分子印迹整体柱在高效液相色谱中的研究进展

分子印迹整体柱具有制备简单、特异选择好及传质阻力低等优点，在高效液相色谱中的应用发展迅速。本文综述了分子印迹整体柱的制备、表征及分离机制等的研究进展。     

壳寡糖-水杨酸接枝物纳米粒用于释放阿霉素的研究

目的 考察壳寡糖/水杨酸纳米粒负载碱化阿霉素的可能性,评价制备而得的微粒给药系统理化性质及其体外释放行为。方法 以碳二亚胺为交联偶合剂合成壳寡糖/水杨酸接枝共聚物,三硝基苯磺酸法测定水杨酸接枝率。运用超声分散法制备壳寡糖/水杨酸空白纳米粒,芘荧光法测定纳米粒临界聚集浓度,动态光散射法测定微粒粒径和表面电位,MTT法考察空白纳米粒的细胞毒性。以碱化阿霉素为模型药物,透析法制备壳寡糖/水杨酸载药纳米粒,经透射电镜考察载药纳米粒的形态,对其体外释放行为进行了研究。结果 合成得到的壳寡糖分子量=9000/水杨酸理论投料量=50%的实际接枝率为16.92%,空白纳米粒的临界聚集浓度为867.0 μg/mL,空白纳米粒的粒径和表面Zeta电位分别为434.0 nm和48.6 mV,对人肝癌细胞Hep-G2的半数抑制浓度为1745μg/mL。在碱化阿霉素理论投药量为10%时壳寡糖/水杨酸载药纳米粒的实际载药量为8.52%,包封率为93.15%。;载药纳米粒的粒径和表面电位分别为214.2 nm和33.6 mV。体外释放结果表明药物的释放呈现pH敏感性;并主要以溶蚀的方式从载体内部释放出来。结论 壳寡糖/水杨酸接枝物可以有效包裹碱化阿霉素并成为粒径均一的纳米粒给药系统。载药纳米粒具有pH敏感和缓释作用。壳寡糖/水杨酸接枝物有望成为潜在的难溶性药物的载体材料。     

Carboxylated Hydroxyethyl Starch: A novel Polysaccharide for the Delivery of Doxorubicin

Hydroxyethyl starch (HES) was interacted with succinic anhydride affording a carboxylated derivative which has proved to be a promising polymeric drug delivery system. Specifically, this polymer is conveniently prepared, is biodegradable, non‐immunogenic, and can encapsulate doxorubicin due to the protonation of the primary amino group of doxorubicin by the carboxylic group located on the branched scaffold of the polysaccharide. In addition, due to the polyhydroxylated character of the polysaccharide, the latter can act as a protective coating in an analogous manner to the PEG‐chains ensuring prolonged circulation in vivo. In vitro experiments showed controlled release of doxorubicin to the nuclei of DU145 prostate cancer cells when the anticancer drug is incorporated in the carboxylated hydroxyethyl starch.     

Reverse Biomembrane Vesicles for Effective Controlled Delivery of Doxorubicin HCl

The stability of liposome preparations under the action of the nonionic detergent Triton X-100 was measured using the fluorescent molecular probe octadecylrhodamine B (R18). The probe inserted in the lipid bilayer shows a self-quenched fluorescence and the degree of quenching depends both on the probe concentration and the phase state of the lipid membrane. The addition of detergent to the liposomes produces a steep decrease in self-quenching caused by dilution of the probe in the bilayer. The curves of steady-state fluorescence intensity show an abrupt change in slope that corresponds to the point at which liposomes break down into lipid-detergent mixed entities that are different from the earlier liposome-monodisperse population. The lytic process was followed in parallel by dynamic light scattering (DLS), and the analysis of the DLS results agree with the interpretation of the fluorescence measurements. The probe R18 therefore is a useful marker to test the stability of liposome preparations. The advantages of the present method are discussed by comparison with other techniques.     

