A covalently crosslinked polysaccharide hydrogel for potential applications in drug delivery and tissue engineering

The development of non-cytotoxic hydrogels that can allow for the controlled release of molecules has important clinical and therapeutic applications. In this paper, we developed a series of in situ hydrogels by combining N,O-carboxymethyl chitosan and oxidized alginate without additional crosslinking agents. The rheological properties of these hydrogels as well as their gelling time, swelling ratio, and in vitro degradation behavior were investigated. We observed that although gelation was rapid at physiological temperature, it was even faster in the presence of higher oxidization degree of alginate. In vitro cytotoxicity study showed that the developed hydrogels were not cytotoxic after 24?h of culturing with NIH-3T3 cells. Additionally, bovine serum albumin was released from the hydrogels initially by diffusion at early stages followed by a degradation-dependent mechanism at later stages. In conclusion, the developed hydrogel might have potential application in the drug delivery system and tissue engineering.     

Chitosan-based thermosensitive hydrogel containing liposomes for sustained delivery of cytarabine

Sustained release thermosensitive solution containing cytarabine-loaded liposome delivery system offers the possibility of reduced dosing frequency and sustained drug action. Biodegradable and biocompatible chitosan-beta-glycerophosphate (C-GP) thermosensitive solution having the property to gel at body temperature and to maintain its physical integrity for longer period of time was used. The C-GP solution containing cytarabine-loaded liposomes (CGPCLL) was studied, and the results showed that the cytarabine liposomes were capable of high encapsulation efficiency (85.2 +/- 2.58%) with the mean diameter of 220 +/- 6.9 nm of extruded cytarabine-loaded liposome. Furthermore, transmission electron microscopy showed spherical-shaped liposomes after extrusion with smooth surface. In vitro studies of CGPCLL in PBS buffer showed that this system can sustain release of encapsulated drug for more than 60 h compared with drug-loaded liposomal suspension (upto 48 h). Pharmacokinetic studies of CGPCLL resulted in higher t(1/2) (28.86 h) and AUC 2526.88 mug/mL h compared with cytarabine-loaded liposomal suspension (CLLS) and C-GP containing free cytarabine (CGPFC) in rats. CGPCLL was capable of sustaining the cytarabine release for more than 60 h in vivo compared with CLLS and CGPFC which showed maximum amount of drug release within 42 and 10 h, respectively. Thus, these results showed that the CGPCLL gels at body temperature and can sustain the delivery of cytarabine effectively.     

Development of novel pH-sensitive nanoparticles loaded hydrogel for transdermal drug delivery

Objective: Difference of pH that exists between the skin surface and blood circulation can be exploited for transdermal delivery of drug molecules by loading drug into pH-sensitive polymer. Eudragit S100 (ES100), a pH-sensitive polymer having dissolution profile above pH 7.4, is used in oral, ocular, vaginal and topical delivery of drug molecules. However, pH-sensitive potential of this polymer has not been explored for transdermal delivery. The aim of this research work was to exploit the pH-sensitive potential of ES100 as a nanocarrier for transdermal delivery of model drug, that is, Piroxicam.

Methods: Simple nanoprecipitation technique was employed to prepare the nanoparticles and response surface quadratic model was applied to get an optimized formulation. The prepared nanoparticles were characterized and loaded into Carbopol 934 based hydrogel. In vitro release, ex vivo permeation and accelerated stability studies were carried out on the prepared formulation.

Results: Particles with an average size of 25–40?nm were obtained with an encapsulation efficiency of 88%. Release studies revealed that nanoparticles remained stable at acidic pH while sustained release with no initial burst effect was observed at pH 7.4 from the hydrogel. Permeation of these nanocarriers from hydrogel matrix showed significant permeation of Piroxicam through mice skin.

Conclusion: It can be concluded that ES100 based pH-sensitive nanoparticles have potential to be delivered through transdermal route.     

Recombinant human serum albumin hydrogel as a novel drug delivery vehicle

Serum albumin acts as a physiological carrier for various compounds including drugs. A hydrogel consisting of recombinant human serum albumin (rHSA) was prepared to take advantage of drug binding ability of albumin for a sustained drug release carrier. The hydrogel was prepared by mixing rHSA and dithiothreitol and casted to a polystyrene mold. Hydrogel formation was thought to occur through the intermolecular interaction of the hydrophobic groups by protein denaturation. The release of sodium benzoate and salicylic acid from the hydrogel completed in 2 h, while warfarin release continued for 24 h. The total amounts of the drugs released from 100 mg of 15 and 5% rHSA hydrogel were 2.3 and 1.4 μmol for warfarin, 1.4 and 1.1 μmol for salicylic acid and 0.9 and 0.9 μmol for sodium benzoate. These results reflected the order of the binding ability of drugs for intact albumin indicating that the drug binding ability of HSA still remained after the hydrogel formation. However, fibroblast cells attached and proliferated well on the hydrogel, indicating that denaturation of rHSA proceeded to the extent to allow the cell attachment. The present rHSA hydrogel might be suitable for a sustained release carrier of drugs having affinity for albumin.     

