环状RGDs修饰的分子刷型共聚物在成像及药物运输中的应用

以具有丰富接枝侧链的阴离子型共轭聚合物分子刷PFPANa为材料,通过简单的一步修饰法在聚合物的部分接枝侧链上引入靶向配体分子c(RGDyK),并利用分子刷侧链上未修饰配体分子的羧基负离子与抗癌药物DOX静电结合,制备了基于分子刷型共轭聚合物的靶向细胞成像和载药系统.研究结果表明载药系统对DOX药物的载药量可达13.3 wt%,体外细胞实验研究结果表明该载药系统可实现对肿瘤细胞的靶向选择性成像,并显著促进了肿瘤细胞对DOX药物的摄取,具有良好的抗肿瘤细胞生长效果,显著提高了药物运输效率.     

辅以时滞的pH-敏感介孔膦酸锆对双氯芬酸钠的可控结肠靶向释放

以pH-敏感介孔膦酸锆作为药物载体, 选用治疗时辰节律性疾病(风湿性关节炎)的药物双氯芬酸钠作为药物模型, 利用蘸涂的方法对载药的pH-敏感介孔膦酸锆进行时滞膜的包覆, 建立起一个时滞型和pH-敏感型相结合的口服结肠靶向给药系统. 在系统研究pH-敏感介孔膦酸锆对双氯芬酸钠吸附和释放的基础之上, 通过调控时滞膜的厚度控制释放双氯芬酸钠的时滞时间约为6 h. 该给药系统在人工模拟胃液中3 h内完全不释放双氯芬酸钠, 而在人工模拟肠液中最初的3 h(可以看成发生在小肠)所释放的双氯芬酸钠仅为全部释放量的9%, 在之后的46 h内(可以看成发生在结肠)缓慢释放的双氯芬酸钠则占全部释放量的90%以上. 这样, pH-敏感介孔膦酸锆作为新型药物载体与时滞效应相结合, 通过时滞和pH-敏感双重控制实现了治疗时辰节律性疾病药物在结肠的定位释放.     

Copolymers: efficient carriers for intelligent nanoparticulate drug targeting and gene therapy

Copolymers are among the most promising substances used in the preparation of drug/gene delivery systems. Different categories of copolymers, including block copolymers, graft copolymers, star copolymers and crosslinked copolymers, are of interest in drug delivery. A variety of nanostructures, including polymeric micelles, polymersomes and hydrogels, have been prepared from copolymers and tested successfully for their drug delivery potential. The most recent area of interest in this field is smart nanostructures, which benefit from the stimuli-responsive properties of copolymeric moieties to achieve novel targeted drug delivery systems. Different copolymer applications in drug/gene delivery using nanotechnology-based approaches with particular emphasis on smart nanoparticles are reviewed.     

Synthesis and characterization of new copolymers of ethyl methacrylate grafted on tapioca starch as novel excipients for direct compression matrix tablets

In last years, the introduction of new materials for drug delivery matrix tablets has become more important. This paper evaluates the physicochemical and mechanical properties of new graft copolymers of ethyl methacrylate (EMA) on tapioca starch (TS) and hydroxypropylstarch (THS), synthesized by free radical polymerization and dried in a vacuum oven (OD) or freeze-dried (FD). Infrared and ¹³C NMR spectroscopies confirm the change of chemical structure of the copolymers and X-ray diffraction shows up the higher amorphization of copolymers respect to the carbohydrates. Particle size analysis and SEM indicate that graft copolymerization leads to an increase of particle size and a more irregular shape. Graft copolymerization implies decrease of density and moisture content values. Heckel equation shows that copolymers have less densification by particle rearrangement and fragmentation than carbohydrates. Concerning the drying methods, FD products have larger plasticity and lower elasticity than OD copolymers. Graft copolymerization produces a decrease of the applied pressure necessary to obtain tablets, ejection force and friction work. Furthermore, graft copolymers show longer disintegration time than tablets from raw starches. These qualities suggest that these copolymers could be used as excipients in matrix tablets obtained by direct compression, and with a potential use in controlled release.     