多柔比星纳米载药系统逆转肿瘤多药耐药的研究进展

多柔比星是治疗乳腺癌、肺癌的1种有效的化疗药物。现存的主要问题是临床使用时肿瘤细胞产生多药耐药。为克服多药耐药,研究者们报道了一些利用纳米载药系统传递多柔比星的方法。纳米载药系统生物相容性好,稳定性高,具有药物控释和靶向性的优点,在药物传递中应用广泛。纳米载药系统可分为无机物纳米系统、基于脂质的纳米系统和聚合物纳米系统3种类型,在多柔比星载药中均有应用。综述近年来有关纳米载药系统最新研究文献,对其研究进展作了分析,并展望了其发展前景。     

Development of Hydrogels for Microneedle-Assisted Transdermal Delivery of Naloxone for Opioid-Induced Pruritus

Transdermal naloxone delivery could be a potential option for treating opioid-induced pruritus, but naloxone does not permeate skin well because of its hydrophilic nature. Microneedles (MNs) could overcome the skin barrier by painlessly creating microchannels in the skin to permit naloxone absorption to therapeutic levels. This study investigated how ionization correlates with naloxone permeation across MN-treated skin. Hydrogels containing 0.2, 0.5, or 1% naloxone were formulated with 1% cross-linked polyacrylic acid (polymer) and adjusted to pH 5, 6.5, or 7.4. Porcine skin was treated with MNs and naloxone gel, and in vitro permeation studies were performed using an in-line diffusion setup. Gel structural properties were evaluated using rheology. All gels had viscoelastic properties and good spreadability. Naloxone permeation through intact skin was highest from pH 7.4 gels when naloxone is unionized, in contrast with undetectable concentrations permeated from pH 5 gels with 100% ionization. Combining MN treatment with pH 5 gels significantly enhanced permeation and resulted in steady-state flux that would achieve therapeutic delivery. Absorption lag time was affected by MN length and naloxone gel concentration. Polymer concentration did not influence drug permeability. This study demonstrates that transdermal naloxone delivery with MNs is a viable treatment option for opioid-induced pruritus.     

Solid Lipid Nanoparticles for Potential Doxorubicin Delivery in Glioblastoma Treatment: Preliminary In Vitro Studies

The major obstacle to glioblastoma pharmacological therapy is the overcoming of the blood–brain barrier (BBB). In literature, several strategies have been proposed to overcome the BBB: in this experimental work, solid lipid nanoparticles (SLN), prepared according to fatty acid coacervation technique, are proposed as the vehicle for doxorubicin (Dox), to enhance its permeation through an artificial model of BBB. The in vitro cytotoxicity of Dox-loaded SLN has been measured on three different commercial and patient-derived glioma cell lines. Dox was entrapped within SLN thanks to hydrophobic ion pairing with negatively charged surfactants, used as counterions. Results indicate that Dox entrapped in SLN maintains its cytotoxic activity toward glioma cell lines; moreover, its permeation through hCMEC/D3 cell monolayer, assumed as a model of the BBB, was increased when the drug was entrapped in SLN. In conclusion, SLN proved to be a promising vehicle for the delivery of Dox to the brain in glioblastoma treatment.     

Hydrogels for Site-Specific Drug Delivery to the Colon: In Vitro and in Vivo Degradation

Novel hydrogels based on N,N-dimethylacrylamide, N-t-butylacrylamide, and acrylic acid cross-linked with azoaromatic compounds of varying length and electron density of the azo bond were synthesized. The cross-links are degradable by microbial azoreductases present predominantly in the colon, and the gels appear to be suitable for colon-specific drug delivery. The degradability in vitro and in vivo was found to be related to the degree of swelling of the gels. The higher the degree of swelling, the higher the degradability. However, structural and electronic factors were also shown to influence reduction of azo bonds.     

Click Chemistry with Polymers,Dendrimers, and Hydrogels for Drug Delivery

During the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagnosis. In addition, polymeric hydrogels with the ability to encapsulate drugs and cells have been developed for drug delivery and tissue engineering applications. In the long road to this successful story, pharmaceutical sciences have been accompanied by parallel advances in synthetic methodologies allowing the preparation of precise polymeric materials with enhanced properties. In this context, the introduction of the click concept by Sharpless and coworkers in 2001 focusing the attention on modularity and orthogonality has greatly benefited polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. The purpose of this Expert Review is to discuss the impact of click chemistry in the preparation and functionalization of polymers, dendrimers, and hydrogels of interest in drug delivery.     

