载药纳米微粒的应用及研究进展

目的：对纳米、纳米科反及其在药物研究中的应用进行介绍。方法：通过对国内外文献的总结。概述了载药纳米微粒中的普通载药微粒,控释载药微粒、靶向定位载药微粒、载药磁性微粒等类别,介绍了复乳化法技术、超声乳化法、等电临界法、氧化还原法等制备载药纳米微粒的方法。结果：纳米技术与现代医药学结合的产物-载药纳米微粒具有易吸收、定向性强等优点。结论：载药纳米微粒的研究开发可解决口服易水解药物的给药途径,延长药物的体内半衰期,更精确的靶向定位给药。减少药物不良反应,消除生物屏障对药物作用的影响。     

聚乳酸及其共聚物脑靶向载药纳米粒的研究进展

目的：综述聚乳酸及其共聚物（PLA/PLGA）脑靶向载药纳米粒（NP）的研究进展。方法：查阅2005-2012年来国内外有关文献,对PLA/PLGA脑靶向载药NP的作用机制、制备方法、功能分子的连接方式、体外体内作用效果评价方法进行综述。结果与结论：受体介导入脑是目前最为成熟的脑靶向给药机制,鼻腔给药也是一种有效的入脑机制;脂溶性载药NP和水溶性载药NP的制备分别采用乳化溶剂挥发法和复乳法;而溶剂扩散法可加快微球的形成,用于制备粒径较小的NP;功能分子主要利用其上的巯基、氨基、羧基或马来酰亚胺等活性基团与PLA或PLGA对应基团进行共价结合,或利用生物素-亲和素体系脑靶向递药;体外效果评价常用大鼠脑微血管内皮细胞（BMVEC）单层培养模型及BMVEC-星形胶质细胞共培养模型;体内效果评价常用荧光显微镜和活体荧光成像、放射自显影法,前者用于考察以荧光素和香豆素等荧光染料标记的脑靶向NP,后者用于以125I、3H、14C等放射性核素标记的脑靶向NP。提高脑靶向的靶向效率、提高载药量、减少PLA/PLGA的用量、改善PLA/PLGA纳米粒体内降解性能和增加稳定性,是今后脑靶向PLA/PLGA载药NP研究的重点方向。     

生物可降解纳米药物转运系统研究进展

纳米药物载体有延长药物作用时间、增加疗效、降低毒副作用、缓控释给药等优点。而生物可降解高分子材料因其良好的生物利用度、载药能力和控释能力以及较低的毒性而被广泛用于纳米药物。本文综述了聚乳酸-羟基乙酸共聚物(PLGA)、聚乳酸(PLA)、聚己内酯(PCL)高分子化合物制备纳米粒的合成和载药方法及应用。     

左氧氟沙星/PLGA亚微粒的制备、表征和体外释药考察

目的:制备左氧氟沙星/PLGA亚微粒,并进行相关表征和体外释放行为考察.方法:采用纳米共沉淀法制备左氧氟沙星/PLGA亚微粒,采用激光粒度分析仪以及扫描电镜分别进行亚微粒粒度测定和形貌分析.同时采用紫外-可见分光光度法(UV)测定其载药量与体外药物释放行为.结果:经过激光粒度分析仪测定,所制备的左氧氟沙星/PLGA亚微粒粒径为197 ～230 nm,Zeta电位为-24 mv.扫描电镜观察亚微粒呈圆形/椭圆形,分布均匀.UV法测定亚微粒的载药量为6.25％～9.38％,包封产率为12.45％ ～46.59％.体外释放结果显示相比于商品化左氧氟沙星滴眼液,所制备的左氧氟沙星/PLGA亚微粒具有良好的缓释效果.结论:通过纳米共沉淀法成功制备粒径均一,高载药量的左氧氟沙星PLGA亚微粒,同时能实现药物的缓慢释放,减少给药次数的目的.     

