载有5-氟脲嘧啶高分子药物的合成、结构及性能的研究

用可溶性淀粉或羧甲基纤维素作载体,合成了侧链连有5-氟脲嘧啶的四个系列的高分子载体药物;用分子筛作催化剂合成了两种新的5-氟脲嘧啶衍生物,利用IR、¹HNMR和质谱确定了它们的结构;研究了高分子药物含氮量随反应条件的变化规律及对其特性粘度的影响;并模拟生理条件在不同pH的缓冲溶液中对5-氟脲嘧啶的水解释放率进行了系统考查,对个别淀粉衍生物进行了生物活性测定。     

壳聚糖/聚乙二醇/聚丙烯酸复合水凝胶的制备及药物控制释放行为研究

本文以壳聚糖(CS)、聚乙二醇(PEG)和丙烯酸(AA)为原料,制备了复合水凝胶CS/PEG/PAA。研究了负载四种具有不同结构和性质的药物(烟酸、烟酰胺、异烟肼和5-氟尿嘧啶)的复合水凝胶CS/PEG/PAA的药物控制释放行为。结果表明,烟酰胺和异烟肼在pH=1.80的缓冲溶液中的药物累积释放率(R)大于其在pH=6.86的缓冲溶液中的释放率;烟酸却在pH=6.86的缓冲溶液中的药物累积释放率(R)大于其在pH=1.80的缓冲溶液中的释放率。而5-氟尿嘧啶在两种缓冲溶液中的药物累积释放量相当。因此,复合水凝胶CS/PEG/PAA也许可以作为一种新型释放药物的载体。     

5-氟尿嘧啶在pH敏感型分子筛控释载体中的缓释行为

以肠溶性的羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)作为包覆材料,制备了HPMCP包覆的SBA-15介孔分子筛药物控释载体(HPMCP/SBA-15),并考察了抗癌药物5-氟尿嘧啶(5-Fu)负载于控释载体后,在不同pH释放环境中的释放行为.结果表明,在模拟胃液中(pH=1.2),HPMCP能明显地延缓5-Fu的释放速度;药物释放4h后,其释放率仅为15%.而在模拟肠液中(pH=7.5)HPMCP迅速溶解,对5-Fu释放速度的影响甚微;药物释放4h后,释放率可达到80%.与此同时,包覆膜的干燥温度影响5-Fu的释放行为,干燥温度越高,药物在模拟胃液中的释放速度越慢.     

用于纳米载药系统的两亲性聚乙二醇-药物分子偶联体的合成及胶束化性质

设计和合成了两亲性树枝状药物载体化合物6-Arm MPEG-Drug Conjugate,其中所使用的模型药物分子为苯甲酸.用1H NMR和13C NMR测试对结构进行了表征. 1H NMR谱图表明载体化合物在有机溶剂和水中表现不同的聚集行为,在水中自组装形成纳米微粒.利用荧光探针技术、动态激光光散射和扫描电镜研究其在水中的胶束化行为.结果显示,该药物载体化合物具有很低的临界胶束浓度,2.5×10-2 mg/mL (5.3×10-6 mol/L);在水溶液中浓度为1.0 mg/mL时的流体力学直径为67.4 nm,多分散指数为0.106;通过扫描电镜观察发现,初始浓度不同形成的聚集体形态也不同,得到了管状和方形结构胶束,而且随着不同水量的加入,聚集态从管状转变为囊泡状结构.     

乳酸-磷酸酯共聚物为载体的高分子药物的合成及其控释研究

以5-氟尿嘧啶(5-FU)为药物模型,以乳酸-磷酸酯共聚物为高分子药物载体,合成了侧链带药的乳酸-磷酸酯共聚物药物。用¹HNMR、IR、UV谱对其结构进行了表征。测定高分子药物中5-FU的含量,研究了高分子药物的体外释药性能及共聚物组成对释药性能的影响。     

