AIE-Featured Redox-Sensitive Micelles for Bioimaging and Efficient Anticancer Drug Delivery

In the present study, an amphiphilic polymer was prepared by conjugating methoxy poly(ethylene glycol) (mPEG) with tetraphenylethene (TPE) via disulfide bonds (Bi(mPEG-S-S)-TPE). The polymer could self-assemble into micelles and solubilize hydrophobic anticancer drugs such as paclitaxel (PTX) in the core. Combining the effect of TPE, mPEG, and disulfide bonds, the Bi(mPEG-S-S)-TPE micelles exhibited excellent AIE feature, reduced protein adsorption, and redox-sensitive drug release behavior. An in vitro intracellular uptake study demonstrated the great imaging ability and efficient internalization of Bi(mPEG-S-S)-TPE micelles. The excellent anticancer effect and low systemic toxicity were further evidenced by the in vivo anticancer experiment. The Bi(mPEG-S-S)-TPE micelles were promising drug carriers for chemotherapy and bioimaging.     

壳聚糖/银复合纳米凝胶的制备及其抗肿瘤药物递送研究

本研究通过自组装技术将N,N'-双(丙烯酰)胱胺接枝到到纳米银粒子表面,得到双键修饰的纳米交联剂(bAG),然后采用双乳液法将bAG掺杂到壳聚糖纳米乳中,通过迈克尔加成反应使bAG表面双键与壳聚糖活性胺基原位交联形成掺杂纳米银的壳聚糖基纳米凝胶。该纳米凝胶可有效装载抗肿瘤药物阿霉素(包封率93%),所负载药物可在微酸性和还原性肿瘤微环境下实现响应性释放。     

Studies on Glutaraldehyde Crosslinked Chitosan Hydrogel Properties for Drug Delivery Systems

Chitosan was crosslinked with different amount of glutaraldehyde to prepare appropriate hydrogels to be used as drug delivery system. The swelling behavior of freeze-dried hydrogels in aqueous media at different temperature and pHs has been examined. The swelling, porosity and biocompatibility behavior of samples were investigated to check effects of polymer/polymer and polymer/drug interactions on these system characteristics. Obtained experimental results illustrates that with increasing crosslinking agent from 0.068 to 0.30, swelling of the prepared samples degrees from 1200% to 600% and pore diameters change from 100 to 500 µm. To investigate systems biocompatibility in gastric conditions, effects of crosslinker concentration on the pepsin enzyme activity have been studied using variation of relative viscosity of the system. Presented results also show that with increasing crosslinker agent concentration activity of enzyme reduces considerably and so crosslinker molar ratio to amine functional groups of chitosan must be less than 0.2.     

Imaging‐Guided pHe and Glutathione Dual Responsive Polypeptide Nanogel for Smart Drug Delivery

A negatively charged polypeptide nanogel, near‐infrared (NIR) cyanine dye (Cy5.5) conjugated and 2,3‐dimethylmaleic anhydride (DMA) modified poly‐l ‐lysine‐co‐l ‐cystine (CDPLC), is synthesized and is used as an imaging‐guided sequential drug delivery system. The CDPLC nanogel can respond to two general stimulations in sequence: extracellular tumor acidic microenvironment pHe (6.8–6.5) and intracellular high concentration glutathione (GSH). Under pHe, the DMA shell of the nanogel is removed and a charge reversal takes place, resulting in positively charged nanogel which can be internalized by cancer cells easily. Once internalized into tumor cells, the increased intracellular GSH concentration further promotes DOX release from the nanogel and DOX is enriched to the nucleus. Cy5.5 is conjugated to the nanogel as an NIR fluorescent probe, making it possible for imaging‐guided drug delivery, which is confirmed by the MTT and confocal laser scanning microscopy via in vitro experiments. The as‐prepared nanogel is a potential theranostic for cancer therapy.     