和厚朴酚泊洛沙姆F-127胶束的制备及其体外抗肿瘤研究

目的以泊洛沙姆F－127为载体制备一种新型的和厚朴酚胶束制剂,以提高其抗肿瘤效果。方法选用泊洛沙姆F－127为药物载体,采用自组装法制备和厚朴酚胶束制剂,通过透射电镜观察和厚朴酚胶束的形貌,采用紫外分光光度法测定载药量、药物包封率以及体外药物释放行为。采用MTT法检测和厚朴酚及其和厚朴酚胶束制剂对BGC－823人胃癌细胞的抑制作用。结果本研究所制备的和厚朴酚胶束纳米制剂,具有壳．核的球型结构。纳米粒子分布较窄,平均粒径为28．7nm。和厚朴酚与泊洛沙姆F－127的投料比影响胶束制剂载药量,随着和厚朴酚与泊洛沙姆F-127的投料比从1：10增加到1：2．5,载药胶束的载药量从（8．4±1．6）％增加到（25．7±2．7）％,而包封率维持在97％左右。体外释放结果显示和厚朴酚可以缓慢地从泊洛沙姆F-127胶束中释放出来。体外抗肿瘤实验结果显示：相比于溶液剂型的和厚朴酚,和厚朴酚／泊洛沙姆F-127胶束具有更好的体外抗BGC．823人胃癌细胞效果。结论和厚朴酚／泊洛沙姆F-127胶束是一种新型的和厚朴酚纳米制剂,能有效提高体外抗BGC．823人胃癌细胞效果。     

多烯紫杉醇纳米粒的制备、表征及其抗肿瘤作用研究

目的 制备多烯紫杉醇纳米粒,并进行体内外抗肿瘤作用。方法 采用反溶剂沉淀联合高压均质法制备DTX-G2 纳米粒;采用动态光散射法、扫描电镜考察粒径和形态,并对其体外释放、膜毒性、体外抗肿瘤活性进行研究;建立4T1荷瘤小鼠模型,以紫杉醇注射液为对照组,10 mg/kg iv 给药,考察体内抗肿瘤作用。结果 制备的DTX-G2 纳米粒粒径为(356.8±6.709)nm,PDI 值为(0.147±0.02),Zeta 电位为(-14.4±0.07)mV,载药量为(62.3±1.9)%。扫描电镜观察纳米粒为片状。DTX-G2 纳米粒体外缓慢释放,在192 h累积释放率达到80.4%;无溶血现象,可采用静脉注射法给药;MTT 结果显示DTX-G2 纳米粒对4T1细胞的毒性强于溶液(IC50, 2.374 μg/mL vs 5.664 μg/mL,P＜0.05);4T1细胞摄取结果显示DTX-G2 纳米粒的摄取量显著高于溶液(20.46 vs 11.01,P＜0.05);体内研究中DTX-G2 纳米粒对4T1 荷瘤小鼠的的抑瘤率显著高于注射液组(75.7% vs 52.4%,P＜0.05)。结论 制备的DTX-G2 纳米粒载药量高、稳定性好,显著提高了多烯紫杉醇的抗肿瘤效果,有望作为一种新型的药物输送系统应用到多烯紫杉醇的临床治疗中。     

胰岛素肠溶PLGA纳米粒的制备及体内外性质的评价

目的制备肠溶胰岛素PLGA纳米粒,并对其理化性质、体外释药以及在正常大鼠体内的降血糖效果进行研究。方法采用改良的乳化溶剂扩散法分别制备了胰岛素PLGA纳米粒和肠溶胰岛素纳米粒(PLGA HP55 NP、PLGA HP50 NP)。通过激光粒度测定仪测定粒径大小,系统考察了肠溶材料HP55的用量及类型对纳米粒性质的影响,以及各种纳米粒在人工胃液、人工肠液中的释药行为和其在正常大鼠体内的降血糖作用,并与PLGA HP50 NP进行了比较。结果制得的最终处方的肠溶纳米粒(PLGA HP55)的粒径为(169±16)nm,胰岛素的载药量为(3.17±0.24)%。肠溶纳米粒在人工胃液中的释药速率明显低于PLGA纳米粒。PLGA纳米粒和肠溶PLGA HP50、PLGA HP55纳米粒均能显著降低正常大鼠的血糖浓度,其在正常大鼠体内24 h相对于皮下注射给药的相对生物利用度分别为(5.46±0.7)%、(6.31±0.64)%和(8.72±0.5)%。结论胰岛素肠溶纳米粒可以有效抑制胰岛素在人工胃液中的释放,与PLGA纳米粒相比显著降低正常大鼠的血糖浓度。其中PLGA HP55纳米粒的降糖作用显著高于PLGA HP50纳米粒。pH值高的纳米粒有望成为胰岛素口服给药的有效载体。     