Fe3O4@mMoO3介孔多功能纳米载体的制备及其微波响应药物传递

以氨基功能化的Fe_3O_4纳米颗粒为磁核,结合直接沉淀法和模板法在其表面包覆上介孔MoO_3层,制备磁性-微波热转换性-介孔结构于一体的多功能核-壳结构复合纳米载体Fe_3O_4@mMoO_3,并对其结构、载药及微波控制靶向给药性进行研究。TEM图表明所得的复合纳米载体具有明显的核壳结构,完美的球形,且壳层中有清晰的孔状结构。磁性和微波热转换特性分析表明,该复合载体兼具良好的磁性和微波热转换特性,可实现药物的靶向可控给药。以布洛芬(IBU)为模型药物,对该复合纳米载体的药物负载能力和微波响应可控释放性进行研究,结果表明,在持续微波辐射90 s时IBU的释放率达到90%,远远高于仅搅拌时的释放率。     

核-隔层-壳结构Fe3O4@MoO3@mSiO2纳米载体的合成及其药物可控释放

利用加热均匀、迅速、热平稳性好和安全性高的微波热响应来实现药物的微波可控释放。引入具有微波热响应性质、热稳定性和化学稳定性好的MoO₃作为微波吸收物质,制备了核-隔层-壳结构Fe₃O₄@MoO₃@mSiO₂纳米药物载体。研究该纳米载体对药物布洛芬（IBU）的负载和微波响应可控释放过程。该纳米载体具有高的比表面积（222 cm²·g^-1）和较大的孔隙体积（0.14 cm³· g^-1）可用来负载药物。同时还具有较好的磁响应性,可实现药物的靶向给药,具有相对好的微波热响应性,可通过MoO₃中间层吸收微波辐射实现药物的可控释放。结果表明,在持续微波辐射360 min时IBU的释放率达到86%,远远高于仅搅拌时的释放率。     

磁性Janus纳米材料的合成及生物性能研究

纳米药物载体在药物输送系统中发挥着极其重要的作用,其中Janus纳米材料因其具有各向异性的特点,能提高药物载体的载药率、靶向性等,成为研究者关注的焦点之一。本实验通过种子异向生长法,以球型磁性Fe_3O_4为内核,在其表面异向生长出棒状介孔二氧化硅,得到球-棒结构的磁性Janus纳米材料(Magnetic Janus Nanomaterials)。在磁性Janus纳米复合材料修饰前后对于布洛芬的搭载及体外释放试验中,发现氨基修饰的磁性Janus纳米复合材料载药率较大且具有缓释的作用。经血液相容性实验发现该材料在200μg·mL~(-1)浓度以下时,溶血率小于5%。     

智能中空药物载体的门控设计

由于具有独特新颖的结构和广泛的应用领域,中空材料已成为合成化学和材料化学研究的热点;特别是其高的表面体积比、低密度及大空腔等特点,成为药物递送载体的最佳选择.通过对中空结构的精确选择和精准修饰,可赋予中空材料独特的刺激响应行为,从而实现该类药物载体的智能设计和药物的可控释放.目前,构建中空智能载体主有以下两条思路:(1)利用自身可对环境中的物理化学刺激做出响应的中空材料作为载体;(2)在中空载体表面修饰功能性分子,以实现在特定的刺激下精确控制孔道的“开-关”转换.其核心在于分子组成和构型的精准调控.基于此,本文综合评述了中空智能载体的可控释放机制.首先介绍中空药物载体的发展历史,随后阐述药物分子在中空结构中的扩散规律,并总结了中空结构载体的智能响应行为、不同的门控机制、控制释放原理以及应用前景,最后对未来的发展做了展望.     

壳聚糖-g-聚甲基丙烯酸凝胶粒的制备及其药物释放行为

以壳聚糖和甲基丙烯酸为原料,硝酸铈铵为引发剂,合成了不同接枝率的壳聚糖-g-聚甲基丙烯酸(CS-g-PMAA),用FTIR、1H NMR和元素分析表征了产物的结构,以柠檬酸三钠和戊二醛为交联剂制备了具有核壳结构的CS-g-PMAA载药体系。 用UV/Vis检测了CS-g-PMAA粒子对模型药物的释放行为。 结果表明,CS-g-PMAA接枝率为12.21%时药物释放速率最慢,其在pH=1.8介质中药物累积释放量(11 h)为44.18%,而壳聚糖粒子的累积释放量高达65.24%,即接枝改性壳聚糖粒子对药物的缓慢控制释放性能较好; CS-g-PMAA粒子的释药行为还依赖于介质的pH值和盐浓度,在低pH值和低盐浓度下,药物释放速率较快;酶环境下由于载体材料的降解使药物释放速率加快。 分析了不同条件下CS-g-PMAA载药粒子中药物的释放机理。     