Multifunctional Polymeric Micelles for Enhanced Intracellular Delivery of Doxorubicin to Metastatic Cancer Cells

Purposes  To develop multifunctional RGD-decorated poly(ethylene oxide)-b-poly(ester) based micelles and assess their pH-triggered core degradation and targeted drug release in tumor cells that overexpress RGD receptors. Methods  Novel poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) based copolymers modified with RGD ligands on PEO and pendent functional groups on PCL, i.e., GRGDS-PEO-b-poly(α-benzylcarboxylate-ε-caprolactone) (GRGDS-PEO-b-PBCL) and GRGDS-PEO-b-poly(α-carboxyl-ε-caprolactone) (GRGDS-PEO-b-PCCL), were synthesized. Chemical conjugation of doxorubicin (DOX) to PCCL core produced GRGDS-PEO-b-P(CL-DOX) micellar conjugates, while GRGDS-PEO-b-PBCL were used to physically encapsulate DOX. For both systems, micellar core degradation, drug release, intracellular drug uptake/disposition, and cytotoxicity against B16F10 metastatic cells were investigated. Results  The PBCL and P(CL-DOX) cores were found resistant to degradation in pH 7.2, but showed 10% and 40% loss in core molecular weight in pH 5.0 within 144 h, respectively. Preferential release of DOX and DOX derivatives from PBCL and P(CL-DOX) cores was noted in pH 5.0, respectively. The GRGDS-modified micelles showed enhanced cellular internalization through endocytosis, increased intracellular DOX release, nuclear localization, and improved cytotoxicity against metastatic B16F10 cells compared to their unmodified counterparts. Conclusions  The results clearly suggest a promise for the development of multifunctional polymeric micelles with RGD ligand decorated shell and endosomal pH-triggered degradable core for selective DOX delivery to metastatic cancer cells.     

pH Triggered Doxorubicin Delivery of PEGylated Glycolipid Conjugate Micelles for Tumor Targeting Therapy

The main objective of this study was aimed at tumor microenvironment-responsive vesicle for targeting delivery of the anticancer drug, doxorubicin (DOX). A glucolipid-like conjugate (CS) was synthesized by the chemical reaction between chitosan and stearic acid, and polyethylene glycol (PEG) was then conjugated with CS via a pH-responsive cis-aconityl linkage to produce acid-sensitive PEGylated CS conjugates (PCCS). The conjugates with a critical micelle concentration (CMC) of 181.8 μg/mL could form micelles in aqueous phase, and presented excellent DOX loading capacity with a drug encapsulation efficiency up to 87.6%. Moreover, the PCCS micelles showed a weakly acid-triggered PEG cleavage manner. In vitro drug release from DOX-loaded PCCS micelles indicated a relatively faster DOX release in weakly acidic environments (pH 5.0 and 6.5). The CS micelles had excellent cellular uptake ability, which could be significantly reduced by the PEGylation. However, the cellular uptake ability of PCCS was enhanced comparing with insensitive PEGylated CS (PCS) micelles in weakly acidic condition imitating tumor tissue. Taking PCS micelles as a comparative group, the PCCS drug delivery system was demonstrated to show much more accumulation in tumor tissue, followed by a relatively better performance in antitumor activity together with a security benefit on xenograft tumor model.     

NIR-/pH-Responsive Drug Delivery of Functionalized Single-Walled Carbon Nanotubes for Potential Application in Cancer Chemo-Photothermal Therapy

Purpose

To establish a NIR (near infrared)-/pH-responsive and sustained-release tumor-targeting drug delivery system (SWNT-PEI/DOX/NGR).

Methods

Functionalized SWNTs with polymerised polymeric poly(ethylene imine) was linked NGR (Asn-Gly-Arg) tumor-targeting peptide by DSPE-PEG2000-Maleimide via the maleimide group and sulfhydryl group of cysteine, in the end, doxorubicin (DOX) was attached to SWNT-PEI to obtain a SWNT-PEI/DOX/NGR delivery system.

Results

The SWNT-PEI/DOX/NGR delivery system has significantly sustained-release effect and the slow release of DOX in normal tissues contribute to reduced systemic toxicity, while under 808 nm NIR laser irradiation or under lower pH environment the release of DOX can be accelerated.

Conclusions

Due to hyperthermia sensitizer effect of DOX, chemo-photothermal exemplified by SWNT-PEI/DOX/NGR tumor-targeting delivery system is a promising approach to anticancer therapy in vivo or in vitro.     