双黄连纳米的制备工艺的研究

目的寻找制备双黄连纳米的最佳处方。设计并优化双黄连纳米的制备工艺。方法选择可在体内生物降解的聚乳酸-聚乙醇酸（50：50）为载体．以双黄连为模型药物．以微粒粒径和包封率为质量控制指标,在单因素实验的基础上用正吏设计法优化工艺．以乳化-溶剂挥发法制备双黄连聚乳酸纳米微粒。结果与结论成功制备了双黄连纳米制剂．并且包封率良好;为双黄连纳米制剂生厂提供了可靠的依据。     

一种透明质酸修饰的7-乙基-10-羟基喜树碱纳米混悬液的制剂制备和抗肿瘤研究

目的:制备透明质酸(HA)修饰7-乙基-10-羟基喜树碱纳米混悬液(S1C1),探究其抗肿瘤治疗作用,为纳米制剂临床应用提供参考。方法:经电荷吸附法制备纳米混悬液(S1C1-HA);经动态光散射粒径仪进行制剂表征和粒径稳定性考察;运用高效液相色谱法(HPLC)测定S1C1-HA的包封率和载药量;采用噻唑蓝法考察游离纳米混悬液对4T1细胞的增殖抑制作用;运用3D多细胞肿瘤球考察纳米混悬剂的肿瘤球渗透力;通过考察纳米混悬液的体内药动学行为、脏器分布行为和抗肿瘤治疗,评价制剂的体内药效。结果:S1C1-HA平均粒径138.04 nm,电位－8.03 mV,体外24 h内粒径稳定性良好,载药量5.44%,包封率90.07%;S1C1半数抑制浓度为S1C1-HA的4.59倍,S1C1-HA的肿瘤渗透能力显著增强;S1C1-HA的半衰期和药时曲线下面积为S1C1的5.55,17.12倍,其体内抗肿瘤治疗效果显著增强。结论:修饰后S1C1-HA能显著增强药物的稳定性、细胞毒性、肿瘤渗透能力,有更优异的体内生物利用度和抗肿瘤治疗作用,S1C1-HA较S1C1更有临床应用潜力。     

用疏水改性的白及多糖制备载紫杉醇纳米粒并对其表征

目的 讨论白及多糖作为药物递送载体的可行性。方法 制备疏水性胆甾醇琥珀酰基白及多糖（CHSB）后,以紫杉醇（PTX）为模型药物,采用透析法制备载药纳米粒子,然后在透射电镜（TEM）下观察其形态;用动态光散射仪（DLS）检测其粒径、粒径分布和Zeta电位;用高效液相色谱法（HPLC）测定其包封率和载药量,并考察其体外释放情况;采用差示量热扫描法（DSC）确证药物在载药纳米粒子中的存在形式;采用MTT法考察纳米粒子的体外抗肿瘤活性,用荧光标记法观察肝癌细胞QGY-7703对纳米粒子的摄取情况。结果 制备的纳米粒呈规则球形,粒度分布均匀,药物包载于纳米粒内部,载药量和包封率在一定范围受CHSB的影响,载药纳米粒对肝癌细胞的杀伤性强于游离药物,在细胞内可观察到罗丹明B标记的纳米粒呈现的荧光。结论 CHSB作为难溶性药物载体具有较高的可行性,因此可作为一种极具潜力的纳米载体材料。     

Nanoscopic core-shell drug carriers made of amphiphilic triblock and star-diblock copolymers

