and regular structure were obtained by the hydrothermal method using a triblock copolymer Pluronic P123 as a template. The mesoporous silicas were impregnated with an aqueous solution of lanthanum(III) chloride in the amount necessary to obtain 1, 3 and 5 wt.% La loading. The physicochemical properties of the modified silicas were characterised by X-ray diffraction, transmission electron microscopy, UV–Vis spectrophotometry and low-temperature nitrogen sorption. The results showed that lanthanum strongly determined structural as well as textural properties of the silicas. The samples of modified silica were checked for the ability to adsorb and release of ibuprofen. The storage capacity of the modified silicas obtained increased with increasing their average pore diameter and percentage content of lanthanum. The amount of ibuprofen adsorbed onto KIT-6 silica modified with La was higher than that adsorbed onto SBA-15 materials. The high coverage of lanthanum on the surface of KIT-6 and SBA-15 solids was found to increase the amount of ibuprofen and the rate of its release.     

Facile synthesis of PEI-based crystalline templated mesoporous silica with molecular chirality for improved oral delivery of the poorly water-soluble drug

The aim of this study was to build up a novel chiral mesoporous silica called PEIs@TA-CMS through a facile biomimetic strategy and to explore its potential to serve as a drug carrier for improving the delivery efficiency of poorly water-soluble drug. PEIs@TA-CMS was synthesized by using a chiral crystalline complex associated of tartaric acid and polyethyleneimine (PEIs) as templates, scaffolds and catalysts. The structural features including morphology, size, pore structure and texture properties were systematacially studied. The results showed that PEIs@TA-CMS was monodispersed spherical nanoparticles in a uniformed diameter of 120–130 nm with well-developed pore structure (S_BET: 1009.94 m²/g, pore size <2.21 nm). Then PEIs@TA-CMS was employed as nimodipine (NMP) carrier and compared with the drug carry ability of MCM41. After drug loading, NMP was effectively transformed from the crystalline state to an amorphous state due to the space confinement in mesopores. As expected, PEIs@TA-CMS had superiority in both drug loading and drug release compared to MCM41. It could incorporate NMP with high efficiency, and the dissolution-promoting effect of PEIs@TA-CMS was more obvious because of the unique interconnected curved pore channels. Meanwhile, PEIs@TA-CMS could significantly improve the oral adsorption of NMP to a satisfactory level, which showed approximately 3.26-fold higher in bioavailability, and could effectively prolong the survival time of mice on cerebral anoxia from 10.98 to 17.33 min.     

Carboxylic modified spherical mesoporous silicas аs drug delivery carriers

The present study deals with the development and functionalization of mesoporous silica nanoparticles as drug delivery platforms. Spherical MCM-41 and SBA-15 silicas with different pore sizes (2.7nm and 5.5nm, respectively) were post-synthesis modified applying a new, two step process. The initial step was the modification with 3-amino-propyltriethoxysilane, and the next was the reaction with succinic anhydride in toluene in order to obtain carboxylic modified mesoporous carriers. The carboxylic-functionalized mesoporous materials were characterized by XRD, nitrogen physisorption, TEM, ATR FT-IR spectroscopy. The successful carboxylic functionalization was proved by the changes of the zeta potential of the mesoporous materials before and after modification. The parent and the carboxylic-modified MCM-41 and SBA-15 materials showed high adsorption capacity (approximately 50wt.%, except for non-functionalized MCM-41) for sulfadiazine that possesses amino functional groups. Mesoporous structure peculiarities lead to different adsorption capacities on the carriers. In vitro release studies showed slower release rate of sulfadiazine from carboxylic modified MCM-41 and SBA-15 mesoporous particles compared to the non modified ones. Both non loaded and drug-loaded silica materials demonstrated no cytotoxicity on Caco-2 cell line. The functionalized mesoporous systems are appropriate drug delivery platforms due to their biocompatibility and the possibility to modify drug release.     

Doxorubicin release from core-shell type nanoparticles of poly(DL-lactide-co-glycolide)-grafted dextran

In this study, we prepared core-shell type nanoparticles of a poly(DL-lactide-co-glycolide) (PLGA) grafted-dextran (DexLG) copolymer with varying graft ratio of PLGA. The synthesis of the DexLG copolymer was confirmed by 1H nuclear magnetic resonance (NMR) spectroscopy. The DexLG copolymer was able to form nanoparticles in water by self-aggregating process, and their particle size was around 50 nm approximately 300 nm according to the graft ratio of PLGA. Morphological observations using a transmission electron microscope (TEM) showed that the nanoparticles of the DexLG copolymer have uniformly spherical shapes. From fluorescence probe study using pyrene as a hydrophobic probe, critical association concentration (CAC) values determined from the fluorescence excitation spectra were increased as increase of DS of PLGA. 1H-NMR spectroscopy using D2O and DMSO approved that DexLG nanoparticles have core-shell structure, i.e. hydrophobic block PLGA consisted inner-core as a drug-incorporating domain and dextran consisted as a hydrated outershell. Drug release rate from DexLG nano-particles became faster in the presence of dextranase in spite of the release rate not being significantly changed at high graft ratio of PLGA. Core-shell type nanoparticles of DexLG copolymer can be used as a colonic drug carrier. In conclusion, size, morphology, and molecular structure of DexLG nanoparticles are available to consider as an oral drug targeting nanoparticles.     