Budesonide-Loaded Pectin/Polyacrylamide Hydrogel for Sustained Delivery: Fabrication,Characterization and In Vitro Release Kinetics

A single ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that causes inflammation of the colonic mucosa at the distal colon and rectum. The mainstay therapy involves anti-inflammatory immunosuppression based on the disease location and severity. The disadvantages of using systemic corticosteroids for UC treatment is the amplified risk of malignancies and infections. Therefore, topical treatments are safer as they have fewer systemic side effects due to less systemic exposure. In this context, pH sensitive and enzymatically triggered hydrogel of pectin (PC) and polyacrylamide (PAM) has been developed to facilitate colon-targeted delivery of budesonide (BUD) for the treatment of UC. The hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), swelling ratio, and drug release. FT-IR spectroscopy confirmed the grafting as well loading of BUD in hydrogel. XRD showed the amorphous nature of hydrogel and increment in crystallinity after drug loading. On the other hand, SEM showed that the hydrogels exhibited a highly porous morphology, which is suitable for drug loading and also demonstrated a pH-responsive swelling behaviour, with decreased swelling in acidic media. The in-vitro release of BUD from the hydrogel exhibited a sustained release behaviour with non-ficken diffusion mechanism. The model that fitted best for BUD released was the Higuchi kinetic model. It was concluded that enzyme/pH dual-sensitive hydrogels are an effective colon-targeted delivery system for UC.     

PNIPAM-b-聚碳酸酯温敏胶束的制备及用作药物控制释放载体的研究

以多孔硅球固定化猪胰脂肪酶(IPPL)为催化剂,温敏性HO-PNIPAM为大分子引发剂,5-甲基-5-烯丙氧羰基-三亚甲基碳酸酯(MAC)和5,5-二甲基三亚甲基碳酸酯(DTC)为共聚单体,通过开环聚合合成了不同结构比例的两亲性嵌段型共聚物P(MAC-co-DTC) -b-PNIPAM.该嵌段型共聚物在水中可自组装形成...     

Chloramphenicol collagen sponges for local drug delivery in dentistry

Drug delivery systems based on natural drug carriers have become important due to their non-toxicity and biodegradability. We report here the synthesis and characterization of new biomaterials like sponges containing collagen, chloramphenicol and glutaraldehyde for dentistry. All sponges favour water absorption, showing that increasing the glutaraldehyde content leads to an increase in water uptake. The sponges showed resistance to collagenase degradation and strong activity against the tested bacteria. Kinetic data showed non-Fickian diffusion behaviour with a slow release rate. Taking into account that dental drug delivery systems exhibit low water absorption, slow drug release, high content of drug delivery, good antimicrobial activity, and resistance to enzymatic action, the results obtained in this study indicate the optimal content of glutaraldehyde for the sponge as being 0.5%. The properties of the designed formulations demonstrate that these sponges could be adequate for the treatment and/or the prophylaxis of infected lesions at the dental level.     

Dendritic Polyglycerol‐Derived Nano‐Architectures as Delivery Platforms of Gemcitabine for Pancreatic Cancer

Dendritic polyglycerol‐co‐polycaprolactone (PG‐co‐PCL)‐derived block copolymers are synthesized and explored as nanoscale drug delivery platforms for a chemotherapeutic agent, gemcitabine (GEM), which is the cornerstone of therapy for pancreatic ductal adenocarcinoma (PDAC). Current treatment strategies with GEM result in suboptimal therapeutic outcome owing to microenvironmental resistance and rapid metabolic degradation of GEM. To address these challenges, physicochemical and cell‐biological properties of both covalently conjugated and non‐covalently stabilized variants of GEM‐containing PG‐co‐PCL architectures have been evaluated. Self‐assembly behavior, drug loading and release capacity, cytotoxicity, and cellular uptake properties of these constructs in monolayer and in spheroid cultures of PDAC cells are investigated. To realize the covalently conjugated carrier systems, GEM, in conjunction with a tertiary amine, is attached to the polycarbonate block grafted from the PG‐co‐PCL core. It is observed that pH‐dependent ionization properties of these amine side‐chains direct the formation of self‐assembly of block copolymers in the form of nanoparticles. For non‐covalent encapsulation, a facile “solvent‐shifting” technique is adopted. Fabrication techniques are found to control colloidal and cellular properties of GEM‐loaded nanoconstructs. The feasibility and potential of these newly developed architectures for designing carrier systems for GEM to achieve augmented prognosis for pancreatic cancer are reported.     

