Drug release profiles from and degradation of a novel biodegradable polymer, 2,2-bis(2-oxazoline) linked poly(-caprolactone)

In the present study, poly (epsilon -caprolactone) (PCL) was modified by introducing oxamide groups into PCL (PCL-O). The degradation (decrease in molecular weight) and erosion (weight loss) of PCL and PCL-O films were studied in PBS (pH 7.4, USP XXIV, 37 degrees C, 26 weeks incubation). The release rates of guaifenesin (M(w) 198.2), griseofulvin (M(w) 352.8), timolol (M(w) 332.4), sodium salicylate (M(w) 160.1) and FITC-dextran (M(w) 4400) from PCL and PCL-O preparations (solvent cast films, compression-molded plates, midi injection-molded rods and microparticles) were examined in PBS (pH 7.4, 37 degrees C). The degradation rate of PCL-O film was faster than that of PCL film while no erosion was observed for either film. When compared to the corresponding drug release from PCL films, the release rates of low molecular weight drugs (M(w)< or =352.8) from PCL-O films were comparable, their releases from both films following closely square-root-of-time kinetics. These results indicate that the oxamide groups had no substantial effect on the release of the low molecular weight drugs. The exception was sodium salicylate which was released faster from PCL-O film. However, FITC-dextran release was notably faster from PCL-O microparticles than from those made of PCL. FITC-dextran release was a combination of diffusion and polymer degradation and thus, the faster degradation of PCL-O enhanced the release of FITC-dextran. In conclusion, the effects of the oxamide groups on drug release profiles were dependent on the drug release mechanisms.     

Preparation and in vitro characterization of paclitaxel-loaded pH-responsive polymeric micelles based on poly(2-ethyl-2-oxazoline)-vitamin E succinate

To ensure the delivery of antitumor drugs to tumor site and quick release in tumor cells, we designed and prepared pH-sensitive polymeric micelles by combining cationic ring-opening polymerization of 2-ethyl-2-oxazoline (EOz) with vitamin Esuccinate (VES), and then encapsulating paclitaxel (PTX) into the micelles self-assembled by poly(2-ethyl-2-oxazoline)-vitamin E succinate (PEOz-VES). The structure of the synthesized PEOz-VES was confirmed by ¹H NMR spectrum, and the molecular weight measured by GPC was 1212 g/mol. The pK_a of PEOz-VES with a low critical micelle concentration of (5.84±0.02) mg/L was determined to be 6.01. The PTX-loaded PEOz-VES polymeric micelles prepared by film hydration method were characterized to have a nanoscaled size of about 30 nm in diameter, a positive Zeta potential of 4.86 mV and uniform spherical morphology by TEM observation. The drug loading content and encapsulation efficiency were (2.63±0.16)% and (84.1±3.38)%, respectively. The in vitro release behavior of PTX from PEOz-VES micelles in PBS displayed pH-dependent pattern and was gradually accelerated with decrease of pH value, implying that the micelles could distinguish endo/lysosomal pH and tumor extracellular pH from physiological pH by accelerating drug release. Therefore, the designed PEOz-VES micelles might have significant promise for anti-cancer drug delivery.     

Novel,dynamic on-line analytical separation system for dissolution of drugs from poly(lactic acid) nanoparticles

A novel method for investigating drug release in a dynamic manner from nanoparticles including, but not limited to, biodegradable poly(lactic acid) (PLA) is reported. The PLA nanoparticles were prepared by the nanoprecipitation method. Two poorly soluble drugs, beclomethasone dipropionate (BDP) and indomethacin, were encapsulated into PLA nanoparticles, and their dissolution from the nanoparticles were followed in a dynamic way. The on-line method comprised a short column (vessel) packed with the PLA nanoparticles, on-line connected to an analytical liquid chromatographic column via a multiport switching valve equipped with two loops. The system allowed monitoring of the drug release profiles in real time, and the conditions for the drug release could be precisely controlled and easily changed. The effects of solvent composition and temperature on the rate of dissolution of the drugs from the PLA nanoparticles were investigated. The system proved to be linear for the drugs tested over the concentration range 10–3000 ng (n = 6, R² = 0.999 and 0.997 for indomethacin and beclomethasone, respectively) and repeatable (RSD of peak areas <0.5%). The recoveries of the dissolution study were quantitative (120 and 103% for indomethacin and beclomethasone, respectively).     