Hydroxybutyl chitosan thermo-sensitive hydrogel: a potential drug delivery system

Drug delivery mediated by hydrogel has shown great promise in controlled drug release field. We report here the development of a hydroxybutyl chitosan (HBC) thermo-sensitive gel to deliver doxorubicine hydrochloride (DOX·HCl) for cancer treatment. Concentrated HBC aqueous solution could transform into hydrogel within 30 s after injection under physiological temperature in non-chemical fashion. The properties of the HBC gels including chemical structure, surface morphology, and rheologic properties were studied. Gelation temperature and gelation time of HBC could be adjusted by HBC concentrations. The gel erosion rate in vivo was faster than solubilization rate in vitro. The mild inflammatory response caused by implantation of the hydrogel was acceptable. The DOX·HCl (1 mg/ml) loaded HBC gels displayed slow release rates that were independent of the HBC concentration, and significantly reduced viability of 4T-1 cells compared with the HBC gels after 1 day incubation. These results indicate that thermo-sensitive HBC hydrogels have promising potential as an injectable drug carrier for pharmaceutical applications.     

A novel vehicle for local protein delivery to the inner ear: injectable and biodegradable thermosensitive hydrogel loaded with PLGA nanoparticles

Delivery of biomacromolecular drugs into the inner ear is challenging, mainly because of their inherent instability as well as physiological and anatomical barriers. Therefore, protein-friendly, hydrogel-based delivery systems following local administration are being developed for inner ear therapy. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing interferon α-2?b (IFN α-2?b) were loaded in chitosan/glycerophosphate (CS/GP)-based thermosensitive hydrogel for IFN delivery by intratympanic injection. The injectable hydrogel possessed a physiological pH and formed semi-solid gel at 37?°C, with good swelling and deswelling properties. The CS/GP hydrogel could slowly degrade as visualized by scanning electron microscopy (SEM). The presence of NPs in CS/GP gel largely influenced in vitro drug release. In the guinea pig cochlea, a 1.5- to 3-fold increase in the drug exposure time of NPs-CS/GP was found than those of the solution, NPs and IFN-loaded hydrogel. Most importantly, a prolonged residence time was attained without obvious histological changes in the inner ear. This biodegradable, injectable, and thermosensitive NPs-CS/GP system may allow longer delivery of protein drugs to the inner ear, thus may be a potential novel vehicle for inner ear therapy.     

Thermosensitive hydrogel of hydrophobically-modified methylcellulose for intravaginal drug delivery

Hydrogels with the advantages of prolonging drug release and administration convenience are necessary for intravaginal drug delivery to prevent sexual transmission of human immunodeficiency virus and other vaginal infections. In this study, the thermosensitive hydrogel of methylcellulose modified by stearic acid (MCS) were evaluated in the presence of NaCl and phosphates, which exhibited sol-to-gel transition performance at body temperature or even lower. The in vitro cytotoxicity and in vivo mucosal irritation were investigated and the results showed that MCS hydrogel possessed good biocompatibility similar with hydroxyethyl cellulose (HEC) gel. Significantly, the release studies revealed that MCS hydrogel could control tenofovir sustained release for 10 h without burst release, longer than that from HEC gel or poloxamer 407 hydrogel. Therefore, MCS thermosensitive hydrogel would be a promising carrier for intravaginal delivery of antiviral drugs for long time controlled release.     

Development of a novel soft hydrogel for the transdermal delivery of testosterone

A soft hydrogel formulation for the transdermal delivery of testosterone (TS) was developed, and the effect of various skin-permeation enhancers was studied in vitro and in vivo. Testosterone was incorporated into a polyvinyl alcohol (PVA)-based soft hydrogel with polyisobutylene (PIB) and various skin-permeation enhancers (dodecylamine, HPE101, oleic acid, or lauric acid). In vitro rat-skin permeation of TS from the soft hydrogel was investigated using Keshary-Chien diffusion cells for 24 hr at 37°C. In vivo plasma-concentration profiles of TS after applying the soft hydrogel on the dorsal skin of rat were determined using a commercial radioimmunoassay kit. The formulated soft hydrogel formed a thin film on the skin within 2 to 3 min after application and remained in a dried-film state for at least 24 hr. Addition of PIB into the hydrogel to increase the adhesion resulted in a negligible reduction in the skin-permeation rate of TS. However, rat-skin permeation of TS increased with the addition of permeation enhancers both in vitro and in vivo. Dodecylamine at the concentration of 3% was the most effective among tested. Plasma concentration of TS significantly increased for at least 24 hr with the addition of dodecylamine. These results suggest the feasibility of the development of a soft hydrogel formulation for the transdermal delivery of TS.     