Application of solid phase peptide synthesis to engineering PEO–peptide block copolymers for drug delivery

This work describes a simple, versatile solid-phase peptide-synthesis (SPPS) method for preparing micelle-forming poly(ethylene oxide)-block-peptide block copolymers for drug delivery. To demonstrate its utility, this SPPS method was used to construct two series of micelle-forming block copolymers (one of constant core-composition and variable length; the other of constant core length and variable composition). The block copolymers were then used to study in detail the effect of size and composition on micellization. The various block copolymers were prepared by a combination of SPPS for the peptide block, followed by solution–phase conjugation of the peptide block with a proprionic acid derivative of poly(ethylene oxide) (PEO) to form the PEO-b-peptide block copolymer. The composition of each block component was characterized by mass spectrometry (MALDI and ES-MS). Block copolymer compositions were characterized by ¹H NMR. All the block copolymers were found to form micelles as judged by transmission electron microscopy (TEM) and light scattering analysis. To demonstrate their potential as drug delivery systems, micelles prepared from one member of the PEO-b-peptide block copolymer series were physically loaded with the anticancer drug doxorubicin (DOX). Micelle static and dynamic stability were found to correlate strongly with micelle core length. In contrast, these same micellization properties appear to be a complex function of core composition, and no clear trends could be identified from among the set of compositionally varying, fixed length block copolymer micelles. We conclude that SPPS can be used to construct biocompatible block copolymers with well-defined core lengths and compositions, which in turn can be used to study and to tailor the behavior of block copolymer micelles.     

Syntheses of amphiphilic biodegradable copolymers of poly(ethyl ethylene phosphate) and poly(3-hydroxybutyrate) for drug delivery

Biodegradable and amphiphilic triblock copolymers poly(ethyl ethylene phosphate)-poly(3-hydroxy-butyrate)-poly(ethyl ethylene phosphate) (PEEP-b-PHB-b-PEEP) have been successfully synthesized through ring-opening polymerization. The structures are confirmed by gel permeation chromatography and NMR analyses. Crystallization investigated by X-ray diffraction reveals that the block copolymer with higher content of poly(ethyl ethylene phosphate) (PEEP) is more amorphous, showing decreased crystallizability. The obtained copolymers self-assemble into biodegradable nanoparticles with a core-shell micellar structure in aqueous solution, verified by the probe-based fluorescence measurements and transmission electronic microscopy (TEM) observation. The hydrophobic poly(3-hydroxybutyrate) (PHB) block serves as the core of the micelles and the micelles are stabilized by the hydrophilic PEEP block. The size and size distribution are related to the compositions of the copolymers. Paclitaxel (PTX) has been encapsulated into the micelles as a model drug and a sustained drug release from the micelles is observed. MTT assay also demonstrates that the block copolymers are biocompatible, rendering these copolymers attractive for drug delivery. Supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No.20060358036)     

Synthesis and Unusual Swelling Behavior of Combined Cationic/Non‐Ionic Hydrogels Based on Chitosan

Hydrogel‐forming copolymers based on chitosan grafted with different amounts of polyacrylamide were synthesized and its swelling capacity determined in distilled water, sodium chloride solutions, as well as in buffer solutions at pH 1.2 and 8.0. The resulting products are highly efficient as hydrogel‐forming materials with swelling at equilibrium going approximately from 300 to 3 000 times the volume of the dry solid polymer in all the investigated media. The products, different to usual hydrogels, swells considerably more and quickly in electrolyte‐containing solutions compared to in distilled water. This has been attributed to their structure that contains non‐ionic polyacrylamide macromolecules grafted onto the trunk polymer chitosan, which is cationic in nature. In‐vitro drug‐release behavior of formulations containing grafted copolymers have been tested using theophylline as a water‐soluble drug and the results were compared with similar formulations containing unmodified chitosan. It was found that tablets based on formulations containing grafted chitosan show higher erosion and swelling compared with those of the matrix based on unmodified chitosan, leading to a higher fraction of theophylline released. It can be concluded that formulations based on the synthesized copolymers are potentially useful for fluid absorbency and as prolonged drug‐release matrices.