脱氧胆酸对胰岛素聚乳酸纳米粒在大鼠小肠吸收的影响

目的 :探讨脱氧胆酸 (DOC)对胰岛素聚乳酸纳米粒 (Ins PLA NP)在小肠吸收的影响。方法 :在正常大鼠小肠分别给予含与不含吸收促进剂DOC的Ins PLA NP后 ,观察降血糖效果。结果 :Ins PLA NP小肠直接给药表现出和缓持久的降血糖效果 ,而DOC在小肠给药中能明显加快Ins PLA NP的吸收并增强药效 ,给药后 0 5h血糖下降至用药前的 (35 49± 6 6 4) % ,显著的降血糖作用可维持 2h左右。结论 :DOC对于Ins PLA NP在小肠部位的吸收具有促进作用     

In vivo toxicity and immunogenicity of wheat germ agglutinin conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles for intranasal delivery to the brain

Biodegradable polymer-based nanoparticles have been widely studied to deliver therapeutic agents to the brain after intranasal administration. However, knowledge as to the side effects of nanoparticle delivery system to the brain is limited. The aim of this study was to investigate the in vivo toxicity and immunogenicity of wheat germ agglutinin (WGA) conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (WGA-NP) after intranasal instillation. Sprague-Dawley rats were intranasally given WGA-NP for 7 continuous days. Amino acid neurotransmitters, lactate dehydrogenase (LDH) activity, reduced glutathione (GSH), acetylcholine, acetylcholinesterase activity, tumor necrosis factor α (TNF-α) and interleukin-8 (IL-8) in rat olfactory bulb (OB) and brain were measured to estimate the in vivo toxicity of WGA-NP. Balb/C mice were intranasally immunized by WGA-NP and then WGA-specific antibodies in serum and nasal wash were detected by indirect ELISA. WGA-NP showed slight toxicity to brain tissue, as evidenced by increased glutamate level in rat brain and enhanced LDH activity in rat OB. No significant changes in acetylcholine level, acetylcholinesterase activity, GSH level, TNF-α level and IL-8 level were observed in rat OB and brain for the WGA-NP group. WGA-specific antibodies in mice serum and nasal wash were not increased after two intranasal immunizations of WGA-NP. These results demonstrate that WGA-NP is a safe carrier system for intranasal delivery of therapeutic agents to the brain.     

乳酸-羟基乙酸共聚物微球的研究进展

通过整理和归纳国内外文献,介绍乳酸-羟基乙酸(PLGA)载药微球的制备方法和作为药物载体的应用。     

Surface modification of poly(lactic acid) nanoparticles by covalent attachment of thiol groups by means of three methods

The aim of the present work was to find a suitable method for the introduction of thiol functions on the surface of poly(DL-lactic acid) (PLA) nanoparticles. Three different approaches were investigated. The modification of the surface involves the activation of PLA carboxylic acid groups followed by the attack of a nucleophile such as cysteine (method #1) or cystamine (method #2 and #3) that provide thiol functions via an amide bond. For the conjugation with cystamine, a second reaction step is required to expose the sulfhydryl function of cystamine that is otherwise protected in a disulfide bond. 1,4-Dithio-DL-threitol (DTT) (method #2) or Tris(2-carboxyethyl)-phosphine hydrochloride (method #3) were evaluated for their ability to reduce this linkage. Method #1 allowed a maximum of 8.5+/-2.8 mmol of thiol functions per mol of PLA to be attached on the surface of the nanoparticles. Method #2 allowed the introduction of a greater number of thiol functions (up to 190+/-15 mmol per mol of PLA). However, this latter method has a major drawback: DTT interacts strongly with the nanoparticle matrix during the reduction step. Method #3 has the advantage over method #2 in that it allowed a significant number of thiol functions to be covalently bound to the particles (up to 107.6+/-0.6 mmol per mol of PLA) without the problem of undesired interaction between DTT and the nanoparticle matrix. The introduction of thiol groups onto the surface of PLA nanoparticles is possible with all three suggested methods. The method #3 provides a straight forward approach for the substitution of carboxylic acid groups with a high number of activated sulfhydryl at the surface of PLA nanoparticles.     

