Preparation of pH- and thermo-sensitive chitosan-PNIPAAm core–shell nanoparticles and evaluation as drug carriers

Environmentally sensitive polysaccharide nanoparticles (NPs) were prepared by in situ polymerization of N-isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) micelles. First, CS was found to develop a cationic micelle-like structure in the acetic acid solution when its concentration was increased to above the critical micelle concentration, as evidenced by fluorescence and TEM. When the NIPAAm was polymerized in the CS micelle solution by using potassium persulfate as initiator, the produced PNIPAAm with anionic chain end(s) became hydrophobic, as long as the reaction temperature was above its phase transition temperature; and therefore it would diffuse into the hydrophobic core of the CS micelles, producing CS-PNIPAAm core–shell NPs. Increasing the feeding amount of NIPAAm increased the monomer conversion and therefore the particle size; yet it decreased the surface zeta potential. Moreover, the CS-PNIPAAm NPs were sensitive to both pH value and temperature. For the study of drug release properties, doxycycline hyclate was used as a model drug and loaded into the NPs at pH 4.5 and 25 °C. The result illustrated that these NPs had a continuous drug release behavior up to 1 week, depending on the pH value and temperature. In addition, enzyme or hydrogen peroxide capable of degrading CS shell was added in the solution to facilitate the drug release.     

Preparation and Characterization of Thermosensitive Nanoparticles for Targeted Drug Delivery

In this study, we have reported novel thermosensitive nanoparticles formulated by an emulsion-solvent evaporation technique using acetaminophen (AAP) as a model drug. The high entrapment efficiency of nanoparticles was 68.56%, particle size about 240.6 nm and zeta potential ?27 mV. Furthermore, the drug release was also investigated both at 37°C and 42°C, respectively. The goal of our study was to obtain a targeted drug delivery system, exploiting the temperature-sensitive behavior. In contrary to normal temperature (37°C), the release rate of AAP was found to noticeably increase at high temperature (42°C) with a larger cumulative amount of drug released. In this way, it would lead to production of nanoparticles having a high thermosensitive behavior on drug release. Thus, this new strategy has the potential to control drug release at the diseased site for targeted drug delivery system (TDDS) with positive temperature-controlled.     

Synthesis and applications of shell cross-linked thermoresponsive hybrid micelles based on poly(N-isopropylacrylamide-co-3-(trimethoxysilyl)propyl methacrylate)-b-poly(methyl methacrylate)

Shell cross-linked (SCL) thermoresponsive hybrid micelles consisting of a cross-linked thermoresponsive hybrid hydrophilic shell and a hydrophobic core domain were synthesized from poly(N-isopropylacrylamide-co-3- (trimethoxysilyl)propyl methacrylate)-b-polymethyl methacrylate (P(NIPAAm-co-MPMA)-b-PMMA) amphiphilic block copolymers. Transmission electron microscopy (TEM) images showed that the SCL micelles formed regularly globular nanoparticles. The SCL micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 33 degrees C, observed by turbidity measurements and dynamic light scattering (DLS). The drug loading and in vitro drug release properties of the SCL micelles bearing a silica-reinforced PNIPAAm shell were further studied, which showed that the SCL micelles exhibited a much improved entrapment efficiency (EE) as well as a slower release rate which allowed the entrapped molecules to be slowly released over a much longer period of time as compared with pure PNIPAAm-b-PMMA micelles.     

核交联的含磺酸甜菜碱pH敏感胶束的制备与表征

制备了一种在疏水段带有侧基叠氮官能团的两亲性pH敏感的聚合物——聚己内酯-聚(甲基丙烯酸二乙氨基乙酯-磺酸甜菜碱)((PCL-ACL)-PDEAS);同时合成了两端带有炔基中间带有二硫键的交联剂,用红外、核磁表征了目标分子.通过两亲性高分子自组装形成胶束,并通过点击化学反应获得了核交联的胶束.通过动态光散射测定粒径,胶束酸碱滴定表征胶束的pH敏感性,还原条件下释放药物的速度,对比了非交联胶束和交联胶束的性质.结果表明,交联胶束在正常生理条件下的释放速度比未交联胶束更慢;而在有DTT的存在条件下,交联胶束由于二硫键断裂,释放速率明显加快.因此,核交联载药胶束有可能响应肿瘤的微环境实现靶向释放.     