The swelling of one of the hydrogels studied here.     

PEO-PPO-PEO在生物医用材料方面的研究进展

聚氧乙烯-聚氧丙烯-聚氧乙烯三嵌段共聚物因其具有良好的生物相容性和蛋白抗性,近年来在生物医用材料中的应用越来越广泛.聚氧乙烯-聚氧丙烯-聚氧乙烯水溶液具有温度敏感的胶束化和热可逆凝胶化特点,被认为是一种具有许多优点的药物传输载体,药物与胶束的核心结合增加了药物的溶解性、代谢稳定性和体内循环时间.本文对聚氧乙烯-聚氧丙烯-聚氧乙烯在生物医用方面的研究进展进行了综述,并重点介绍了其在药物传输载体,组织工程等方面的研究进展.     

Biopolymer based nanomaterials in drug delivery systems: A review

Drug delivery systems (DDS) are used to achieve a higher therapeutic effects of a pharmaceutical drug or natural compound in a specific diseased site with minimal toxicological effect and these systems consists of liposomes, microspheres, gels, prodrugs and many. Nanotechnology is a rapidly developing multi-disciplinary science that ensures the fabrication of the polymers to nanometer scale for various medical applications. Uses of biopolymers in DDS ensure the biocompatibility, biodegradability and low immunogenicity over the synthetic ones. Biopolymers such as silk fibroins, collagen, gelatin, albumin, starch, cellulose and chitosan can be easily made into suspension that serve as delivery vehicles for both macro and mini drug molecules. There are various methods such as supercritical fluid extraction, desolvation, electrospraying, spray-drying, layer-by-layer self-assembly, freeze-drying and microemulsion introduced to make these DDS. This drug carrier systems enhance the drug delivery actively and can be used in ocular, transdermal, dental or intranasal delivery systems. This review describes the new trends in nanomaterials based drug delivery systems mainly using biopolymers such as proteins (silk fibroin, collagen, gelatin and albumin) and polysaccharides (chitosan, alginate, cellulose and starch).     

Functional Polyion Complex Micelles for Potential Targeted Hydrophobic Drug Delivery

Polyion complex (PIC) micelles have gained an increasing interest, mainly as promising nano-vehicles for the delivery of various hydrophilic charged (macro)molecules such as DNA or drugs to the body. The aim of the present study is to construct novel functional PIC micelles bearing cell targeting ligands on the surface and to evaluate the possibility of a hydrophobic drug encapsulation. Initially, a pair of functional oppositely charged peptide-based hybrid diblock copolymers were synthesized and characterized. The copolymers spontaneously co-assembled in water into nanosized PIC micelles comprising a core of a polyelectrolyte complex between poly(L-aspartic acid) and poly(L-lysine) and a biocompatible mixed shell of disaccharide-modified poly(ethylene glycol) and poly(2-hydroxyethyl methacrylate). Depending on the molar ratio between the oppositely charged groups, PIC micelles varying in surface charge were obtained and loaded with the natural hydrophobic drug curcumin. PIC micelles’ drug loading efficiency, in vitro drug release profiles and antioxidant activity were evaluated. The preliminary results indicate that PIC micelles can be successfully used as carriers of hydrophobic drugs, thus expanding their potential application in nanomedicine.     

Next Generation Multiresponsive Nanocarriers for Targeted Drug Delivery to Cancer Cells

C?H bond activation of 2‐methoxyethylamino‐bis(phenolate)‐yttrium catalysts allowed the synthesis of BAB block copolymers comprised of 2‐vinylpyridine (2VP; monomer A) and diethylvinylphosphonate (DEVP; monomer B) as the A and B blocks, respectively, by rare‐earth‐metal‐mediated group‐transfer polymerization (REM‐GTP). The inherent multi‐stimuli‐responsive character and drug‐loading and ‐release capabilities were observed to be dependent on the chain length and monomer ratios. Cytotoxicity assays revealed the biocompatibility and nontoxic nature of the obtained micelles toward ovarian cancer (HeLa) cells. The BAB block copolymers effectively encapsulated, transported, and released doxorubicin (DOX) within HeLa cells. REM‐GTP enables access to previously unattainable vinylphosphonate copolymer structures, and thereby unlocks their full potential as nanocarriers for stimuli‐responsive drug delivery in HeLa cells. The self‐evident consequence is the application of these new micelles as potent drug‐delivery vehicles with reduced side effects in future cancer therapies.     