Apoferritin Modified Magnetic Particles as Doxorubicin Carriers for Anticancer Drug Delivery

Magnetic particle mediated transport in combination with nanomaterial based drug carrier has a great potential for targeted cancer therapy. In this study, doxorubicin encapsulation into the apoferritin and its conjugation with magnetic particles was investigated by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). The quantification of encapsulated doxorubicin was performed by fluorescence spectroscopy and compared to CE-LIF. Moreover, the significant enhancement of the doxorubicin signal was observed by addition of methanol into the sample solution.     

温敏凝胶原位植入给药系统的研究进展

采用温敏凝胶的原位给药系统是理想的长效给药系统。该文从凝胶材料和给药系统的制备、凝胶的机体反应和体内降解以及药物控释三方面,综述了该给药系统的研究进展,总结了关键技术和科学问题,分析了面临的挑战与解决途径。水凝胶网络的不规则形态和较低的机械强度,其植入后引起的机体炎性反应、组织融合与水分快速流失及这些反应造成的凝胶网络结构和降解速率的个体差异性变化,是控制药物释放的主要困难。通过提高凝胶表面亲水性,降低其表面正电荷,或在其表面修饰抗炎性多肽,可减轻炎性作用、减缓组织融合;通过与亲水性高分子形成共混凝胶或互穿凝胶网络以及共价交联等方式,可提高凝胶强度,保持凝胶网络的空间结构和水分;通过在凝胶表面建立扩散屏障、加强药物和凝胶骨架的相互作用、构建微粒/原位凝胶复合释药系统等技术,可进一步改善药物释放特征。     

A Novel Stimuli-Responsive Magnetite Nanocomposite as De Novo Drug Delivery System

A novel stimuli-responsive magnetite nanocomposite as de novo drug delivery system for cancer chemotherapy is developed successfully through the incorporation of magnetite nanoparticles into PEG-b-(PNIPAAm-b-PAA)₂ copolymer. The chemical structures of samples were characterized using FTIR and ¹H NMR spectroscopies. Furthermore, thermal property, morphology, size, and magnetic properties of the nanocomposite were investigated. The DOX loading and encapsulation efficiencies as well as stimuli-responsive drug release ability of the nanosystem were studied. As results, at pH 5.3 and temperature of 41°C the nanocomposite exhibited higher drug release values, which qualified it for cancer chemotherapy according to especial features of cancerous tissue.     

姜黄素衍生物及其递药系统的抗癌活性新进展

姜黄素具有抗炎、抗癌、抗氧化及抗纤维化等多种药理作用.主要从三个方面展开综述:近年来姜黄素衍生物的合成及抗癌活性研究进展;近年来姜黄素新型递药系统的研究进展;姜黄素辅助用于临床抗癌联合用药的应用研究.     

PMMA/PHEA Interpenetrating Network Embedded With Iron Oxide Nanoparticles for Drug Delivery Applications

Semi-interpenetrating polymer networks (IPNs) are prepared from poly methyl methacrylate and 2-hydroxy ethyl acrylate networks with the presence of super-paramagnetic ferric oxide nanoparticles (<30 nm) through free radical polymerization. PMMA/PHEA semi-IPNs having blend ratio 60:40, 50:50, 40:60 (wt/wt) are characterized with respect to swelling, crosslink density, FTIR, DSC, TGA, SEM, and drug loading and drug release properties. Bactericidal effect on IPNs is checked by cell growth study of E. coli.     