5-Fluorouracil derivatives with serum protein binding potencies

To develop an optimal delivery system for 5-fluorouracil (5FU) using serum protein as a drug carrier, a series of its benzyl derivatives was synthesized. Then their binding to the serum protein was investigated by equilibrium dialysis. The benzyl derivatives of 5FU were strongly bound to rat plasma protein or human serum albumin. The bound percentage increased with increasing hydrophobicity. It was suggested that the benzyl derivative of 5FU existed in the blood as a complex with serum albumin and circulated for a long time as a polymeric drug does.     

A polymeric composite carrier for oral delivery of peptide drugs: Bilaminated hydrogel film loaded with nanoparticles

A smart polymeric composite carrier consisting of carboxylated chitosan grafted nanoparticles (CCGN) and bilaminated films with one alginate-Ca²⁺ mucoadhesive layer and one hydrophobic backing layer was developed as a novel carrier for peptide. Calcein, hydrophilic and hydrolytic degradative, was entrapped into CCGN as a model peptide and its release behavior was investigated. Morphology study showed a uniform distribution of CCGN in the homogeneous and porous hydrogel. CCGN was characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), particle size measurement, and ζ potential measurement. The composite carrier was characterized by differential scanning calorimetry (DSC), scanning electron microscope (SEM) and fluorescence microscopy. The carrier exhibited high mucoadhesive force and pH-sensitivity, in that release of the nanoparticles and the model peptide calcein were both restricted in acidic environment while a fast and complete release was achieved in neutral medium. Therefore, this novel carrier would be a promising candidate for hydrophilic peptide drugs via oral administration.     

Acetaminophen particle design using chitosan and a spray-drying technique

In this study matrices were prepared from particles of poorly water-soluble drugs such as acetaminophen (Act) to determine the drug release rate from these matrix particles. The matrix particles were prepared by incorporating drugs into chitosan powder (Cht, carrier) using a spray-drying method. The formation of composite particles was confirmed by scanning electron microscopic (SEM) analysis. The matrix particles prepared by spray-drying were spherical with a smooth surface. The crystallinity of acetaminophen in the composite particles was evaluated by powder X-ray diffraction and differential scanning calorimetry (DSC). The degree of crystallinity of acetaminophen in the matrix particles decreased with a reduction in the weight ratio of acetaminophen relative to the carrier. These results indicate that a solid dispersion of acetaminophen in chitosan forms matrix particles. The interaction between acetaminophen and chitosan was also investigated by FT-IR analysis. FT-IR spectroscopy of the acetaminophen solid dispersion suggested that the carbonyl group of acetaminophen and the amino group of chitosan formed a hydrogen bond. There were some differences at pH levels of 1.2 and 6.8 in the release of acetaminophen from the physical mixture compared to the matrix particles. At pH 1.2, the release from the matrix particles (Act : Cht=1 : 5) was more sustained than from the physical mixtures. The 70% release time, T70, of acetaminophen from the matrix particles (Act : Cht=1 : 5) increased in pH 1.2 fluid by about 9-fold and in pH 6.8 fluid by about 5-fold compared to crystalline acetaminophen. These results suggest that matrix particles prepared by spray-drying are useful as a sustained release preparation.     

Preparation and characterization of a novel water soluble amino chitosan (amino-CS) derivative for facilitated transport of CO<Subscript>2</Subscript>

With the goal of obtaining a water soluble polymeric carrier for preparation of fixed facilitated transport membranes, a water soluble amino containing chitosan derivative was prepared through Michael-addition reaction between chitosan and ethyl acrylate followed by amidation of the ester groups with an appropriate diamine. This derivative was characterized using ¹H-NMR spectroscopy. Then, facilitated transport membranes were prepared by casting a thin layer of chitosan derivative/poly(vinyl alcohol) blend on a porous polysolfune support; and the effect of fixed carrier’s content, feed temperature and feed pressure on the CO₂ permeance, and CO₂/CH₄ selectivity of produced membranes were studied. A facilitated transport mechanism for CO₂ through this membrane was concluded.     