Parameter Estimation for Simultaneous Saccharification and Fermentation of Food Waste Into Ethanol Using Matlab Simulink

The increase in waste disposal and energy costs has provided an incentive to convert carbohydrate-rich food waste streams into fuel. For example, dining halls and restaurants discard foods that require tipping fees for removal. An effective use of food waste may be the enzymatic hydrolysis of the waste to simple sugars and fermentation of the sugars to ethanol. As these wastes have complex compositions which may change day-to-day, experiments were carried out to test fermentability of two different types of food waste at 27 degrees C using Saccharomyces cerevisiae yeast (ATCC4124) and Genencor's STARGEN enzyme in batch simultaneous saccharification and fermentation (SSF) experiments. A mathematical model of SSF based on experimentally matched rate equations for enzyme hydrolysis and yeast fermentation was developed in Matlab Simulink. Using Simulink parameter estimation 1.1.3, parameters for hydrolysis and fermentation were estimated through modified Michaelis-Menten and Monod-type equations with the aim of predicting changes in the levels of ethanol and glycerol from different initial concentrations of glucose, fructose, maltose, and starch. The model predictions and experimental observations agree reasonably well for the two food waste streams and a third validation dataset. The approach of using Simulink as a dynamic visual model for SSF represents a simple method which can be applied to a variety of biological pathways and may be very useful for systems approaches in metabolic engineering in the future.     

Versatile Pectin Grafted Poly (N-isopropylacrylamide); Modulated Targeted Drug Release

This study describes synthesis and optimization of pectin grafted poly(N-isopropylacrylamide) hydrogels as vehicles for colon-targeted theophylline model drug release. The gels were prepared in the presence of N, N′–methylenebisacrylamide (MBAA) crosslinker and ceric ammonium nitrate (CAN) initiator under N₂ atmosphere. Optimum conditions, in terms of percent of grafting (%G), were determined as follows: pectin = 1.0 g, [NIPAAm] = 26.51 mM, [MBAA] = 0.65 mM, [CAN] = 0.073 mM, polymerization temperature = 30°C and time = 4.0 h. Hydrogels were characterized by FTIR, TGA, DSC, XRD and SEM. The formed hydrogel did not have a thermo-sensitivity behavior. The in vitro percent drug release was studied in terms of different percent of grafting and different polymerization temperatures under two pH values namely 5.5 and 7.4. Conclusively, the optimum colon-targeted vehicle properties that provide the least drug release at pH5.5 and the most drug release at pH7.4 were as follows: [NIPAAm] = 26.51 mM and [MBAA] = 0.56 mM, polymerization temperature = 30°C and %G = 55.5.     

Structural Characteristics of Semen coicis Resistant Starch and Its Effect on the Proliferation of Bifidobacterium bifidum

Semen coicis resistant starch is a type of starch which has undergone retrogradation. In this study,the structural characteristics of Semen coicis native starch,high-amylose maize starch,and heat-moisture treated Semen coicis resistant starch were investigated. The field emission scanning electron microscopy results indicated that compared to Semen coicis native starch and high-amylose maize starch,the surface of heat-moisture treated Semen coicis resistant starch was rough and full of irregular layered strips. The Fourier transform infrared spectroscopy measurements indicated the degree of ordered structure values of Semen coicis native starch,high-amylose maize starch,and heat-moisture treated Semen coicis resistant starch are 1.355,1.372,and 1.410,respectively,and the degree of double helix values is 1.931,1.942,and 2.027,respectively,indicating that the degree of ordered structure and double helix structure of heat-moisture treated Semen coicis resistant starch is both higher than those of Semen coicis native starch and high-amylose maize starch. ~(13) C nuclear magnetic resonance spectroscopy showed that Semen coicis native starch and high-amylose maize starch exhibited A-type crystal structures,while heat-moisture treated Semen coicis resistant starch displayed B-type crystal structures. The relative crystallinity of Semen coicis native starch,high-amylose maize starch,and heat-moisture treated Semen coicis resistant starch is 76.41,85.36,and 87.25,respectively,and the percentages of amorphous region are 5.78,4.72,and 4.39,respectively. Additionally,heat-moisture treated Semen coicis resistant starch could increase the proliferation of Bifidobacterium bifidum more than Semen coicis native starch or high-amylose maize starch. Bifidobacterium bifidum displayed a higher tolerance under simulated gastrointestinal tract conditions such as low p H,bile acid,pepsin,and trypsin in heat-moisture treated Semen coicis resistant starch medium than in Semen coicis native starch or high-amylose maize starch media.     