Influence of the homogenisation procedure on the physicochemical properties of PLGA nanoparticles

Pilocarpine HCl-loaded PLGA nanoparticles were prepared by emulsification solvent evaporation. Three different stabilisers, polyvinylalcohol (PVA), Carbopol and Poloxamer were used, as well as mixtures thereof. The influence of the homogenisation pressure and number of cycles on the properties of nanoparticles were studied. Particle size was shown to depend on the stabiliser used. An increase of the homogenisation pressure or the number of cycles resulted in a decrease in particle size. The zeta potential value was influenced mainly by the nature of the stabiliser. Particles stabilised with poloxamer or PVA showed a slightly negative zeta potential value, while samples stabilised with carbopol possessed a more negative zeta potential, which became less negative after homogenisation. Drug encapsulation depended strongly on the stabiliser used. The higher drug entrapment of the carbopol-stabilised particles could be explained by an electrostatic interaction between the negatively charged carboxyl groups of carbopol and the positively charged, protonated pilocarpine. The drug release patterns of the particles prepared were quite similar. Differences between the release patterns of the homogenised particles could be attributed both to differences in size as well as drug encapsulation. Turbidimetric measurements suggested an interaction between mucin and PLGA nanoparticles exclusively stabilised with Carbopol.     

Preparation,optimization by 2<Superscript>3</Superscript> factorial design,characterization and in vitro release kinetics of lorazepam loaded PLGA nanoparticles

The aim of this work was to formulate the lorazepam loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles by optimization of different preparation variables using 2³ factorial design. The effect of three independent factors, the amount of polymer, concentration of the stabilizer and volume of organic solvent was investigated on two dependent responses, i.e., particle size and % drug entrapment efficiency. By using PLGA as polymer, PVA as a stabilizer and dimethyl sulfoxide as organic solvent lorazepam loaded PLGA nanoparticles were successfully developed through modified nanoprecipitation method. FTIR and DSC studies were carried out to examine the interaction between the excipients used and to explore the nature of the drug, the formulation and the nature of drug in the formulations. These nanoparticles were characterized for particle size, shape, zeta potential, % drug entrapment efficiency, % process yield and in vitro drug release behavior. In vitro evaluation showed particles size between 161.0 ± 5.4 and 231.9 ± 4.9 nm, % drug entrapment efficiency of formulations was in the range of 60.43 ± 5.8 to 75.40 ± 1.5, % process yield at 68.34 ± 2.3 to 81.55 ± 1.3 was achieved and in vitro drug release for these formulations was in the range of 49.2 to 54.6%. Different kinetics models, such as zero order, first order, Higuchi model, Hixson-Crowell model and Korsmeyer- Peppas model were used to analyze the in vitro drug release data. Preferred formulation showed particle size of 161.0 ± 5.4 nm, PDI as 0.367 ± 0.014,–25.2 mV zeta potential, drug entrapment efficiency as 64.58 ± 3.6% and 72.48 ± 2.5% process yield. TEM results showed that these nanoparticles were spherical in shape, and follow the Korsmeyer-Peppas model with a release exponent value of n = 0.658.     