Evaluation of poly(lactic acid) as a biodegradable drug delivery system for parenteral administration

Poly(lactic acid) (PLA) microspheres of 1–10 μm diameter prepared by emulsion deposition and containing entrapped prednisolone released the drug rapidly into an aqueous medium. Similarly sized microparticles prepared by a fusion process exhibited a more prolonged drug release profile and may have potential as a long-acting parenteral delivery system. Both methods of fabricating the polymer produced material which was cytotoxic when phagocytosed by mouse peritoneal macrophages. The intracellular toxicity and hence potential irritancy in vivo was only partially overcome by incorporating anti-inflammatory drug. Compressed implants of the same polymers containing prednisolone 10% w/w (100 mg·cm⁻³) and weighing 12 mg were readily administered and sustained the delivery of the drug for over 30 days without complications at the implantation site.     

In vivo evaluation of thiolated poly(acrylic acid) as a drug absorption modulator for MRP2 efflux pump substrates

Recently, several polymers have been reported to modulate drug absorption by inhibition of intestinal efflux pumps such as multidrug resistance proteins (MRPs) and P-glycoprotein (P-gp). The aim of the present study was to evaluate the efficiency of thiolated poly(acrylic acid) (PAA-Cys) to act as a drug absorption modulator for MRP2 efflux pump substrates in vivo, using sulforhodamine 101 as representative MRP2 substrate. In vitro, the permeation-enhancing effect of unmodified PAA and PAA₂₅₀-Cys_, displaying 580 μmol free thiol groups per gram polymer, was evaluated by using freshly excised rat intestinal mucosa mounted in Ussing-type chambers. In comparison to that of the buffer control, the sulforhodamine 101 transport in the presence of 0.5% unmodified PAA₂₅₀ and 0.5% (w/v) PAA₂₅₀-Cys was 1.3- and 4.0-fold improved, respectively. In vivo, sulforhodamine 101 solutions containing 4% (w/v) unmodified PAA₂₅₀ or 4% (w/v) thiolated PAA₂₅₀ were orally given to rats. The PAA₂₅₀-Cys solution increased the area under the plasma concentration-time curve (AUC_0-12) of sulforhodamine 101 3.8-fold in comparison to control and 2.2-fold in comparison to unmodified PAA₂₅₀. This in vivo study revealed that PAA₂₅₀-Cys significantly increased the oral bioavailability of MRP2 substrate sulforhodamine 101.     

Folate-modified poly(2-ethyl-2-oxazoline) as hydrophilic corona in polymeric micelles for enhanced intracellular doxorubicin delivery

The transmembrane transport of drug loaded micelles to intracellular compartment is quite crucial for efficient drug delivery. In the current study, we investigated the cellular internalization and anticancer activity of doxorubicin loaded micelles with folate modified stealthy PEOz corona. Folate-decorated micelles incorporating doxorubicin were characterized for particle size, degree of folate decoration, drug loading content and encapsulation efficiency, morphology, and surface charge. The targeting capability and cell viability were assessed using HeLa, KB, A549 and MCF-7/ADR cell lines. In vitro study clearly illustrated the folate receptor (FR) mediated targeting of FA modified micelles to FR-positive human HeLa, KB and MCF-7/ADR cells, while specific delivery to FR-negative A549 cells was not apparently increased at the same experimental conditions. Cytotoxicity assay showed 60% and 58% decrease in IC₅₀ values for HeLa and KB cells, while only a slight decrease for A549 cells, following treatment with folate modified formulations. The enhanced intracellular delivery of FA modified micelles in MCF-7/ADR cells was also observed. In vivo antitumor tests revealed DOX entrapped FA-PEOz-PCL micelles effectively inhibited the tumor growth and reduced the toxicity to mice compared with free DOX. The current study showed that the targeted nano-vector improved cytotoxicity of DOX and suggested that this novel PEOz endowed stealthy micelle system held great promise in tumor targeted therapy.     