RAFT Polymerization for the Synthesis of Tertiary Amine‐Based Diblock Copolymer Nucleic Acid Delivery Vehicles

The synthesis and characterization of a family of nine pH‐responsive, diblock copolymers designed to effectively deliver nucleic acids are reported. The stabilizing A block is comprised of an oligo(ethylene glycol) methyl ether methacrylate to impart water solubility. The cationic blocks of varying degrees of polymerization (DPs) are derived from three pH responsive, tertiary amine‐containing methacrylates capable of complexing negatively charged nucleic acids. The cytotoxicity studies utilizing human embryonic kidney cells (HEK‐293) and Michigan Cancer Foundation‐7 (MCF‐7) breast cancer cells indicate no decrease of cell viability with the diblock copolymers, with the exception of the two highest DPs of the cationic blocks with ethyl‐substitutes tertiary amine. Gene knockdown experiments indicate high siRNA delivery and MYC gene knockdown in MCF‐7 breast cancer cells for eight of the nine studied block copolymers. The results of the current study enable further development of the pH‐responsive copolymer family for promising nucleic acid delivery vehicles applicable for clinical use.     

Novel method to characterize the hydrolytic decomposition of biopolymer surfaces

Present pharmaceutical research is focused on the development, modification and characterisation of new drug delivery systems. Among the many different substances, biodegradable polymers and copolymers are of practical importance, especially if their degradation byproducts are non-toxic. The polymeric drug carriers are not easily wettable by water or aqueous solutions, i.e. they are hydrophobic. This surface hydrophobicity is unfavourable for keeping drug carriers circulating in the blood long enough to release the drug so that it reaches its target. Therefore, copolymers with components of different hydrophobicity were introduced, to make them less hydrophobic and hence more suitable for drug delivery in the human body. Exploratory experiments with one homopolymer, , -poly(lactic acid), , -PLA and two of its copolymers, , -poly(lactic/glycolic acid), and , -PLGA with 85/15 and 50/50 copolymer ratios were carried out. Films of these substances were prepared by dip coating onto hydrophobic and hydrophilic substrates. The changes in wettability of the polymer layers, caused by the direct contact with an aqueous environment (soaking the samples in distilled water), have been studied to model the hydrolytic decomposition of polymer surfaces and to follow the changes in their wettability by dynamic contact angle measurements in a non-destructive manner. It was found that each polymer film became less hydrophobic (dynamic contact angles decreased) and more heterogeneous as the decomposition progressed with time. Increasingly significant decreases in contact angles were observed for the copolymer films containing 15 and 50% glycolic acid, during the 50–80-day-long study. These findings were supported by gel chromatographic analysis of the soaking liquids. It was concluded that the homopolymer layer of , -PLA was the most resistant to hydrolysis and the stability of copolymer films decreased with increasing glycolic acid ratio in the copolymers. This is accordance with the fact that the less crystalline poly(glycolic acid) is more hydrophilic and hence less resistant to hydrolytic decomposition, than the poly(lactic acid). The effect of pH on the rate of hydrolysis of polymer films was also established; the influence of pH on the decomposition was best demonstrated, again, for the copolymer with 50/50 component ratio. The outcome of these experiments showed that the contact angle measuring method enables us to detect, follow and interpret the hydrolytic decomposition of biopolymer substances in a non-invasive manner.