薄膜包衣法制备中药复方结肠定位定时片

目的应用薄膜包衣法制备复方盐酸小檗碱结肠定位定时片。方法以肠溶丙烯酸树脂Eudragit L100与Eudragit S100为pH敏感层材料,以乙基纤维素水分散体(Surelease)为时滞层包衣材料,采用包衣锅包衣法制成结肠定位定时片;以体外释放度为考察指标,使包衣片释药特性基本符合设计要求。结果体外释放度试验表明,当pH敏感层增重4%、时滞层增重6%时,可控制药物在到达小肠后3h释药,且不受胃排空的影响。结论通过调整时滞层、肠溶层包衣厚度,包衣片可基本达到结肠定位释药的预期效果。     

多西他赛pH敏感型聚(2-乙基-2-噁唑啉)-聚(D,L-丙交酯)自组装胶束的制备及其性质

目的利用两亲性嵌段共聚物聚(2-乙基-2-噁唑啉)-聚(D,L-丙交酯)[poly(2-ethyl-2-oxazo-line)-poly(D,L-lactide),PEOz-PDLLA]的自组装性能制备pH敏感型多西他赛胶束,并对其相关性质进行考察。方法运用阳离子开环聚合反应得到PEOz-PDLLA,通过FITR、1H-NMR和凝胶色谱法对其结构进行表征,采用电位滴定法测定共聚物pKa,应用荧光探针技术确定临界胶束浓度(criticalm icelle concentration,CMC)。动态光散射法和Zeta电位测试仪测定胶束的粒径和Zeta电位。以薄膜分散法包载多西他赛,并用透析法研究载药胶束的体外释放度。结果PEOz-PDLLA的亲水/疏水段分子质量比值为0.76,pKa为6.41,CMC为0.8×10-3g.L-1。载药胶束包封率为94.9%、载药量质量分数为8.7%、平均粒径为(35.3±4.9)nm、Zeta电位为(25.51±2.14)mV,在pH5.0的释放介质中释药速度加快。结论PEOz-PDLLA嵌段共聚物可自组装形成胶束,高效包载多西他赛,体外释放具有pH敏感性。     

pH-sensitive nanoparticles of poly(amino acid) dodecanoate complexes

Nanoparticles were formed by the complexation of poly( -arginine) (PLA), poly( -histidine) (PLH) and poly( -lysine) (PLL) with dodecanoic acid (C12). Dynamic light scattering, ζ potential measurements, atomic force microscopy, fluorescence, and circular dichroism spectroscopy were used for their characterization. It was found that the diameters of the poly( -arginine) dodecanoate (PLA-C12), poly( -histidine) dodecanoate (PLH-C12), and poly( -lysine) dodecanoate (PLL-C12) complex nanoparticles were in the range 120–200 nm. Furthermore, the pH-sensitive dissolution and the surface charges can be adjusted by choosing PLA, PLH and PLL. The particle stability against basic pH values increases with increasing pK_a value of the poly(amino acid) in the series PLH-C12, PLL-C12 and PLA-C12. The particles as such show a core-shell morphology. Their cores are formed by stoichiometric poly(amino acid) dodecanoate complexes while the shells stabilizing the particles are formed by cationic poly(amino acid) chains in an uncomplexed state. The particles were tested as containers for hydrophobic molecules such as pyrene, which served as a fluorescence probe for measuring the polarity within the particles, and Q₁₀ which functioned as a model drug. The maximum uptake of Q₁₀ into the nanoparticles is about 13% (w/w), thereby making the complexes attractive as simple drug carriers for controlled release purposes. Circular dichroism measurements revealed that the poly(amino acid) chains of PLA-C12 and PLL-C12 adopt predominantly an -helix and that of PLH-C12 a β-sheet.     

含原酸酯基团的pH敏感纳米载体在抗肿瘤药物递送中的应用进展

pH敏感型纳米药物载体在癌症治疗方面的研究正受到越来越多的关注,显示出诸多优势和良好的应用前景。已报道的pH敏感型纳米药物载体包括多种类型。本文针对含原酸酯基团的pH敏感纳米药物载体,综述了其近年来的研究进展,并介绍了该类药物载体在抗肿瘤药物递送中的应用。     

Physicochemical aspects of doxorubicin-loaded pH-sensitive polymeric micelle formulations from a mixture of poly(l-histidine)-b-poly(l-lactide)-b-poly(ethylene glycol)

In this study, doxorubicin (DOX) was physically incorporated into pH-sensitive micelles made from a mixture of poly(l-histidine)-b-poly(ethylene glycol)/poly(l-lactide)-b-poly(ethylene glycol) (75/25, wt.%). The DOX-loaded mixed micelles were formulated using dialysis methods and optimal DOX incorporation was achieved at a drug/polymer feed ratio of 0.2 (wt./wt.) when a proper amount of aqueous phase (0.2, v./v.) was added into the common solvent (DMSO) solution, followed by dialysis at 4 °C. Based on the results obtained from dynamic light scattering, UV-Vis absorption, and fluorescence experiments, it was demonstrated that the encapsulated drugs were mainly located inside the hydrophobic micelle cores, well protected and inaccessible to the exterior molecules. Under in vitro conditions, although the microstructure of the micelles was altered below pH 8.0 by the encapsulated drugs, the drug-loaded micelles still exhibited a desirable ability to control the drug release in response to tumor extracellular pH.     