Strategy for Cytoplasmic Delivery Using Inorganic Particles

Pharmaceutical Research - Endosome escape is a key process for intracellular uptake of intact biomolecules and therapeutics, such as nucleic acids. Lysosome escape is a more common pathway during...     

局部递药水凝胶用于肿瘤术后治疗的研究进展

目前,手术仍然是大多数恶性实体肿瘤的主要治疗方式。为了防止复发与转移,临床上通常在术后辅以全身化疗或放疗来清除残余的肿瘤细胞,但是这些方案一般都会产生明显的毒副作用,术后患者的顺应性差。局部用药物制剂能经一定给药方式使药物直接定位于术后创面,提高病灶处的药物浓度,从而以更小的剂量有效地防止肿瘤原位复发甚至远端转移,有望成为更理想的术后治疗方案。水凝胶由于良好的生物相容性、可降解性、易于包载多种治疗剂和释药可控等特点,受到了越来越多的关注。综述近几年水凝胶应用于肿瘤术后治疗的研究进展,重点阐述可注射用和喷雾用原位凝胶的原理、特点和代表性研究。展望水凝胶用于术后局部治疗的前景,以期为术后用水凝胶的基础研究、新制剂立项及转化研究提供参考。     

类弹性蛋白聚合物(ELPs)水凝胶的药物控释研究进展

综合国内外文献报道,简要介绍新型刺激响应性水凝胶类弹性蛋白聚合物(ELPs)的性质,并重点阐述其在药物控制释放方面的应用研究。ELPs是一种通过基因工程方法合成的多肽聚合物,其结构由类弹性蛋白的肽段单元重复串连组成。在一定浓度下具有特殊的反向热胶凝性质,即低温时为液体,升温至一定温度时形成凝胶。因其良好的生物相容性、生物可降解性和低免疫原性,ELPs在药物控制释放方面展示了广泛的应用前景。     

In Vitro and In Vivo Study of Gal-OS Self-Assembled Nanoparticles for Liver-Targeting Delivery of Doxorubicin

A liver-targeting drug delivery system for doxorubicin (DOX), that is, DOX-loaded self-assembled nanoparticles based on galactosylated O-carboxymethyl chitosan-graft-stearic acid conjugates (Gal-OS/DOX), has been prepared. The objective of the present study was to investigate the preparation, in vitro release, in vivo pharmacokinetics, and tissue distribution of Gal-OS/DOX nanoparticles. The drug-loaded nanoparticles were spherical in shape with mean size of 181.9 nm. In vitro release profiles indicated that the release of DOX from Gal-OS/DOX nanoparticles behaved with a sustained and pH-dependent drug release. Pharmacokinetics study revealed Gal-OS/DOX nanoparticles exhibited a higher AUC value and a prolonged residence time of drug in the blood circulation than those of DOX solution. Furthermore, Gal-OS/DOX nanoparticles increased the uptake of DOX in liver and spleen, but decreased uptake in heart, lung, and kidney in the tissue distribution study. These results suggested that the Gal-OS/DOX nanoparticles could prolong blood circulation time, enhance the liver accumulation, and reduce the side effect especially the cardiotoxicity of DOX. In conclusion, Gal-OS/DOX nanoparticles could be a promising drug delivery system for liver cancer therapy.     

The Relation Between Swelling Properties and Cross-Linking of Hydrogels Designed for Colon-Specific Drug Delivery

Copolymers of 2-hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAA)-based hydrogels containing 5% and 10% of a cross-linking agent were studied as drug delivery systems. Terephthalic acid was covalently linked with HEMA, abbreviated as CA (cross-linking agent). Free radical cross-linking copolymerization of HEMA and methacrylic acid (MAA) in three different molar ratios, mixed with a particulate 3, 3-azobis (6-hydroxy benzoic acid) (ABHB) as an azo derivative of 5-aminosalicylic acid with the various ratios CA as cross-linking agent were carried out with using 2, 2, Azobisisobutyronitrile as initiator at the temperature range 60–70°C. The compositions of the cross-linked three-dimensional polymers were determined by FTIR spectroscopy. Glass transition temperature of the network polymers was determined calorimetrically. The hydrolysis of drug-polymer conjugates was carried out in cellophane membrane dialysis bags containing an aqueous buffer solution (pH 7.4 and pH 1) at 37°C. The drug-release profiles indicate that the amount of drug release depends on its degree of swelling and cross-linking.