Use of Self-Assembled Colloidal Prodrug Nanoparticles for Controlled Drug Delivery of Anticancer,Antifibrotic and Antibacterial Mitomycin

Herein we present the synthesis of a polymeric prodrug nanomaterial capable of spontaneous, self-assembled nanoparticle formation and of the conjugation (encapsulation) of drugs with amino and/or carboxyl and/or hydroxyl groups via ester and/or amide linkage. Mitomycin C (MMC) a versatile drug with antibiotic, antibacterial and antineoplastic properties, was used to prove this concept. The in vitro drug release experiments showed a fast release for the pure MMC (k = 49.59 h⁻ⁿ); however, a significantly lower MMC dissolution rate (k = 2.25, 1.46, and 1.35 h⁻ⁿ) was obtained for the nanoparticles with increased cross-link density (3, 10, 21%). The successful modification and conjugation reactions were confirmed using FTIR and EDX measurements, while the mucoadhesive properties of the self-assembled particles synthesized in a simple one-pot reaction were proved by rheological measurement. The prepared biocompatible polymeric prodrugs are very promising and applicable as a drug delivery system (DDS) and useful in the area of cancer treatment.     

温敏凝胶原位植入给药系统：进展与挑战

采用温敏凝胶的原位给药系统是理想的长效给药系统。本文从凝胶材料和给药系统的制备、凝胶的机体反应和体内降解以及药物控释三方面,综述了该给药系统的研究进展,总结了关键技术和科学问题,分析了面临的挑战与解决途径。水凝胶网络的不规则形态和较低的机械轻度,其植入后引起的机体炎性反应、组织融合与水分快速流失及这些反应造成的凝胶网络结构和降解速率的个体差异性变化,是控制药物释放的主要困难。通过提高凝胶表面亲水性,降低其表面正电荷,或在其表面修饰抗炎性多肽,可减轻炎性作用、减缓组织融合;通过与亲水性高分子形成共混凝胶或互穿凝胶网络,以及共价交联等方式,可提高凝胶强度,保持凝胶网络的空间结构和水分;通过在凝胶表面建立扩散屏障、加强药物和凝胶骨架的相互作用、构建微粒/原位凝胶复合释药系统等技术,可进一步改善药物释放特征。     

A Carbodiimide Cross-Linked Silk Fibroin/Sodium Alginate Composite Hydrogel with Tunable Properties for Sustained Drug Delivery

Carbodiimide cross-linked silk fibroin (SF)/sodium alginate (SA) composite hydrogels with superior stability and tunable properties are developed by varying preparation parameters. SF/SA blend ratio modulation allows to achieve composite hydrogel gelation times of 18–65 min, and rheological analysis shows that the speed of gel formation, the hydrogel network's density, and the hydrogels’ compressive properties are closely related to the blend ratio. The G′ of different hydrogels varies substantially from 28 to 413 Pa, and the hydrogel with higher SF content has a greater stiffness. The composite hydrogels present appropriate porosity of 76.63–85.09% and pore size of 316–603 µm. Hydrogel stability improves significantly after cross-linking, and substantial swelling occurs due to the hydrophilicity of SA. The 7/3 and 6/4 SF/SA hydrogels are more resistant to degradation in PBS, and cytotoxicity testing confirmed their biocompatibility. For release studies in vitro, two model compounds are used as drug models, tetracycline hydrochloride, and bovine serum albumin (BSA). Different ratios of SF/SA have a greater influence on the release of BSA. This study provides a practical preparation method for flexible SF/SA composite hydrogels, which can help design hydrogels with specific physicochemical properties for different applications, especially drug delivery.     

Radiation Synthesis of Polyampholytic and Reversible pH-Responsive Hydrogel and Its Application as Drug Delivery System

Graft copolymerization of acrylic acid (AA) and acrylamide (AAm) onto chitosan (CS) was carried out using gamma irradiation. Their swelling behavior was investigated. The hydrogels before and after alkaline hydrolysis were confirmed by FTIR spectroscopic studies. The hydrogels show ampholytic and reversible pH-responsiveness characteristics. The swelling variations were explained according to swelling theory based on the hydrogel chemical structure. The ability of the prepared copolymer to be used as gastric antibiotic delivery system was estimated using amoxicillin trihydrate as a model drug. Release of amoxicillin trihydrate from these investigated hydrogels was studied. For non-ionized drugs, such as amoxicilin trihydrate, the electrostatic polymer/ polymer interactions take place between the cationic groups from CS and the anionic ones from PAA resulting in entrapping the drug into the mesh space of the hydrogel. The non-ionized amoxicillin release was controlled by the swelling/eroding ratio.     