A novel amphiphilic nano hydrogel using ketene based polyester with polyacrylamide for controlled drug delivery system

A ketene based Low molecular weight polymer (LMKP) having ester functional group was prepared using glycine through surface initiated anionic polymerization. NMR, ATR-FTIR & SEC were used to characterize the LMKP. The LMKP and acrylamide (AAm) were co-polymerised in methyl ethyl ketone to yield semi-IPN nanohydrogels (NHG). Benzoyl peroxide (BPO) was used as an initiator and N,N-methylene bisacrylamide (MBA) as crosslinking agent. Formation of NHG was confirmed through frequency shift in LMKP and poly acrylamide (PAAm) in FTIR spectroscopy. Photon correlation spectroscopy reveals that the sizes of the NHG were in the range of 140-225 nm and Transmission Electron Micrograph (TEM) also confirms the nano dimension of NHG. Biocompatibility of the NHG was confirmed through the cytotoxicity analysis. The swelling and diffusion behaviour of NHG, prepared under various formulations, were evaluated. The swelling pattern of NHG was studied at different pH conditions. The drug delivery capacity of NHG was investigated using ciprofloxacin as a model drug. The drug release kinetics of NHG suggested their anomalous (non-fickian) behaviour.     

A casein-polysaccharide hybrid hydrogel cross-linked by transglutaminase for drug delivery

A protein-polysaccharide hydrogel was reported as a biocompatible, biodegradable, and non-toxic material that had biomedical applications such as drug delivery. The hydrogel, composed of 10% casein and 1% konjac glucomannan (KGM), was formed with 0.4 wt% transglutaminase (MTG) as the cross-linker. The physicochemical properties of the protein-polysaccharide hydrogel were investigated by SEM observation, FT-IR analysis, swelling ratio test, and stability test. The results of the stability test proved that the hydrogel with KGM had an obviously improved stability. Its degradation rate also decreased from 100% to less than 60% compared with the hydrogel without KGM at the end of the test. The results of the swelling ratio test demonstrated that the addition of KGM restricted the mobility of the chains, and decreased the swelling ratio of the hydrogel. The results of the FT-IR revealed hydrogen bond interactions during the gelation process upon the addition of KGM. To investigate in vitro release behavior, docetaxel was chosen as a model drug incorporated into the casein/KGM hydrogels. The hydrogel with 1% KGM exhibited a good drug release behavior.     

Alginate microsphere-collagen composite hydrogel for ocular drug delivery and implantation

A composite collagen hydrogel containing protein encapsulated alginate microspheres was developed for ocular applications. Bovine serum albumin (BSA) served as a drug model. The composite hydrogel retained optical clarity and mechanical robustness of control hydrogels without microspheres. A sustained release of BSA was achieved during an 11-day period in neutral phosphate buffer. The composite hydrogel supported human corneal epithelial cell growth and had adequate mechanical strength and excellent optical clarity for possible use as therapeutic lens for drug delivery and/or use as corneal substitute for transplantation into patients who have corneal diseases.     

Cell-based drug delivery systems for biomedical applications

Spurred by numerous achievements in nanoscience and nanotechnology, the evolution of nanoparticulate drug delivery systems (nano-DDSs) is in its rapid growth period and attracting considerable attention due to their unique advantages in biomedical applications. Natural particulates ranging from mammalian cells to bacteria possess their own distinctive delivery processes and mechanisms, which inspires more design and development of cell-based DDSs by integrating the innate functions of cells with the nanoscale characteristics of nanoparticles. In this review article, we focus on the recent advances in cell-based DDSs for site-specific delivery of therapeutics and enhanced treatment of diseases. The promise and perils of cell-based DDSs are also discussed.     