Sustained release of 5-fluorouracil from polymeric nanoparticles

The use of biodegradable nanoparticles loaded with 5-fluorouracil was investigated as a potential means to sustain the release of this drug. Nanoparticles prepared from four biodegradable polymers were loaded with 5-fluorouracil using three loading concentrations of drug and three different concentrations of added polymer. Washing particles using a centrifugation/re-suspension with ultrasound protocol was found to dislodge the majority of drug, resulting in an over-estimation of incorporation efficiency and low levels of strongly entrapped drug. Increasing the initial 5-fluorouracil concentration before polymer/monomer addition increased the drug loading in both washed and unwashed particles. Increasing the amount of polymer used to make nanoparticles did not increase loadings, but did produce increased amounts of unusable polymer waste. Drug release from nanoparticles was evaluated using a Franz cell diffusion apparatus, which showed an initial burst effect followed by a slower release phase over 24 h. Indeed, nanoparticles prepared from poly(lactide-co-glycolide) released 66% of their 5-fluorouracil payload over this period. It was concluded that 5-fluorouracil-loaded nanoparticles could be readily included into a hydrogel-based delivery system to provide sustained drug release for trans-epithelial drug-delivery applications.     

Drug release from extruded solid lipid matrices: Theoretical predictions and independent experiments

The aim of this study was to use a mechanistically realistic mathematical model based on Fick‘s second law to quantitatively predict the release profiles from solid lipid extrudates consisting of a ternary matrix. Diprophylline was studied as a freely water-soluble model drug, glycerol tristearate as a matrix former and polyethylene glycol or crospovidone as a pore former (blend ratio: 50:45:5% w/w/w). The choice of these ratios is based on former studies. Strains with a diameter of 0.6, 1, 1.5, 2.7 and 3.5 mm were prepared using a twin-screw extruder at 65 °C and cut into cylinders of varying lengths. Drug release in demineralised water was measured using the USP 32 basket apparatus. Based on SEM pictures of extrudates before and after exposure to the release medium as well as on DSC measurements and visual observations, an analytical solution of Fick’s second law of diffusion was identified in order to quantify the resulting diprophylline release kinetics from the systems. Fitting the model to one set of experimentally determined diprophylline release kinetics from PEG containing extrudates allowed determining the apparent diffusion coefficient of this drug (or water) in this lipid matrix. Knowing this value, the impact of the dimensions of the cylinders on drug release could be quantitatively predicted. Importantly, these theoretical predictions could be confirmed by independent experimental results. Thus, diffusion is the dominant mass transport mechanism controlling drug release in this type of advanced drug delivery systems. In contrast, theoretical predictions of the impact of the device dimensions in the case of crospovidone containing extrudates significantly underestimated the real diprophylline release rates. This could be attributed to the disintegration of this type of dosage forms when exceeding a specific minimal device diameter. Thus, mathematical modelling can potentially significantly speed up the development of solid lipid extrudates, but care has to be taken that none of the assumptions the mathematical theory is based on is violated.     

Study on formulation variables of methotrexate loaded mesoporous MCM-41 nanoparticles for dissolution enhancement

The aim of this study was to develop methotrexate loaded mesoporous MCM-41 nanoparticles for improved dissolution of methotrexate. The mesoporous MCM-41 nanoparticles act as carrier for drug and increase the solubility of the drug. In order to achieve this objective small pore size MCM-41 nanoparticles have been synthesized followed by drug loading process. The process of drug loading was optimized using full 33 factorial design. With a view to obtain maximum drug loading three variables, concentration of drug solution, stirring rate, and drug:carrier ratio were optimized using a full 33 factorial design. Using statistically designed experiments, the inclusion of methotrexate in MCM-41 nanoparticles was successfully carried out to obtain a drug loading of about 48%. X-ray powder diffraction and differential scanning calorimetry revealed the presence of methotrexate in amorphous form and FT-IR spectroscopy showed the presence of light interactions between the silicate silanols and the drug. The decrease of Brunauer, Emmett and Teller specific surface area and pore volume between free MCM-41 and the inclusion compound was the proof of the presence of methotrexate inside the mesopores. The inclusion compound was submitted to in vitro dissolution tests and a remarkable dissolution rate improvement was observed in comparison to the crystalline drug in all tested conditions.     

Mussel-inspired polydopamine coated mesoporous silica nanoparticles as pH-sensitive nanocarriers for controlled release

A novel pH-sensitive controlled release system is proposed by using mussel-inspired polydopamine (PDA) coated mesoporous silica nanoparticles (MSNs) as nanocarriers. MSNs with a large pore diameter are synthesized by using 1,3,5-trimethylbenzene as a pore-expanding agent and are modified with a PDA coating by virtue of oxidative self-polymerization of dopamine in neutral pH. PDA coated MSNs are characterized by FTIR, TEM, N₂ adsorption and XPS techniques. The PDA coating can work as pH-sensitive gatekeepers to control the release of drug molecules from MSNs in response to the pH-stimulus. Doxorubicin (DOX, an anticancer drug) can be released in the acid media and blocked in the neutral media.