HPMC/PNIPAAm温度敏感性水凝胶的制备及其对5-氟尿嘧啶的控制释放

以线型的羟丙基甲基纤维素(HPMC)和N-异丙基丙烯酰胺 (NIPAAm) 为原料,制备具有温度敏感性的半互穿网络水凝胶.采用荧光显微镜、红外光谱等对凝胶结构进行表征,并对不同HPMC / NIPAAm配比(W/W)的水凝胶的温度敏感性、溶胀和退溶胀动力学进行了研究.另外,以5-氟尿嘧啶(5-FU)为目标化合物,研究了...     

Carbohydrate-based Biomedical Copolymers for Targeted Delivery of Anticancer Drugs

A variety of strategies and carrier molecules have been used to direct therapeutic agents to tumor sites. The incorporation of a specific targeting moiety to drug carrier may result in active drug uptake by malignant cells. Carbohydrates are important mediators of cell–cell recognition events and have been implicated in related processes such as cell signaling regulation, cellular differentiation, and immune response. The biocompatibility of carbohydrates and their ability to be specifically recognized by cell-surface receptors indicate their potential utility as ligands in targeted drug delivery for therapeutic applications. Yet, carbohydrates are not ideal targeting ligands because they are difficult to synthesize, bind weakly to carbohydrate receptors, and are prone to suffer from enzyme degradation due to labile glycosidic linkages. This review describes the design and development of HPMA-based biomedical copolymers to facilitate the selective delivery of drugs to tumor tissues via carbohydrate–endogenous lectin interactions. Various carbohydrate-decorated HPMA copolymer–drug conjugates are presented and the application of the copolymers for drug delivery is discussed. Current efforts to increase the affinity of carbohydrate ligands for their target receptors through multivalent display are also discussed. These novel HPMA copolymer carbohydrate conjugates hold promise as clinically relevant drug delivery systems for cancer therapy.     

Macrocyclic Amphiphiles for Drug Delivery

Nanoparticles are the most crucial part of nanomedicine and various kinds of nanoparticles have been developed for drug delivery. As a new kind of nanoparticles, macrocyclic amphiphiles are gaining more and more attention in the field of nanomedicine due to their intrinsic features of molecular recognition and robust assembly. In this review, we summarized the reported works of drug delivery using macrocyclic amphiphiles, including cyclodextrin, calixarene, cucurbituril and pillararene species. These macrocyclic amphiphiles, serving as a new matrix of nanomedicine, can enhance drug solubility, improve drug stability, selectively deliver drugs to disease both in vitro and in vivo.     

Characterization and Application of Intercalated Montmorillonite with Verapamil and its Polymethyl Methacrylate Nanocomposite in Drug Delivery

This work examined two drug delivery systems: the first system studied the adsorption of Verapamil hydrochloride drug into montmorillonite clay (MMT) by intercalation process to prepare MMT-Verapamil hybrid at different intercalating time, temperatures, pH values and initial drug concentrations. The second system includes the preparation of MMT-Verapamil hybrid combined with polymethyl methacrylate via an emulsion polymerization process to produce a novel nanocomposite material to be used in drug delivery. The polymerization process was carried out using an ultrasonic technique to achieve a biologically safe drug delivery system. Best conditions for the intercalation of verapamil hydrochloride drug into the interlayer of MMT clay were found to be at 50°C and 1 hr using pH ranges of 4–6. The prepared MMT-Verapamil hybrid and the produced MMT-verapamil-MMA nanocomposite material were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM) and thermal gravimetric analysis (TGA). The in-vitro release profile of Verapamil in the case of a drug hybrid is faster than the release in the case of a drug nanocomposite in both gastric and intestinal fluids where, in the case of gastric fluid (pH 1.2), about 40% of the loaded drug was released from the drug hybrid in the first 4 h against only 37% in 5 h in the case of drug nanocomposite. Also in the intestinal fluid (pH 7.4), the verapamil release from drug hybrid reached 68% in 5 h against only 57% was released from drug nanocomposites in 7 h.     

