Novel PLGGE graft polymeric micelles for doxorubicin delivery

Novel poly{(lactic acid)-co-[(glycolic acid)-alt-(L-glutamic acid)]}-g-monomethyl poly(ethylene glycol) (PLGGE) micelles were prepared and used as carriers for anti-tumor drug delivery. Three PEGylated PLGG copolymers (PLGGE2000, PLGGE1100 and PLGGE500) were characterized by XRD, TG and DSC. The critical micelle concentrations (CMCs) of the amphiphilic copolymers were 1.04, 0.55 and 0.13 μg/mL, respectively. The TEM, AFM and DLS measurements revealed that the micelles were homogeneous spherical nanoparticles with the diameters ranged from 50 to 150 nm when THF was used as solvent in the preparation of the micelles. Interestingly, extended cylindrical micelles were obtained using CHCl 3 as solvent. The micelles could trap doxorubicin (DOX) in the core with the highest drug loading content up to 23.7%. The mean diameter of drug loaded micelles was much bigger than that of blank micelles. The in vitro drug release of the micelles was diffusion-controlled release within the first 36 h and initial burst release was not obvious. However, after 36 h, the release rate in pH 5.0 was faster than that in pH 7.4 due to the degradation. The PLGGE micelles were nontoxic to both NIH 3T3 fibroblasts and HepG2 cells. The in vitro cytotoxicity against HepG2 cells demonstrated that the drug loaded micelles exhibited high inhibition activity to cancer cells. CLSM observation of HepG2 cells showed that DOX released from the micelles could be delivered into cell cytoplasm and cell nuclei. PLGGE micelles are potential promising carriers for anti-tumor drug delivery.     

Preparation and cellular uptake of PLGA particles loaded with lamivudine

Poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles loaded with lamivudine and coated with bovine serum albumin (BSA) were prepared via a double emulsion method. The influences of experiments parameters such as volume of inner aqueous phase, concentration of organic phase and ultrasonication time on the particle size and drug entrapment efficiency were investigated, obtaining PLGA particles with a diameter of ~260 nm and drug entrapment efficiency of ~35%. The particles were observed by scanning electron microscopy and transmittance electron microscopy, showing a core-shell structure. BCA assay found that 58 mg BSA was present on/in 1 g LPB particles. The loaded lamivudine showed a burst release at beginning and sustained release until 24 h in physiological conditions. Low pH could accelerate the release of lamivudine from PLGA particles, making the PLGA particles potential intelligent intracellular drug carriers. The PLGA particles were readily internalized into the human liver cells within a short time and increased gradually with the prolongation of incubation time regardless of the loading of lamivudine. The particles either resided within lysosomes or transferred to cytoplasm, but could not enter into the cell nucleus. The cell viability was not significantly influenced in the presence of the particles regardless of lamivudine encapsulation, suggesting that this kind of particles may be a good candidate for the intracellular anti-hepatitis B drug delivery.     

Thermo-Responsive Electrospun Nanofibers from Poly( N-isopropylacrylamide )/Polyvinyl Pyrrolidone Blends

A novel nanofiber composite poly(N-isopropylacrylamide)(PNIPAAm)/polyvinyl pyrrolidone(PVP)was successfully prepared by electrospinning.Analogous medicated fibers loaded with ketoprofen(KET)as a model drug were prepared.X-ray diffraction(XRD)demonstrated that the drug was presented in the fibers with an amorphous form.Both scanning and transmission electron microscopy showed that the fibers had an even diameter and smooth surface,and no phase separation was observed.The KET loaded nanofibers did not affect the morphology of the fibers,and no drug aggregation was separated from the polymer fibers.Water contact angle measurements proved that the PNIPAAm/PVP fibers switched from hydrophilic to hydrophobic when the temperature increased the lower critical solution temperature of 32℃.In vitro drug release studies were also undertaken and the result indicated that the PNIPAAm/PVP blend nanofiber presented the properties of the two polymers,having temperature-sensitive systems with sustained release properties.In addition,MTT assay demonstrated that the nanofiber film was non-toxic and suitable for cell growth.Thus,the nanofiber can be used as thermoresponsive carriers for sustained release of poor water soluble drugs.     