Preparation and characterization of m PEG grafted chitosan micelles as 5-fluorouracil carriers for effective anti-tumor activity

The objective of this study was to investigate the potential of methoxy polyethylene glycol（m PEG）grafted chitosan（m PEG-g-CS） to be used as a drug carrier. m PEG-g-CS was successfully synthesized by one-step method with formaldehyde. The substitution degree of m PEG on chitosan was calculated by elemental analysis and was found to be（3.23 0.25）%. m PEG-g-CS self-assembled micelles were prepared by ultrasonic method with the controlled size of 178.5–195.1 nm and spherical morphology. Stable dispersion of the micelles was formed with the zeta potential of 2.3–30.2 m V. 5-Fluorouracil（5-FU）, an anticancer chemotherapy drug, was used as a model drug to evaluate the efficiency of the new drug delivery carrier. The loading efficiency of 5-FU was（4.01 0.03）%, and the drug-loaded m PEG-g-CS self-assembled micelle showed a controlled-release effect. In summary, the m PEG-g-CS self-assembled micelle is proved to be a promising carrier with controlled particle size and controlled-release effect. Therefore, it has great potential for the application as 5-FU carriers for effective anti-tumor activity.     

Solid lipid nanoparticles prepared by solvent diffusion method in a nanoreactor system

In this study, water-in-oil (W/O) miniemulsion was used as nanoreactor to prepare solid lipid nanoparticles (SLN) by solvent diffusion method. n-Hexane, Tween 80 and Span 80 were used as the oil phase and surfactant combination for preparation of W/O miniemulsion, respectively. The stable miniemulsion with the particle size of 27.1 ± 7.6 nm was obtained when the composition of water/Tween 80/Span 80/n-hexane was 1 ml/18 mg/200 mg/10 ml. Clobetasol propionate (CP) was used as a model drug. The physicochemical properties of the SLN, such as particle size, zeta potential, surface morphology, drug entrapment efficiency, drug loading capacity and in vitro drug release behaviors were investigated, comparing with those of SLN prepared by conventional aqueoethod. The SLN prepared by the novel method displayed smaller particles size and higher dus solvent diffusion mrug entrapment efficiency than those of SLN prepared by the conventional method. The drug entrapment efficiency decreased with increasing of charged amount of drug, and 15.9% of drug loading was achieved as the charged amount of drug was 20%. The in vitro drug release tests indicated that the drug release rate was faster than that of SLN prepared by the conventional method, and the drug content in SLN did not affect the in vitro drug release profile.     

壳聚糖基多功能纳米药物载体的体外研究

制备了一种壳聚糖基多功能纳米药物载体系统, 并探讨了其体外释药性质. 合成了甲氨蝶呤-壳聚糖偶联物(MTX-CS), 甲氨喋呤(MTX)的取代度为6.3%; MTX-CS具有两亲性, 在水性介质中能自组装形成纳米粒子, 平均粒径为(269.5±18.3) nm, zeta电位为(25.7±0.9) mV. MTX-CS纳米粒子能有效包载抗血管生成药Combretastatin A-4(CA-4), 当药物/载体材料投料比为1∶4 时, 载药量为15.7%, 包封率为62.8%. 体外释放实验结果显示, CA-4释放较快, MTX释放缓慢, 有利于发挥2种药物的协同抗肿瘤作用.     

Thermosensitive pluronic micelles stabilized by shell cross-linking with gold nanoparticles

Gold nanoparticles were employed to prepare shell cross-linked Pluronic micelles that exhibit a reversibly thermosensitive swelling/shrinking behavior. Two terminal hydroxyl groups of Pluronic F127 were thiol-functionalized to form self-assembling Pluronic micelles in aqueous solution with exposed -SH groups in an outer shell layer. The thiol groups present in the outer shell were cross-linked by gold nanoparticles synthesized through NaBH4 reduction of gold precursor anions. The resultant shell cross-linked gold-Pluronic micelles exhibited a temperature-dependent volume transition: their hydrodynamic diameter was changed from 157.1 +/- 15.6 nm at 15 degrees C to 53.4 +/- 5.5 nm at 37 degrees C as determined by dynamic light scattering. The critical micelle temperature measured by a pyrene solubilization technique suggested that the reversible swelling/shrinking behavior of the micelles was caused by hydrophobic interactions of cross-linked or grafted Pluronic copolymer chains in the micelle structure with increasing temperature. Transmission electron microscopy directly revealed that the shell cross-linked micelles were indeed produced by gold nanoparticles covalently clustered on the surface. These novel self-assembled organic/inorganic hybrid micelles would hold great potential for diagnostic and therapeutic applications.     

