羟基喜树碱pH敏感阳离子纳米脂质体的制备

 目的 以羟基喜树碱作为模型药物研究pH敏感阳离子纳米脂质体用于包载抗癌药物的制备工艺。方法 采用薄膜分散法制备羟基喜树碱阳离子脂质体;用羧甲基壳聚糖物理修饰阳离子脂质体;用葡聚糖凝胶柱色谱法分离游离药物;用紫外分光光度法测定包封率;用单一因素考察法优选处方;经高压乳匀得到纳米脂质体(粒径小于100 nm);用激光粒度分析仪测定Zeta电位、粒径大小。结果 最佳处方制备的药物平均包封率为(78.5±0.9)％(n=3);包衣纳米脂质体的Zeta电位为-31.3 mV,平均粒径为96 nm。结论 使用本方法制备pH敏感阳离子纳米脂质体工艺简单,有望获得高靶向性的抗癌药物传递系统。     

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。     

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。     

Evolution of a physiological pH 6.8 bicarbonate buffer system: Application to the dissolution testing of enteric coated products

The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro-in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH 7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP-55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT® L100-55, EUDRAGIT® L30D-55 and EUDRAGIT® L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1 M HCl for 2 h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer (mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer.     

眼用即型凝胶基质的成胶性研究

目的:研究眼用原位凝胶基质的成胶性,并建立温度敏感型、离子敏感型和pH敏感型眼用原位凝胶的基质处方。方法:使用人工泪液,模拟眼部生理条件综合考虑黏度、突跃点等因素来考察各类基质处方的成胶性并筛选基质处方。结果:眼部生理条件下,0.02%卡波姆P934、0.02%卡波姆P940和0.5%羟丙基甲基纤维素(HPMC)-K4M合用、0.45%的去乙酰结冷胶、24%泊洛沙姆P407与10%泊洛沙姆P188合用等三种情况下有合适的成胶性。结论:pH敏感型、离子敏感型、温度敏感型眼用原位凝胶的适用基质处方分别为0.02%卡波姆P934+0.02%卡波姆P940+0.5%羟丙基甲基纤维素(HPMC)-K4M合用、0.45%的去乙酰结冷胶、24%泊洛沙姆P407+10%泊洛沙姆P188合用。     

Ketal containing amphiphilic block copolymer micelles as pH-sensitive drug carriers

pH-Responsive linkages have been widely exploited in the development of polymeric drug delivery systems, which trigger drug release selectively at tumor tissues or endosomes and lysosomes of cells. Herein we report new pH-sensitive amphiphilic poly(ketal adipate)-co-poly(ethylene glycol) block copolymers (PKA-PEG), which have acid-cleavable ketal linkages in their hydrophobic backbone. PKA-PEG copolymers self-assemble to form stable micelles with a mean diameter of ~175 nm, which can encapsulate a payload of anticancer drugs and rapidly dissociate to release drug payload at the acid environment. The micelles are biocompatible and exhibit abilities to disrupt endosomes to enhance the cytosol drug delivery. Taken together, we anticipate that the pH-sensitive PKA-PEG micelles have great potential as anticancer drug carriers.     

Anionic LPD complexes for gene delivery to macrophage: Preparation,characterization and transfection in vitro

In the present study, anionic lipid/peptide/DNA (LPD) complexes consisting of pH-sensitive liposome and protamine were introduced as the carriers targeting RAW 264.7 cell line, which had been reported to be difficult for transfection. The LPD complexes were physically characterized. The pH sensitivities and sizes of liposomes were investigated. The zeta potentials of LPD complexes altered significantly with the addition of protamine sulfate and anionic liposomes. It was demonstrated that the carriers produced an increase in the stability of plasmid DNA against DNase I. The TEM showed that the size distribution of LPD complexes was irregular. In the in vitro transfection, the efficiency of LPD complexes was higher than that of Lipofectamine? 2000 and protamine/DNA complexes, but lower than that of electroporation. A possible mechanism for the internalization of plasmid DNA mediated by the anionic LPD complexes was also proposed. With a high safety certificated by MTT assay, LPD complexes prepared in this study might be potentially employed as a macrophage gene therapy.     

Enhanced transfection of tumor cells in vivo using “Smart” pH-sensitive TAT-modified pegylated liposomes

Liposomes have been prepared loaded with DNA (plasmid encoding for the green fluorescent protein, GFP) and additionally modified with TATp and PEG, with PEG being attached to the liposome surface via both pH-sensitive hydrazone and non-pH-sensitive bonds. The pGFP-loaded liposomal preparations have been administered intratumorarly in tumor-bearing mice and the efficacy of tumor cell transfection was followed after 72 h. The administration of pGFP–TATp–liposomes with non-pH-sensitive PEG coating has resulted in only minimal transfection of tumor cells because of steric hindrances for the liposome-to-cell interaction created by the PEG coat, which shielded the surface-attached TATp. At the same time, the administration of pGFP–TATp–liposomes with the low pH-detachable PEG resulted in at least three times more efficient transfection since the removal of PEG under the action of the decreased intratumoral pH leads to the exposure of the liposome-attached TATp residues, enhanced penetration of the liposomes inside tumor cells and more effective intracellular delivery of the pGFP. This result can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems.     

A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery

Abstract

The pH-sensitive liposomes have been extensively used as an alternative to conventional liposomes in effective intracellular delivery of therapeutics/antigen/DNA/diagnostics to various compartments of the target cell. Such liposomes are destabilized under acidic conditions of the endocytotic pathway as they usually contain pH-sensitive lipid components. Therefore, the encapsulated content is delivered into the intracellular bio-environment through destabilization or its fusion with the endosomal membrane. The therapeutic efficacy of pH-sensitive liposomes enables them as biomaterial with commercial utility especially in cancer treatment. In addition, targeting ligands including antibodies can be anchored on the surface of pH-sensitive liposomes to target specific cell surface receptors/antigen present on tumor cells. These vesicles have also been widely explored for antigen delivery and serve as immunological adjuvant to enhance the immune response to antigens. The present review deals with recent research updates on application of pH-sensitive liposomes in chemotherapy/diagnostics/antigen/gene delivery etc.     

A validated 1H NMR method for the determination of the degree of deacetylation of chitosan

A method for the determination of the degree of deacetylation (DDA) of chitosan by ¹H NMR spectroscopy has been formally validated. Chitosans with DDA ranging from 48 to 100% have been used for the validation. The method is found to be simple, rapid and more precise than other known techniques like IR or titration for %DDA measurements. The precision, ruggedness, robustness, specificity, stability and accuracy of the technique are discussed in this paper.