Synthesis and properties of novel gemini surfactant with short spacer

Cationic gemini surfactant dimethylene-1,2-bis(dodecyldiethylammonium bromide), referred to as C12C2C12(Et) was synthesized, and its surface property and aggregation behavior in aqueous solution were studied. The value of γ at the critical micelle concentration (γcmc) is much smaller than that of the surfactant homologues with longer spacer. Spherical and elongated micelles were formed in the aqueous solution of this gemini surfactant,and the spherical micelles were absolutely dominant compared to the elongated micelles at our studied concentration quantitatively.     

Effects of Volume Ratios of Water Phase to Oily Phase on Morphology and Releasing Performance of Emulsion Electrospun Fibers

Emulsion electrospinning as a novel process in spinning core-sheath fibers shows a promising potential in drug release control. The volume ratio of water phase to oily phase is one of the critical parameters in forming core-sheath fibers. In this study, water phase was presented by hydrophilic tetracycline hydrochloride and oily phase by hydrophobic poly （E-caprolactone） （PCL）. The effects of volume ratios of water phase to oily phase on fiber morphology and in vitro drug release were investigated. Scanning electron microscopy （ SEM ）, transmission electron microscopy （ TEM）, and eonfoeal laser scanning microscopy（CLSM） were used to observe the morphology, core.sheath structure of the fibers and drug loading in the fibers, respectively. Samples of three different volume ratios of water phase to oily phase, 1： 25, 1：15, and 1：10, were prepared with the same concentration of drug solution. Experiment results showed that, with an increase in the volume ratios of water phase to oily phase, the fiber diameter increased and diameter distribution scattered. The drug entrapment efficiency of the fibers reduces with the increase in volume ratios, L e. , from 73.48 % in the ratio of 1 ： 25, 62.23 % in 1 ： 15, down to 45.63 % in 1：10. In vitro release tests showed that a higher volume ratio of water phase to oily phase would lead to a lower release rate resulted from thicker fiber sheath.     

Synthesis and evaluation of methionine and folate co-decorated chitosan self-assembly polymeric micelles as a potential hydrophobic drug-delivery system

In this study, an amphiphilic copolymer folate-succinyl-methionine-chitosan-octyl (FSMCO) was successfully synthesized step by step for self-assembling polymeric micelles. The copolymers formed micelle-like nanoparticles by their amphiphilic characteristics and structures were examined by UV-Vis absorption and Fourier transform spectroscopy. The sizes of blank and ICG derivativeloaded micelles measured by dynamic light scattering were about 170 and 140 nm, respectively, which were spherical in shape with an average zeta potential of 10 mV. Further studies on the stability showed that the micellar solutions maintain their sizes at room temperature for 1 month without distinct aggregation or dissociation. ICG derivative was much better photostable after being entrapped by the new carrier. The prepared FSMCO micelles displayed a good drug loading content (11.7%), entrapment efficiency (66.5%) and sustained release rate for the model drug fluorescein. The copolymers demonstrated weeny cytotoxicity toward Bel-7402, L02 and A549 cells when incubated for 2 d. Ligands modified micelles endowed preferable cell targeting capability and beautiful cell inhibition of HCPT-FSMCO on Bel-7402 tumor cells. This kind of polymeric micelles may be a promising nanovehicle in delivering near-infrared dyes for tumors imaging and chemotherapeutic drugs for cancer therapeutics.     

Effects of Polyethylene Oxide Concentration on the Size of Beads in Electrospun Beaded Nanofibers

Embedding particle drugs in beaded nanofibers by electrospinning has been shown a potential approach to control drug release in tissue engineering. The bead size is one of the critical parameters in controlling the drug release rate. In this study,the relationship between polymer concentration and beads size was investigated. Aqueous polyethylene oxide（ PEO） solutions with different concentrations were prepared to obtain various beaded nanofibers by electrospnning. Optical microscope and scanning electron microscope（ SEM） were used to observe the variation tendency of bead size. With an increase in the polymer concentration,the diameter of fibers between beads became bigger,while the fiber uniformity improved. In addition, the polymer concentration influenced the distribution of bead diameter. Higher polymer concentration would reduce the possibility of small-sized beads formation and improve the uniformity of bead diameter. The study provides a possible way to control the size of beads,which is helpful for further research on the control of particle drug release.     