卡莫氟-聚乳酸纳米纤维缓释体系的制备及体外缓释性能

目的：以聚乳酸纳米纤维为载体,制备卡莫氟-聚乳酸纳米纤维药物缓释体系,研究其体外药物释放性能.方法：用静电纺丝制备卡莫氟-聚乳酸纳米纤维药物缓释体系,用紫外分光光度法研究药物的在37℃模拟体液中的释放性能.结果：溶剂不同,纤维的形貌有很大差别;纳米纤维体外药物释放速度也大不相同,缓释曲线符合Higuchi方程.结论：随着溶液的导电性和介电常数的增加,静电纺丝纤维的直径明显变小,纤维表面也逐渐光滑;纳米纤维的形貌对体外药物释放速度有较大影响.     

Preparation and evaluation of 188Re sulfide colloidal nanoparticles loaded biodegradable poly (L‐lactic acid) microspheres for radioembolization therapy

Radioembolization with radioactive microspheres has been an effective method for the treatment of liver lesions. The aim of this study was to prepare carrier‐free ¹⁸⁸Re loaded poly (L‐lactic acid) (PLLA) microspheres through ¹⁸⁸Re sulfide colloidal nanoparticles (¹⁸⁸Re‐SC nanoparticles). The formation of ¹⁸⁸Re‐SC nanoparticles was confirmed by ultraviolet‐visible spectrophotometry. The labeling yield of ¹⁸⁸Re‐SC nanoparticles was verified using the RTLC method. Effects of synthesis parameters on morphology and size of prepared ¹⁸⁸Re‐sulfide colloidal‐PLLA microspheres (¹⁸⁸Re‐SC‐PLLA microspheres) were studied by scanning electron microscopy. In vitro stability of ¹⁸⁸Re‐SC‐PLLA microspheres was investigated in normal saline at room temperature and in human serum at 37°C. In vivo distribution studies and gamma camera imaging were performed in healthy BALB / c mice. The microspheres could be prepared with sizes between 13 and 48 μm (modal value 29 μm) and radiolabeling efficiency >99%. After incubation, the microspheres were found stable in vitro up to 72 hours. The biodistribution after intravenous injection in healthy BALB / c mice showed high accumulation in lung as a first capture pathway organ for microsphere followed by great retention over 48 hours for these microspheres. These data show that ¹⁸⁸Re‐SC‐PLLA microspheres are suitable candidate for clinical studies.     

Intravenous fate of poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes

The objective of this study was to assess the in vivo fate of poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-based polyplexes after intravenous administration into mice. Circulation kinetics and tissue distribution in terms of plasmid localization and transfection efficiency were assessed. To gain more insight into the observed biodistribution and gene expression profile, the interaction of pDMAEMA-based polyplexes with blood components (erythrocytes and albumin) was investigated in vitro. In the case of i.v. injection of positively charged polyplexes at a dose of 30 microg DNA most of the radioactivity was found in the lungs and the liver 60 min after injection. In the case of pDMAEMA/DNA polyplexes with a negative charge, uptake occurred mainly by the liver. Administration of positively charged complexes at a 30 microg DNA dose resulted in reporter gene expression primarily in the lungs. Injection of negatively charged complexes and naked plasmid did not result in luciferase expression in any of the organs examined. In vitro turbidity experiments showed the induction of a charge dependent aggregation process upon addition of albumin to the polyplexes pointing out to the involvement of aggregate formation in the dominant lung uptake of the positively charged polyplexes. Also, incubations of polyplexes after pre-incubation with a physiological concentration of albumin with washed erythrocytes confirmed that polyplexes induce the formation of extremely large structures. This paper underlines the need for the design of systems with reduced interaction with blood components to promote the delivery of DNA to target tissues outside the lungs.     