聚合物复合物层层组装膜的高效负载及大分子和小分子药物的差别性释放

基于聚合物复合物和层层组装技术实现了大分子药物硫酸软骨素和小分子药物头孢曲松钠在聚合物膜中的高效负载以及差别性释放. 壳聚糖(CHI)和大分子药物硫酸软骨素(CSS)通过静电相互作用力复合, 制备了壳聚糖-硫酸软骨素复合物(CHI-CSS). 以CHI-CSS复合物和透明质酸(HA)为构筑基元, 通过层层组装构筑负载有硫酸软骨素的聚合物复合物膜. 利用后扩散的负载方法将小分子药物头孢曲松钠(CTX)负载到聚合物膜中, 从而实现大分子和小分子2种药物在聚合物膜中的负载. 聚合物膜中负载的CTX和CSS在生理条件下具有快慢不同的差别性释放动力学特性, CTX在6 h内快速释放, 而CSS长效缓释长达14 d. 快速释放的抗生素CTX能够有效抑制细菌感染, 而酶降解作用下缓慢释放的CSS可促进伤口愈合, 在包括头颈外科在内的外科术后感染防治领域有良好应用前景.     

Molecular dynamics simulation study of drugs adsorption in UiO-66

Metal-organic frameworks (MOFs) are novel porous materials that have been extensively used in sensors, catalysis, gas storage and separation, and drug deliver owing to their adjustable pore size, large surface area and high porosity. Among diverse MOFs, UiO-66 can be a promising carrier for drug delivery due to high porosity and chemical stability. However, the adsorption mechanism of drugs in UiO-66 has not been identified and need a further investigation. Hence, we utilized molecular dynamic (MD) simulation to investigate the adsorption mechanism of UiO-66 as drug carriers. The MD simulation of UiO-66 exhibits the busulfan loading of 80 %, ibuprofen of 20 % and 5-fluorouracil of 30 %, respectively. We also demonstrated that the host-guest interaction between UiO-66 and drugs is dominated by the Van der Waals force. UiO-66 shows the highest affinity for busulfan compared with ibuprofen and 5-fluorouracil. In addition, it is certified the linear relation between the adsorption atoms and the interaction energy, which could help us to predict the interaction energy between drugs and UiO-66 by the contact atoms.     

Synthesis and characterization of HPMA copolymer-5-FU conjugates

N-（2-Hydroxypropyl） methacrylamide copolymer-5-fluorouracil （PHPMA-FU） conjugates were synthesized by a novel and simplified synthetic route, and characterized by UV, FTIR and HPLC analyses. The conjugated content of 5-fluorouracil （5-FU） was 3.41 ± 0.07 wt%. The stabilities of PHPMA-FU conjugates under different conditions were studied. The results showed that HPMA copolymer was a potential carrier for tumor-targeting delivery of 5-FU.     

Synthesis and characterization of ramose tetralactosyl-lysyl-chitosan-5-fluorouracil and its in vitro release

In order to improve drug loading and achieve a good release effect, this paper adopts the ramose method, choosing chitosan as the carrier and 5-fluorouracil (5-Fu) as a model drug. Ramose chitosan-lysyl-5-Fu(3) and ramose tetralactosyl-lysyl-chitosan-5-Fu(6) were synthesized successfully, then the in vitro release of (6) was researched. The results show that the drug loading of (3) and (6) are 9.17 and 1.63% (w/w), respectively. The in vitro release behavior of (6) in pH 7.4 phosphate buffer solution and pH 1.2 HCl?CKCl solution were studied. The zero order release time that (6) maintains in alkaline and acidic media are 64 and 24?h, and the total release by 184?h are 71.97 and 82.34%, respectively. The performance is smooth throughout the whole stage of release, and the concentration of cumulative release is lower in the alkaline environment than in the acidic environment over the same time.