The aim of this work was to design injectable nanocarriers for drug delivery based on PCL-PEO amphiphilic block copolymers with linear ABA triblock and 4-armed (BA)(4) star-diblock architectures (A=PEO, B=PCL). The copolymers were obtained by coupling of a monofunctional -COOH end-capped PEO (M(n)=2.0kDa) with linear or 4-armed star-shaped PCL macromers bearing -OH terminal groups and were characterized by (1)H NMR spectroscopy and size exclusion chromatography. DSC and X-ray diffraction experiments showed that separate crystalline phases of PCL and PEO are present in bulk copolymers. Nanoparticles were produced by nanoprecipitation (NP) and by a new melting-sonication procedure (MS) without the use of toxic solvents, and characterized for size, polydispersity, zeta potential and core-shell structure. Nanoparticles were loaded with all-trans-retinoic acid (atRA) as a model drug and their release features assessed. Results demonstrate that both techniques allow the formation of PEO-coated nanoparticles with a hydrodynamic diameter that is larger for nanoparticles prepared by MS. atRA is released from nanoparticles at controlled rates depending on size, loading and, more important, preparation technique, being release rate faster for MS nanoparticles. Some biorelevant properties of the carrier such as complement activation were finally explored to predict their circulation time after intravenous injection. It is demonstrated that nanoparticles prepared by MS do not activate complement and are of great interest for future in vivo applications.     

Encapsulation of 9-nitrocamptothecin, a novel anticancer drug, in biodegradable nanoparticles: factorial design, characterization and release kinetics.

This study was aimed at developing a polymeric drug delivery system for a new and potent antitumor drug, 9-nitrocamptothecin (9-NC), intended for both intravenous administration and improving the therapeutic index of the drug. To achieve these goals, 9-NC loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles were prepared by nanoprecipitation method and characterized. The full factorial experimental design was used to study the influence of four different independent variables on response of nanoparticle drug loading. Analysis of variance (ANOVA) was used to evaluate optimized conditions for the preparation of nanoparticles. The physical characteristics of PLGA nanospheres were evaluated using particle size analyzer, scanning electron microscopy, differential scanning calorimetry and X-ray diffractometry. The results of optimized formulations showed a narrow size distribution with a polydispersity index of 0.01%, an average diameter of 207+/-26 nm, and a drug loading of more than 30%. The in vitro drug release profile showed a sustained 9-NC release up to 160 h indicating the suitability of PLGA nanoparticles in controlled 9-NC release. Thus prepared nanoparticles described here may be of clinical importance in both stabilizing and delivering camptothecins for cancer treatment.     

Brain targeting with surface-modified poly(d,l-lactic-co-glycolic acid) nanoparticles delivered via carotid artery administration

In this study, we investigated surface-modified nanoparticles (NP) formulated using a biodegradable polymer, poly(d,l-lactide-co-glycolide) (PLGA), for targeting central nervous system (CNS) diseases. Polysorbate 80 (P80), poloxamer 188 (P188), and chitosan (CS) were used to modify the surfaces of PLGA NP to improve the brain delivery of NP. Surface-modified PLGA NP were formulated using an emulsion solvent diffusion method. 6-Coumarin was used as a fluorescent label for NP. The different formulations of 6-coumarin-loaded PLGA NP were injected into rats via carotid arteries. NP remaining in the brain were evaluated quantitatively, and brain slices were observed using confocal laser scanning microscopy (CLSM). Carotid artery administration was more effective for delivering NP into the brain compared to intravenous administration. After administration, NP concentrations in the brain were increased by NP surface modification, especially CS- and P80-PLGA NP. CLSM observations indicated that P80-PLGA NP could cross the blood-brain barrier and thus serve as a drug delivery system for the CNS. These results indicate that surface-modified PLGA NP have a high potential for use in CNS delivery systems.     