Synthesis of redox derivatives of lysine and related peptides containing phenothiazine or tris(2,2′-bipyridine)ruthenium(II)

Boc-l -Lysine derivatives and lysine-containing peptides bearing the electron donor 10H-phenothiazine (PTZ) or the redox chromophore tris(2,2′-bipyridine)ruthenium(II) dication ([Rub₃,]^2H, where b is 2,2-bipyridine) have been synthesized and characterized. SeO₂ oxidation (53% yield) of 4,4′-dimethyl-2,2′-bipyridine, Ag_2:O oxidation (85% yield) of the monoaldehyde, complexation (96% yield) of 4′-methyl-2,2′-bipyridine-4-carboxylic acid (m-OH) with Rub₂Cl_2:. activation (81% yield) of the acid [Rub₂m-OH]²⁺ (PF₆^?)₂, and condensation (83% yield) of the succinimido ester [Rub₂m-OSu]²⁺ (PF₆^?)₂ with Boc-Lys furnished the protected redox-chromophore module [Boc-Lys(Rub₂m)-OH]²⁺(PF₆^?)₂ in 29% overall yield over five steps. The first two steps constitute the first practical synthesis of the monocarboxylic acid m-OH (45% overall yield). Also prepared were m-OSu, Boc-Lys(m)-OH, Boc-Lys(m)-OCH₃, and [Rub₂m-NHCH₃]²⁺ (PF₆^?)_2:. Activation (91% yield) of 3-(10H-phenothiazine-10)propanoic acid (PTZpn-OH) and condensation (92% yield) of the succinimido ester PTZpn-OSu with Boc-Lys furnished the protected electron-donor module Boc-Lys(PTZpn)-OH (84% overall yield). The latter was used in solid-phase syntheses of two redox tripeptides. CH₃CO-Ala-Lys(PTZpn)-Ala-OH and [Rub₂m-Ala-Lys(PTZpn)-Ala-OH]² (PF₆^?)₂. The electrochemical properties of these redox amino acids and peptides were similar to those of PTZpn-OH, [Rub₂ m-OH]2⁺(PF₆)₂. or [Rub₂ m-NHCH₃]²⁺ (PF₆^?)₂. Lys(PTZpn). [Lys(Rub₂m)]²⁺ (PF₆)_2:. and other redox modules may be useful for engineering light-harvesting proteins, photovoltaic cells, and other molecular electronic devices.     

Neomycin-loaded poly(styrene sulfonic acid-co-maleic acid) (PSSA-MA)/polyvinyl alcohol (PVA) ion exchange nanofibers for wound dressing materials

In this study, poly(styrene sulfonic acid-co-maleic acid) (PSSA-MA) blended with polyvinyl alcohol (PVA) was electrospun and then subjected to thermal crosslinking to produce PSSA-MA/PVA ion exchange nanofiber mats. The cationic drug neomycin (0.001, 0.01, and 0.1%, w/v) was loaded onto the cationic exchange fibers. The amount of neomycin loaded and released and the cytotoxicity of the fiber mats were analyzed. In vivo wound healing tests were also performed in Wistar rats. The results indicated that the diameters of the fibers were on the nanoscale (250 ± 21 nm). The ion exchange capacity (IEC) value and the percentage of water uptake were 2.19 ± 0.1 mequiv./g-dry fibers and 268 ± 15%, respectively. The loading capacity was increased upon increasing the neomycin concentration. An initial concentration of 0.1% (w/v) neomycin (F3) showed the highest loading capacity (65.7 mg/g-dry fibers). The neomycin-loaded nanofiber mats demonstrated satisfactory antibacterial activity against both Gram-positive and Gram-negative bacteria, and an in vivo wound healing test revealed that these mats performed better than gauze and blank nanofiber mats in decreasing acute wound size during the first week after tissue damage. In conclusion, the antibacterial neomycin-loaded PSSA-MA/PVA cationic exchange nanofiber mats have the potential for use as wound dressing materials.     