In vitro study of poly(ethylene carbonate) as a drug-eluting stent coating

An in vitro feasibility study of the use of poly(ethylene carbonate) (PEC) as a biodegradable coating material for drug-eluting stents is reported, and the performance of PEC is compared with that of poly(lactic-co-glycolic acid) (PLGA). Scanning electron microscopy (SEM) images of PEC and PLGA discs after treatment with an alkaline KO2 solution as a superoxide source showed that the PEC maintained its integrity whereas holes and small particles appeared during the treatment of PLGA. Sirolimus and paclitaxel were loaded into PEC and PLGA in order to study drug release performance. Attenuated total reflectance–infrared (ATR– FTIR) spectroscopy of sirolimus, PEC and the sirolimus-loaded PEC coating showed that no chemical reaction occurred between sirolimus and PEC. The results of atomic force microscopy (AFM) revealed that the mean roughness (Ra) values of the bare metal stent (BMS) and the drugeluting stent (DES) were 2.3 nm and 1.0 nm, respectively. After balloon expansion experiments, no delamination or destruction of the PEC coating was observed. The drug release profile of sirolimus was different from that of paclitaxel when PEC was employed as the drug carrier, and the release curves of sirolimus were different when PEC and PLGA were used as drug carriers. All the experimental results demonstrated that PEC was one of the best potential stent-coating materials.     

In Vitro Cytotoxicity and Protein Drug Release Properties of Chitosan/Heparin Mlcrospheres

Chitosan/heparin microspheres were prepared using the water-in-oil emulsification solvent evaporation technique. The microsphere diameters were controlled by selecting the fabrication process parameters. Scanning electron micrographs showed that the chitosan/heparin microspheres were regular and the surface morphology was smooth. Fourier transform infrared showed that the chitosan amino groups reacted with heparin carboxylic groups to form acylamides in the microspheres. Analysis of the microsphere cytotoxicity showed that they had no cytotoxic effect and behaved very similar to the negative control （polystyrene）. To analyze the protein drug release profiles of the microspheres, bovine serum albumin was loaded as a model drug into the microspheres and released in vitro. Marked retardation was observed in the BSA release profiles. The results show that chitosan/heparin microspheres may provide a useful controlled release protein drug system for used in pharmaceutics.     

p-Hydroxybenzoic acid (p-HA) modified polymeric micelles for brain-targeted docetaxel delivery

Chemotherapies for brain diseases have been hampered due to the inability of transport of drug across the blood-brain barrier (BBB). In order to overcome the barrier, p-hydroxybenzoic acid (p-HA), a small molecule of benzamide analogue, was used as a ligand for brain-targeted drug delivery. The p-HA was conjugated to PEG-DSPE to form p-HA-PEG-DSPE. Docetaxel-loaded polymeric micelles were prepared by a thin-film hydration method using methoxy-poly(ethylene glycol)-distearoylphosphatidyl- ethanolamine (mPEG 2000 -DSPE) as a carrier and the p-HA-PEG-DSPE as a brain targeted material. The prepared micelles showed spherical with a mean diameter of (18±3) nm. Encapsulation efficiency and drug loading were (83.49±1.3)%, (7.7±1.2)% for un- modified micelles and (80.65±1.6)%, (7.47±1.8)% for p-HA-modified micelles, respectively. In vitro cellular uptake experiments showed that the p-HA-modified micelles increased BCECs cellular uptake by 1.2 times compared to the unmodified micelles. Ex vivo near-infrared fluorescence imaging showed that brain uptake of the p-HA-modified micelles was 1.3-1.8 times higher than that of the unmodified micelles. In vitro cytotoxicity assay against glioblastoma cell U87 MG showed that inhibition rate of the p-HA-modified micelles increased by 1.2 times compared to that of the unmodified micelles and 1.7 times compared to that of DTX. Survival time of nude mice bearing intracranial glioblastoma showed that the lifetime of saline group, Taxotere group, mPEG-DSPE/DTX micelles group and p-HA-PEG-DSPE/DTX micelles group was 22, 27, 32 and 45.8 d, representively, which indicated that anti-glioblastoma activity of DTX could be significantly enhanced by the p-HA-modified polymeric micelles. These results demonstrated that the p-HA-modified micelles could be a promising brain-targeted drug delivery system for hydrophobic drugs against glioblastoma.     