共同装载吴茱萸碱和Fe3O4纳米粒子的磁性药物载体的制备

以单甲醚-聚乙二醇-聚（丙交酯-乙交酯）（mPEG-PLGA）作为载体,采用溶液透析的方法共同装载抗癌药物吴茱萸碱和Fe₃O₄ 磁性纳米粒子. 通过透射电子显微镜、红外光谱、紫外-可见光谱及体外释放实验、普鲁士蓝染色、体外毒性实验和磁靶向研究,综合评价了磁性纳米药物载体的性能. 结果表明,磁性药物载体胶束分散性良好,粒径均一,有较高的载药量和包封率,能够实现药物缓释,具有磁靶向特性.     

Fabrication of PEGylated Chitosan Nanoparticles Containing Tenofovir Alafenamide: Synthesis and Characterization

Tenofovir alafenamide (TAF) is an antiretroviral (ARV) drug that is used for the management and prevention of human immunodeficiency virus (HIV). The clinical availability of ARV delivery systems that provide long-lasting protection against HIV transmission is lacking. There is a dire need to formulate nanocarrier systems that can help in revolutionizing the way to fight against HIV/AIDS. Here, we aimed to synthesize a polymer using chitosan and polyethylene glycol (PEG) by the PEGylation of chitosan at the hydroxyl group. After successful modification and confirmation by FTIR, XRD, and SEM, TAF-loaded PEGylated chitosan nanoparticles were prepared and analyzed for their particle size, zeta potential, morphology, crystallinity, chemical interactions, entrapment efficacy, drug loading, in vitro drug release, and release kinetic modeling. The fabricated nanoparticles were found to be in a nanosized range (219.6 nm), with ~90% entrapment efficacy, ~14% drug loading, and a spherical uniform distribution. The FTIR analysis confirmed the successful synthesis of PEGylated chitosan and nanoparticles. The in vitro analysis showed ~60% of the drug was released from the PEGylated polymeric reservoir system within 48 h at pH 7.4. The drug release kinetics were depicted by the Korsmeyer–Peppas release model with thermodynamically nonspontaneous drug release. Conclusively, PEGylated chitosan has the potential to deliver TAF from a nanocarrier system, and in the future, cytotoxicity and in vivo studies can be performed to further authenticate the synthesized polymer.     

Micellization and reversible pH-sensitive phase transfer of the hyperbranched multiarm PEI-PBLG Copolymer

A novel, hyperbranched, amphiphilic multiarm biodegradable polyethylenimine-poly(gamma-benzyl-L-glutamate) (PEI-PBLG) copolymer was prepared by the ring-opening polymerization of gamma-benzyl-L-glutamate-N-carboxyanhydride (BLG-NCA) with hyperbranched PEI as a macroinitiator. The copolymer could self-assemble into core-shell micelles in aqueous solution with highly hydrophobic micelle cores. As the PBLG content was increased, the size of the micelles increased and the critical micelle concentration (CMC) decreased. The surface of the micelles had a positive zeta potential. The cationic micelles were capable of complexing with plasmid DNA (pDNA), which could be released subsequently by treatment with polyanions. The PEI-PBLG copolymer formed unimolecular micelles in chloroform solution. The pH-sensitive phase-transfer behavior exhibited two critical pH points for triggering the encapsulation and release of guest molecules. Both the encapsulation and release processes were rapid and reversible. Under strong acidic or alkaline conditions, the release process became partially or completely irreversible. Thus, this copolymer system should be an attractive candidate for a gene- or drug-delivery system in aqueous media and could provide the phase-transfer carriers between water and organic media.     