姜黄素PLGA纳米粒的制备及制剂学性质分析

目的制备姜黄素(Curcumin,Cur)聚乳酸羟基乙酸共聚物(PLGA)纳米粒(Cur-PLGA-NPs)并对其理化性质进行考察。方法采用改良的自乳化溶剂挥发法制备纳米粒,通过正交设计,以粒径、包封率和载药量为评价指标优化处方工艺。结果制备Cur-PLGA-NPs的优化条件为PLGA 100 mg,泊洛沙姆188浓度1.0%,丙酮与乙醇体积比3∶1,有机相体积15 m L。按优化条件所制备的Cur-PLGA-NPs粒径为(120.33±2.44)nm,多分散系数为0.10±0.02,包封率为84.50%±1.13%,载药量为4.75%±0.22%。结论采用改良的自乳化溶剂挥发法成功制备了Cur-PLGA-NPs,为后续"纳米粒-脂质体系统"的研究奠定了基础,有望实现药物在肝脏的浓集。     

雷公藤甲素聚乳酸纳米粒对大鼠睾丸组织的影响

目的　观察采用聚乳酸纳米粒能否减轻雷公藤甲素的大鼠睾丸毒性。方法　雄性Wistar大鼠分别ig 0 .2及 0 .6mg·kg- 1雷公藤甲素 (非纳米粒组 )及其聚乳酸纳米粒混悬液 (纳米粒组 ) ,连续给药 15d ,以ig生理盐水的大鼠为对照组 ,测定睾丸的脏器系数及其组织匀浆液中酸性磷酸酶 (ACP)活性和果糖含量 ,光镜观察睾丸组织的病理学变化。结果在 0 .6mg·kg- 1剂量下 ,非纳米粒组睾丸ACP活性和果糖的含量均明显低于纳米粒组 (P <0 .0 5 )。光镜观察显示 ,雷公藤甲素 0 .6mg·kg- 1可引起大鼠睾丸的损伤 ,非纳米粒组引起的病变程度明显重于纳米粒组 ,主要表现为睾丸萎缩 ,各级生精细胞变性、坏死、数量减少或消失 ,出现了多核巨细胞。结论以聚乳酸作为药物载体的纳米体系 ,可明显减轻雷公藤甲素对睾丸的毒性     

Controlled transdermal iontophoresis of sulfosalicylic acid from polypyrrole/poly(acrylic acid) hydrogel

A conductive polymer–hydrogel blend between sulfosalicylic acid-doped polypyrrole (PPy) and poly(acrylic acid) (PAA) was used as a carrier/matrix for the transdermal drug delivery under applied electrical field. PAA films and the blend films were prepared by solution casting with ethylene glycol dimethacrylate (EGDMA) as a cross-linking agent, followed by the blending of PPy particles and the PAA matrix. The effects of cross-linking ratio and electric field strength on the diffusion of the drug from PAA and PPy/PAA hydrogels were investigated using a modified Franz-diffusion cell with an acetate buffer of pH 5.5 and at 37 °C, for a period of 48 h. The diffusion coefficient of the drug is calculated using the Higuchi equation, with and without an electric field, at various cross-linking ratios. The drug diffusion coefficient decreases with increasing drug size/mesh size ratio, irrespective of the presence of the conductive polymer as the drug carrier. The diffusion coefficient, at the applied electric field of 1.0 V, becomes larger by an order of magnitude relative to those without the electric field.     

聚(2-乙基丙烯酸)脂肪酰胺衍生物构建的酸敏脂质体

本实验合成了系列聚(2-乙基丙烯酸)长链脂肪酰胺衍生物，并采用高分子插入法制备了聚(2-乙基丙烯酸)酸敏高分子脂质体。应用荧光指示剂、粒径仪、荧光显微镜及细胞实验，系统研究了高分子修饰和脂肪胺的链长对高分子衍生物嵌入脂质体的效率和质量的影响。结果表明，高分子插入法可以制备聚(2-乙基丙烯酸)酸敏高分子脂质体。(1) 高分子嵌入量与高分子脂肪胺的链长无关，但与高分子修饰度相关。(2) 高分子嵌入量与起始的高分子-脂质体比例成正比。(3) 在酸性条件下聚(2-乙基丙烯酸)脂质体可产生显著的脂质体融合及释药行为。(4) 聚(2-乙基丙烯酸)脂质体在细胞内呈现出良好的酸敏诱导释药特性。实验证明这种方法制备的脂质体具有良好的酸敏释药性能，并且制备方法简便，可控性好，实用性强。