磷脂胆碱聚乳酸自组装胶束的结构与性能

用与天然磷脂结构和相对分子质量类似的磷脂月E{碱聚乳酸(Phosphorylcholine-containing poly(L-lactide),PLLA.pc)$sJ备自纽装胶束,采朋透射电镜和激光共聚焦显微镜进行观察.研究结果表明:胶束为外壳亲水内核疏水的实心球:表面张力法测得临界胶束质量浓度(Critical micelle concentration,CMC)~23 mg/L,显著低于天然磷脂胆碱质鼍浓度;当氯化钠质量分数低于0.9%时,CMC无明显变化,表明胶柬在生理盐水中较稳定:胶束被稀释时,动态光散射测得胶束粒径和粒径分布均逐渐变小,表明体系是动态体系;在37℃恒温条件下放置15 h,胶束数量、粒径和分布均变小,表明胶束可随时间降解;PLLA-PC胶束生物相容性好,可降解,可望成为新型的控释药物载体.     

不同结构两亲性嵌段共聚物的合成、药物负载及释放行为研究

采用阴离子活性聚合(AROP)的方法分别合成3种不同结构的两亲性嵌段共聚物:线型共聚物聚乙氧基乙基缩水甘油醚-聚乙二醇(PEEGE-PEO-(OH))、星型聚合物PEEGE-PEO-(OH)_3以及类树枝状聚合物PEEGE-PEO-(OH)_(24).通过~1H-NMR及GPC等手段对聚合物的结构进行表征.采用透析法制备负载阿霉素的聚合物胶束,通过透射电镜(TEM)和动态光散射(DLS)对胶束的形貌及尺寸进行表征.结果表明:3种胶束均具有球形结构;与线型及星型聚合物相比,两亲性类树枝状聚合物具有最高的载药效率与载药量;体外药物释放结果显示3种聚合物均具有pH敏感释放特性,且类树枝状表面致密结构可降低药物在中性环境下的释放率.     

叶酸修饰pH响应壳聚糖衍生物胶束的制备及性能表征

制备了叶酸（FA）、胆固醇琥珀酸单酯（CHS）共修饰的羟丙基壳聚糖衍生物（CHS-HPCHS-FA）,该衍生物在水中能够自组装形成粒径为200~400nm的胶束。研究了疏水片段CHS的取代度对胶束的临界胶束浓度、粒径、载药及释药性能的影响,分析了胶束pH响应控释药物的机理,结果表明,疏水片段取代度高的产物,其临界胶束浓度较低,形成的胶束粒径较小,载药效率较高。体外溶出结果显示,载药胶束在pH5.5条件下释药速率明显比pH7.4条件下更快,体现了pH响应控释药物的效果。体外细胞毒性实验结果表明,胶束的生物相容性较好,且叶酸修饰的载药胶束可增强肿瘤细胞的摄取,细胞毒性明显增大。     

双嘧达莫嵌段共聚物胶束的制备及体外药物释放

以聚癸二酸酐-聚乙二醇-聚癸二酸酐为载体材料,采用沉淀/溶剂挥发法制备双嘧达莫载药胶束,DLS法测定胶束的粒径,紫外分光光度法测定胶束的载药量、包封率和药物的释放度.结果发现载药胶束的粒径大于空白胶束的粒径;随着共聚物中疏水链段比例的增加,胶束的载药量和包封率都上升,而且药物释放时间延长;调节嵌段共聚物的链段组成,可以调节药物的释放动力学过程.     