Preparation of poly epsilon-caprolactone nanoparticles containing magnetite for magnetic drug carrier

Magnetic poly epsilon-caprolactone (PCL) nanoparticles were prepared in a well shaped spherical form by the o/w emulsion method. The influence of some preparative variables on the size and surface property was investigated. Nanoparticles were smooth, well individualized and homogeneous in size. The presence of magnetite and its superparamagnetic characteristic were confirmed by transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FT-IR) and vibrating sample magnetometer (VSM), respectively. The anti-cancer drug was encapsulated in the magnetic nanoparticle during preparation. A typical release behavior was observed for 30 days. In vitro experiment of magnetic susceptibility under external magnetic field demonstrated that the magnetic PCL nanoparticles have sufficient magnetic susceptibility for a potential magnetic drug carrier for targeted delivery.     

PLGA nanoparticles in drug delivery: the state of the art

Nanoparticles represent drug delivery systems suitable for most administration routes. Over the years, a variety of natural and synthetic polymers have been explored for the preparation of nanoparticles, of which Poly(lactic acid) (PLA), Poly(glycolic acid) (PGA), and their copolymers (PLGA) have been extensively investigated because of their biocompatibility and biodegradability. Nanoparticles act as potential carries for several classes of drugs such as anticancer agents, antihypertensive agents, immunomodulators, and hormones; and macromolecules such as nucleic acids, proteins, peptides, and antibodies. The options available for preparation have increased with advances in traditional methods, and many novel techniques for preparation of drug-loaded nanoparticles are being developed and refined. The various methods used for preparation of nanoparticles with their advantages and limitations have been discussed. The crux of the problem is the stability of nanoparticles after preparation, which is being addressed by freeze-drying using different classes of lyoprotectants. Nanoparticles can be designed for the site-specific delivery of drugs. The targeting capability of nanoparticles is influenced by particle size, surface charge, surface modification, and hydrophobicity. Finally, the performance of nanoparticles in vivo is influenced by morphological characteristics, surface chemistry, and molecular weight. Careful design of these delivery systems with respect to target and route of administration may solve some of the problems faced by new classes of active molecules.     

Brain targeting and toxicity study of odorranalectin-conjugated nanoparticles following intranasal administration

In order to improve brain uptake of nanoparticles following nasal administration, odorranalectin (OL), the smallest lectin with much less immunogenicity than other members of lectin family, was conjugated to the surface of poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NP) in this study. The bioactivity of OL conjugated to the nanoparticles was verified by haemagglutination tests.Tissue distribution of OL-modified and unmodified nanoparticles (OL-NP and NP) was evaluated following intranasal (i.n.) administration by in vivo fluorescence imaging technique using DiR as a tracer, comparing with that of unmodified nanoparticles after intravenous (i.v.) injection. Besides, the nasal toxicity of OL-NP was evaluated on Calu-3 cell lines, toad palate and rat nasal mucosa.The results of TEM examination and dynamic light scattering showed a generally spherical shape of OL-NP with an average volume-based diameter around 90 nm. The haemagglutination test proved that OL retained its haemagglutination activity when conjugated to nanoparticles. The brain targeting indexes of NP and OL-NP following i.n. administration and NP following i.v. injection were 5.8, 11.6 and 0.08, respectively.Thus,i.n. administration demonstrated much better brain targeting efficiency than i.v. injection, and OL modification facilitated the nose-to-brain delivery of nanoparticles.Moreover, the toxicity assessment suggested good safety of OL-NP both in vitro and in vivo. In summary, odorranalectin-conjugated nanoparticle could be potentially used as a nose-to-brain drug delivery carrier for the treatment of CNS diseases.     

Magnetic poly epsilon-caprolactone nanoparticles containing Fe3O4 and gemcitabine enhance anti-tumor effect in pancreatic cancer xenograft mouse model