Enhanced Intercellular Retention Activity of Novel pH-sensitive Polymeric Micelles in Wild and Multidrug Resistant MCF-7 Cells

Purpose The purpose of this work was to demonstrate the advantage of using pH-sensitive polymeric mixed micelles (PHSM) composed of poly(l-histidine) (polyHis)/poly(ethylene glycol) (PEG) and poly(l-lactic acid) (pLLA)/PEG block copolymers with folate conjugation to increase drug retention in wild-type and MDR tumor cells. Materials and Methods Both wild-type and multidrug resistant (MDR) human breast adenocarcinoma (MCF-7) cell lines were used to investigate the accumulation and elimination of doxorubicin (DOX), PHSM with folate (PHSM/f), and pH-insensitive micelles composed of pLLA/PEG block copolymer with folate (PHIM/f). Results Cells treated with PHSM/f showed decelerated elimination kinetics compared to cells treated with PHIM/f. MDR cells treated with drug-containing PHSM/f for 30 min retained 80% of doxorubicin (DOX) even after incubation for 24 h in the absence of drug. On the other hand, cells treated with drug-containing PHIM/f retained only 40% of DOX within the same period of time. Flow cytometry and confocal microscopy confirmed these results. Conclusions Cellular entry of the micelles occurred via receptor-mediated endocytosis using folate receptors. The pH-induced destabilization of PHSM/f led to rapid distribution of drug and polymer throughout the cells, most likely due to polyHis-mediated endosomal disruption. This reduced the likelihood of drug efflux via exocytosis from resistant tumor cells.     

pH及温度双重敏感性纳米粒水凝胶的制备及表征

目的:制备具有pH及温度双重敏感性的纳米水凝胶,并使其粒径控制在100nm以下。方法:利用聚合沉淀法合成聚N-异丙基丙烯酰胺(PNIPA)及聚(N-异丙基丙烯酰胺-丙烯酸)(PNIPA-co-AA)纳米水凝胶。通过马尔文粒度仪与透射电子显微镜考察了纳米水凝胶的粒径分布,并以500nm处的透光率表征了PNIPA与PNIPA-co-AA的低临界溶解温度(LCST)和pH敏感特性。结果:通过调节表面活性剂十二烷基硫酸钠(SDS),得到了25～250nm不同粒径大小的纳米水凝胶;PNIPA-co-AA的LCST与参与共聚的丙烯酸单体有关,其LCST可由34℃(PNIPA的LCST)提高至35～45℃;同时PNIPA-co-AA对pH具有较好的敏感性。结论:PNIPA-co-AA纳米水凝胶有望成为智能型控释和靶向性药物载体。     

Programming the composition of polymer blend particles for controlled immunity towards individual protein antigens

In order for a more precise control over the quality and quantity of immune responses stimulated by synthetic particle-based vaccines, it is critical to control the colloidal stability of particles and the release of protein antigens in both extracellular space and intracellular compartments. Different proteins exhibit different sizes, charges and solubilities. This study focused on modulating the release and colloidal stability of proteins with varied isoelectric points. A polymer particle delivery platform made from the blend of three polymers, poly(lactic-co-glycolic acid) (PLGA) and two random pH-sensitive copolymers, were developed. Our study demonstrated its programmability with respective to individual proteins. We showed the colloidal stability of particles at neutral environment and the release of each individual protein at different pH environments were dependent on the ratio of two charge polymers. Subsequently, two antigenic proteins, ovalbumin (OVA) and Type 2 Herpes Simplex Virus (HSV-2) glycoprotein D (gD) protein, were incorporated into particles with systematically varied compositions. We demonstrated that the level of in vitro CD8⁺ T cell and in vivo immune responses were dependent on the ratio of two charged polymers, which correlated well with the release of proteins. This study provided a promising design framework of pH-responsive synthetic vaccines for protein antigens of interest.     

Preparation and Swelling Behaviors of High-Strength Hemicellulose-g-Polydopamine Composite Hydrogels

Hemicellulose-based composite hydrogels were successfully prepared by adding polydopamine (PDA) microspheres as reinforcing agents. The effects of PDA microsphere size, dosage, and nitrogen content in hydrogel on the mechanical and rheological properties was studied. The compressive strength of hydrogel was increased from 0.11 to 0.30 MPa. The storage modulus G’ was increased from 7.9 to 22.0 KPa. The gaps in the hemicellulose network are filled with PDA microspheres. There is also chemical cross-linking between them. These gaps increased the density of the hydrogel network structure. It also has good water retention and pH sensitivity. The maximum cumulative release rate of methylene blue was 62.82%. The results showed that the release behavior of hydrogel was pH-responsive, which was beneficial to realizing targeted and controlling drug release.     

茶碱分子表面印迹微球的制备及其体外释药性能

通过分子表面印迹技术,采用铈盐-羟基氧化还原引发体系,以交联聚乙烯醇(CPVA)微球为基质、对苯乙烯磺酸钠(SSS)为功能单体、茶碱(TP)为模板药物分子、N,N′-亚甲基双丙烯酰胺(MBA) 为交联剂,制备了TP分子表面印迹微球MIP-PSSS/CPVA。采用红外光谱测定其结构,扫描电镜观察其表面形貌,静态法考察印迹微球MIP-PSSS/CPVA对TP的结合性能及载药印迹微球的体外释药行为。结果表明：TP分子表面印迹微球MIP-PSSS/CPVA对TP具有较高的识别选择性和结合亲合性,当pH=1时,微球对TP的结合容量达到92 mg/g。该印迹微球在模拟胃液中基本不释药;在模拟小肠液中的第2~6 h,累积释放率仅为21%;而在模拟结肠液中突释,之后持续缓慢地释放,表现出优良的pH敏感和时滞双重型结肠定位释药特性。