巯基-烯点击化学法制备还原响应两亲性聚合物

以胱胺二盐酸盐、氯甲酸烯丙酯、1,6-己二硫醇及端巯基聚乙二醇单甲醚等为原料,通过巯基-烯点击化学反应,合成了疏水段含二硫键的两亲性三嵌段共聚物mPEG-bP1-b-mPEG.对mPEG-b-P1-b-mPEG在水溶液中的自组装行为进行了深入的研究.结果表明,mPEG-b-P1-b-mPEG的临界胶束浓度为0.032 mg/mL,形成胶束的平均粒径为61.3nm.包载模拟药物尼罗红的释放行为研究表明,在D,L-二硫苏糖醇(DTT)存在的条件下,包裹在胶束中的尼罗红可以被释放出来,显示出快速的还原响应性能,表明合成的两亲性三嵌段共聚物mPEG-b-P1-b-mPEG有望作为疏水性药物载体,应用于药物控释领域.     

羧甲基壳聚糖纳米胶束的制备与光响应性研究

智能响应性聚合物胶束作为药物控释传递系统的载体引起广泛关注,其中光刺激因为可控性高、清洁高效等优点被广泛研究.该文以丁二酸酐为连接臂将1-芘甲醇(PyM)接枝到羧甲基壳聚糖(CMCS)的氨基上制得两亲性大分子(PMS-g-CMCS),然后在水溶液中自组装成光响应纳米胶束.采用动态光散射(DLS)和透射电镜(TEM)表征胶束的大小和形态,并研究光刺激前后胶束的大小变化;通过核磁和荧光研究胶束的光响应机制.结果表明该胶束为类球形核-壳结构,粒径约200 nm,且具有较好储存稳定性;在紫外(UV)光照下,能发生结构改变,其光响应机制可归因于连接PyM的酯键断裂.胶束显示出可用作疏水性药物或农药光控释放载体的潜力.     

两亲梳状聚衣康酸的合成及其阿霉素的缓释体系

采用自由基聚合法合成聚衣康酸(PIA),并将PIA接枝十二胺合成两亲性梳状聚合物(PIA-g-DDA).利用动态光散射(DLS)测试PIA-g-DDA的溶液性质,并研究其流体力学直径和烷基链接枝比率对粒径大小的影响.以芘为分子探针,通过荧光光谱法测定PIA-g-DDA的临界胶束浓度(CMC);利用两亲性梳状聚合物PIA-g-DDA包埋阿霉素(DOX),通过相转移的方法制备聚合物载药体系PIA-g-DDA@DOX.结果表明:烷基链接枝率越高,聚合物的胶束粒径越小;其CMC=2.01×10-2 mg/mL;该载药体系包埋率高,载药量大,缓释作用明显.     

PEG-g-poly（aspartamide-co-N,N-dimethylethylenediamino aspartamide）： Synthesis, characterization and its application as a drug delivery system

PEG-g-poly(aspartamide-co-N,N-dimethylethylenediamino aspartamide) (PEG-DMEDA-PASP) was synthesized by two-step ring-opening reactions of polysuccinimide (PSI) with α-methoxy-ω-amino-poly(ethylene glycol) and N,N-dimethylethylenediamine. The polymer structure was confirmed by ¹H NMR and FT-IR. The resultant PEG-DMEDA-PASP with ammonium glycyrrhizinate (AMG) could form polymeric micelles in aqueous solution. The results of transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements revealed that these polymeric micelles were spherical particles with a narrow diameter distribution and that their average diameter was ca. 70 nm. These polymeric micelles had high-loading capacity (58%) and encapsulation efficiency (70%) for AMG. The results of in vitro release experiments showed that these polymeric micelles possessed sustained-release effects, with a release rate of 25% within 3 h and 90% within 24 h.