Block ionomer complex micelles with cross-linked cores for drug delivery

Soft polymeric nanomaterials were synthesized by template-assisted method involving condensation of the poly(ethylene oxide)-b-polycarboxylate anions by metal ions into core-shell block ionomer complex micelles followed by chemical cross-linking of the polyion chains in the micelle cores. The resulting materials represent nanogels and are capable of swelling in a pH-dependent manner. The structural determinants that guide the self-assembly of the initial micelle templates and the swelling behavior of the cross-linked micelles include the block ionomer structure, the chemical nature of metal ions, the structure of the cross-links and the degree of cross-linking. The application of these materials for loading and release of a drug, cisplatin, is evaluated. These cross-linked block ionomer micelles have promise for delivery of pharmaceutical agents. The text was submitted by the authors in English. This work was supported by the grants from U.S.A. National Institute of Health CA116590 (T.B.), National Science Foundation DMR-0513699 (A.V.K. and T.B.) and Department of Defense USAMRMC 06108004 (A.V.K.).     

Preparation,Characterization and Drug Release Behavior of 5-Fluorouracil Loaded Carboxylic Poly(ε-caprolactone) Nanoparticles

In this paper, 5-Fluorouracil (5-FU) loaded carboxylic poly(ε-caprolactone) nanoparticles have been prepared by emulsification/solvent evaporation o/w method, and the drug release behaviors of 5-FU were investigated. The novel carboxylic poly (ε-caprolactone) (P(CL-OPD)-mal) was synthesized via conjugation of maleic anhydride to sodium borohydride (NaBH₄) reduced poly(ε-caprolactone-co -4- carbonyl -ε-caprolactone) (P(CL-OPD)), while P(CL-OPD) was synthesized in bulk by ring-opening polymerization of ε-caprolactone and 4-carbonyl-ε-caprolactone (OPD) with stannous octoate as a catalyst. Their structures were confirmed by ¹HNMR, FT-IR and GPC. Dynamic light scattering (DLS), transmission electron microscopy (TEM), zeta potential measurements were used for nanoparticle characterization. TEM and DLS showed the nanoparticles were with spherical shape and uniform size distribution (mean diameter 70～100 nm), respectively. Zeta potential analysis revealed that the nanoparticles had an increased negative surface with the increase of carboxyl group concentration. UV spectroscopy was adopted to study the entrapment and release behaviour. The maximum 5-FU loading efficiency was 14.39% with the entrapment efficiency be 42%. In vitro release studies were performed in PBS at 37°C. Results of the study showed that the release behavior can be well-controlled, and the balanced release was up to 96 h. P(CL-OPD)-mal nanoparticles would provide increased benefit in biomedical and pharmaceutical applications.     

Development of Ciprofloxacin HCl-Based Solid Lipid Nanoparticles Using Ouzo Effect: An Experimental Optimization and Comparative Study

This study was performed to develop solid lipid nanoparticles of water soluble drug ciprofloxacin HCl using quick solvent diffusion evaporation technique (ouzo effect). A statistical central composite rotatable design was used to study the effect of independent variables. In the subsequent step, optimized SLN were further compared with nanostructured lipid carriers and nanoemulsion for particle size, zeta potential, drug entrapment, drug release, and stability. Comparative study revealed that the drug encapsulation efficiencies were enhanced by adding the Capmul MCM C8 into the solid lipid nanoparticles. The in vitro drug release study of all three formulations showed rapid release for nanoemulsion while controlled release for SLN. Stability study of all the formulation proved that nanostructured lipid carrier and SLN could prevent the drug expulsion during the storage period. Results of the study suggested that the SLN and nanostructured lipid carriers produced by the principle of ouzo effect could potentially be exploited for better drug entrapment efficiency and controlled drug release of water soluble actives.     