抗癌药递药有机纳米载体

近年来,癌症研究的热点已经转移到研究化学治疗药新型纳米载体上来。有机纳米载体如脂质体和微胶粒,有着低毒性和多样性(运送多种药物和偶联物到靶点)的优点。这为治疗和诊断结和起来(治疗诊断学)提供了可能。已经成功应用这种纳米形式的经典化疗药物大多是脂溶性药物、小干扰RNA、生物制剂和特异性纳米球。脂质体和微胶粒利用了实质性肿瘤表面高通透性和表面张力,提高了药物在靶区域的聚集(被动打靶)。这在临床上表现为脂质体类药物剂型表现出高药效和低副作用的优点。联合给药和复合治疗方案如辐射、热疗促进药物在靶点从纳米载体释放大多还在临床前研究阶段。更复杂的治疗形式为同时引入治疗药、靶向剂及显影剂,这方面的制剂也在体外实验模型中取得了较好的结果。     

Controlled Liposome Delivery from Chitosan-Based Thermosensitive Hydrogel for Regenerative Medicine

This work describes the development of an injectable nanocomposite system based on a chitosan thermosensitive hydrogel combined with liposomes for regenerative medicine applications. Liposomes with good physicochemical properties are prepared and embedded within the chitosan network. The resulting nanocomposite hydrogel is able to provide a controlled release of the content from liposomes, which are able to interact with cells and be internalized. The cellular uptake is enhanced by the presence of a chitosan coating, and cells incubated with liposomes embedded within thermosensitive hydrogels displayed a higher cell uptake compared to cells incubated with liposomes alone. Furthermore, the gelation temperature of the system resulted to be equal to 32.6 °C; thus, the system can be easily injected in the target site to form a hydrogel at physiological temperature. Given the peculiar performance of the selected systems, the resulting thermosensitive hydrogels are a versatile platform and display potential applications as controlled delivery systems of liposomes for tissue regeneration.     

Hybrid Nanoparticles and Composite Hydrogel Systems for Delivery of Peptide Antibiotics

The growing number of drug-resistant pathogenic bacteria poses a global threat to human health. For this reason, the search for ways to enhance the antibacterial activity of existing antibiotics is now an urgent medical task. The aim of this study was to develop novel delivery systems for polymyxins to improve their antimicrobial properties against various infections. For this, hybrid core–shell nanoparticles, consisting of silver core and a poly(glutamic acid) shell capable of polymyxin binding, were developed and carefully investigated. Characterization of the hybrid nanoparticles revealed a hydrodynamic diameter of approximately 100 nm and a negative electrokinetic potential. The nanoparticles demonstrated a lack of cytotoxicity, a low uptake by macrophages, and their own antimicrobial activity. Drug loading and loading efficacy were determined for both polymyxin B and E, and the maximal loaded value with an appropriate size of the delivery systems was 450 µg/mg of nanoparticles. Composite materials based on agarose hydrogel were prepared, containing both the loaded hybrid systems and free antibiotics. The features of polymyxin release from the hybrid nanoparticles and the composite materials were studied, and the mechanisms of release were analyzed using different theoretical models. The antibacterial activity against Pseudomonas aeruginosa was evaluated for both the polymyxin hybrid and the composite delivery systems. All tested samples inhibited bacterial growth. The minimal inhibitory concentrations of the polymyxin B hybrid delivery system demonstrated a synergistic effect when compared with either the antibiotic or the silver nanoparticles alone.