We prepared magnetic (Fe(3)O(4)) poly epsilon-caprolactone (PCL) nanoparticles (mean diameter 164 +/- 3 nm) containing an anticancer drug (gemcitabine) using emulsion-diffusion method in order to develop more efficient drug delivery for cancer treatment. Nanoparticles were smooth, well individualized and homogeneous in size. The values of magnetizations for the magnetic PCL nanoparticles were observed around 10.2 emu/g at 2000 Oe magnetic field intensity and showed super-paramagnetic property. In case of the drug, the drug loading contents was 18.6% and entrapment efficiency was 52.2%. The anti-tumor effects caused by these particles were examined using nude mice bearing subcutaneous human pancreatic adenocarcinoma cells (HPAC) in vivo. We divided that these mice were randomly assigned to one of five treatment groups for experimental contrast. The antitumor effect was showed with 15-fold higher dose when compared to free gemcitabine. From the result, the magnetic PCL nanoparticles may provide a therapeutic benefit by delivering drugs efficiently to magnetically targeted tumor tissues, thus achieving safe and successful anti-tumor effects with low toxicity.     

Evaluation of nanoparticles loaded with benzopsoralen in rat peritoneal exudate cells

Psoralens are widely used for the treatment of hyperproliferative skin disease. In this work, we prepared nanoparticles (NP) containing a benzopsoralen (3-ethoxy carbonyl-2H-benzofuro[3,2-f]-1-benzopiran-2-one) by the solvent evaporation technique. We evaluated important NP parameters such as particle size, drug encapsulation efficiency, effect of the encapsulation process over the drug's photochemistry, zeta potential, external morphology, and in vitro release behavior. We also investigated the nanoparticle as a drug delivery system (DDS), as well as its target delivery to the action site, which is a very important parameter to increase the therapeutic use of psoralens and to reduce their side effects. The uptake of benzopsoralen-loaded PLGA nanoparticles by different kinds of cells found in rat peritoneal exudates was also studied. The photodamage promoted by irradiation with UV light revealed morphological characteristics of cell damage such as cytoplasmic vesiculation, mitochondrial damage, and swelling of both the granular endoplasmatic reticulum and nuclear membrane. This encapsulation method maintained the drug's properties and improved drug delivery to the target cell.     

不同表面活性剂修饰的汉防己甲素PLGA纳米粒制备表征及体外评价

目的:基于纳米粒的递送系统,以改善天然化合物汉防己甲素对肺癌的功效。方法:选取聚乙烯醇、普朗尼克-F127和双十二烷基二甲基溴化铵3种不同的稳定剂,采用单乳化扩散溶剂挥发法制备载汉防己甲素的PLGA纳米粒,考察不同稳定剂对载药纳米粒粒径、ζ电位以及对肺癌A549细胞摄取的影响。结果:2%,1%和0.1%浓度的PVA、PF127和DMAB制备的纳米粒呈表面光滑、大小均一的球形,粒径范围均控制在180~200nm;药物包封率为50%~60%;体外释放实验显示,在pH 7.4的PBS溶液中3组载药纳米粒均呈现缓慢持续释药;细胞学实验结果表明3组纳米粒给药系统均表现出比药物更强的抗肿瘤活性。结论:对PLGA进行表面修饰制备的纳米载体能使汉防己甲素的给药效率得到明显提升。     

Cyrene™ as an Alternative Sustainable Solvent for the Preparation of Poly(lactic-co-glycolic acid) Nanoparticles

Toxic and environmental harmful organic solvents are widely applied to prepare poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NP) in standard preparation methods. Alternative non-toxic solvents suffer from disadvantages like high viscosity and plasticizing effects. To overcome these hurdles, Cyrene? as a new sustainable, non-toxic and low viscous solvent was used to formulate PLGA NPs. A new preparation method was developed and optimized. Small sized blank NPs around 220 nm with a narrow size distribution and highly negative charge (<?23 mV) were obtained. To test the application for drug delivery, the lipophilic model drug atorvastatin was encapsulated in high drug loads with comparable physicochemical characteristics as the blank NPs, and a total drug release within 24 h. No changes of the crystallinity or plasticizing effects could be observed. Highly purified NPs were obtained with a residual Cyrene? content <2.5%. Finally, the biocompatibility of Cyrene? itself and of the NPs formed in the presence of Cyrene? was demonstrated in a hen's egg test. Conclusively, the use of Cyrene? as solvent offers a simple, fast and non-toxic procedure for preparation of PLGA NPs as drug delivery systems circumventing the downsides of standard methods.