Preparation and characteristics of linoleic acid-grafted chitosan oligosaccharide micelles as a carrier for doxorubicin

The linoleic acid (LA)-grafted chitosan oligosaccharide (CSO) (CSO-LA) was synthesized in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), and the effects of molecular weight of CSO and the charged amount of LA on the physicochemical properties of CSO-LA were investigated, such as CMC, graft ratio, size, zeta potential. The results showed that these chitosan derivatives were able to self-assemble and form spherical shape polymeric micelles with the size range of 150.7–213.9 nm and the zeta potential range of 57.9–79.9 mV, depending on molecular weight of CSO and the charged amount of LA. Using doxorubicin (DOX) as a model drug, the DOX-loaded CSO-LA micelles were prepared by dialysis method. The drug encapsulation efficiencies (EE) of DOX-loaded CSO-LA micelles were as high as about 75%. The sizes of DOX-loaded CSO-LA micelles with 20% charged DOX (relating the mass of CSO-LA) were near 200 nm, and the drug loading (DL) capacity could reach up to 15%. The in vitro release studies indicated that the drug release from the DOX-loaded CSO-LA micelles was reduced with increasing the graft ratio of CSO-LA, due to the enhanced hydrophobic interaction between hydrophobic drug and hydrophobic segments of CSO-LA. Moreover, the drug release rate from CSO-LA micelles was faster with the drug loading. These data suggested the possible utilization of the amphiphilic micellar chitosan derivatives as carriers for hydrophobic drugs for improving their delivery and release properties.     

Amphiphilic block poly(propylene carbonate)‐block‐allyloxypolyethyleneglycol copolymer based shell cross‐linked micelles for controlled release of drug

Amphiphilic block poly(propylene carbonate)‐block‐allyloxypolyethyleneglycol (PPC‐b‐APEG) copolymer was synthesized by the click chemistry, and its structure were characterized. PPC‐b‐APEG can self‐assemble into micelles without emulsifier in water. Shell cross‐linked micelles were obtained by the reaction of the allyloxy groups, which were exposed on the outer of the PPC‐b‐APEG micelles, and N‐vinylpyrrolidone (NVP). The morphology and size of the micelles before and after cross‐link reactions were characterized. The research result shows that the shell cross‐linking could improve the stability of micelles. The particle size of uncross‐linked micelle was about 800 nm. The size of cross‐linked micelles increased with increasing amount of cross‐linking degree. To better evaluate the release behavior of PPC‐b‐PEG copolymer, doxorubicin (DOX)‐loaded micelles were synthesized using DOX as the model drug. Results showed that the DOX releasing rate decreased with increasing of NVP. The shell cross‐linking do decrease the burst release behaviours of DOX and reduce the DOX release rate.     

Preparation,Characterization of Hydrophobic Drug in Combine Loaded Chitosan/Cyclodextrin/Trisodium Citrate Nanoparticles and in vitro Release Study

Chitosan/cyclodextrin/trisodium citrate(CS/CD/TSC) nanoparticles with ibuprofen(IBU) loaded were prepared via the ionic cross-linking method, with trisodium citrate selected as the cross-linking agent. The drug-loading capacity, particle size, zeta potential and surface morphology of the obtained nanoparticles were investigated. The results show a good drug-loading capacity. The prepared nanoparticles were spherical in shape with an average size of 293.7 nm and a zeta potential of +30.72 mV. The in vitro release studies show that the controlled release of IBU from the nanoparticles was followed. The drug release from CS/β-CD/TSC nanoparticles followed non-Fickian or anomalous diffusion.     

聚甘油酸-g-胆固醇胶束的制备及药物释放性能研究

以甘油酸为单体,通过本体缩聚制备了水溶性生物降解高分子聚甘油酸,利用聚甘油酸侧基上的羟基固定生物相容性好的疏水性分子胆固醇,通过亲疏水作用自组装形成胶束.以形成的胶束作为载体负载抗肿瘤药物阿霉素,研究了药物的体外释放行为.将肝癌细胞HepG2与载药胶束共培养研究其体外抗肿瘤效果.研究结果表明,聚甘油酸-g-胆固醇共聚物...