A novel injectable chlorhexidine thermosensitive hydrogel for periodontal application: preparation, antibacterial activity and toxicity evaluation

The aim of this paper was to evaluate the application potential of CS–HTCC/GP–0.1%Chx thermosensitive hydrogel which was synthesized using chitosan (CS), quaternized CS, and α,β-glycerophosphate (α,β-GP) loading with 0.1% chlorhexidine (Chx) (w/v) for periodontal treatment. An aqueous solution of CS–HTCC/GP–0.1%Chx was transformed into hydrogel at 6 min when the temperature was increased to 37°C. The scan electron microscopy (SEM) image of the gel was a porous, loose and crosslinked network. In vitro, Chx released over 18 h from the CS–HTCC/GP thermosensitive hydrogel in artificial saliva pH 6.8. Release rate could be controlled through adjustment of α,β-GP or Chx concentration. CS–HTCC/GP–0.1%Chx thermosensitive hydrogel exhibited excellent inhibitory activity against primary periodontal pathogens. CS–HTCC/GP–0.1%Chx thermosensitive hydrogel had no acute toxicity; the maximum tolerated dose in rats was 400 mg/ml. All results indicated that CS–HTCC/GP–0.1%Chx thermosensitive hydrogel is a strong candidate as a local drug delivery system for periodontal treatment.     

Arsonoliposomes: novel nanosized arsenic-containing vesicles for drug delivery

Natural and synthetic arsenolipids, have been discovered, synthesized, and evaluated for their biological activity. Arsonolipids, are analogs of phosphonolipids, in which P has been replaced by As. The synthesis of arsonolipids has been explored and a simple one-pot method with high yield is currently available for their preparation. However, although arsonolipids posses interesting biophysical and biochemical properties their anticancer or antiparasitic activity is not considered adequate for therapeutic applications. But when arsonolipids are incorporated in liposomes, the vesicles formulated have interesting possibilities, as seen in a number of studies. In cell culture studies, nanosized arsonolipid-containing liposomes or else arsonoliposomes, showed increased toxicity against cancer cells (compared to that of arsenic trioxide) but at the same time were less toxic than arsenic trioxide for normal cells. Furthermore, arsonoliposomes also demonstrate antiparasitic activity in vitro. Nevertheless, As is rapidly cleared from blood after in vivo administration of arsonoliposomes, and this will highly limit possible therapeutic applications. In addition, the fact that arsonoliposomes were observed to aggregate and subsequently fuse into larger particles in presence of cations, may also be considered as a problem. Thereby, methods to modulate the stability of arsonoliposomes and, perhaps, their in vivo distribution (as surface property modification) are currently being investigated. In very recent experiments it has been shown that arsonoliposome pegylation results in the formation of liposomes with very high membrane integrity. In addition, pegylation results in increased physical stability of arsonoliposomes and abolishment of cation-induced aggregation and fusion. Nevertheless, further in vivo studies are required in order to prove if pegylation alters arsonoliposome in vivo kinetics in a positive way, without affecting their activity. From studies performed thus far it is concluded that arsonoliposomes are nanosized-vesicles with interesting properties that justify further exploitation towards the development of therapeutic systems for cancer or parasitic diseases.     

A comparative study of chitosan and poloxamer based thermosensitive hydrogel for the delivery of PEGylated melphalan conjugates

Abstract

Objective: Although the melphalan (ML) used extensively for the management of breast cancer, its clinical application is limited due to significant hemolytic activity. In the present work, a comparative analysis of two distinct in situ-based thermogelling polymers of PEGylated ML was performed.

Methods: Briefly, the PEGylated conjugate of the melphalan (MLPEG 5000) for local and sustained drug release action is loaded into two different thermogelling polymeric systems, namely chitosan- and poloxamer-based systems. The synthesized conjugate was loaded to a chitosan (MLP 5000) and poloxamer-based (MPX-CG) thermogelling injectable hydrogels. These thermogelling hydrogels were evaluated for in vitro hydrolysis, in vitro hemolytic activity. and in vitro anticancer activity.

Results: The lower percent cumulative hydrolysis was witness for both the hydrogels. MPX-CG and MLP 5000 hydrogels as predicted had shown lower percent cumulative hydrolysis of 3.31?±?0.1 and 1.67?±?0.1 after 6?h. The percentage hemolysis of MPX-CG and MLP 5000 even at a concentration of 32?µg/ml was found to be 39.23?±?1.24% and 34.23?±?2.24%, observed at 1?h, respectively. Both the hydrogels showed similar anticancer pattern, the MPX-CG hydrogel showed low cell viability of 8.4?±?1.1% at a concentration of 150?µM and the MLP-5000 hydrogel showed slight higher cell viability (13.12?±?5.4%) as compared with MPX-CG hydrogel.

Conclusion: Hence, from the present study it can be well understood that both the chitosan- and the poloxamer-based thermogelling hydrogel proves to be an effective drug delivery systems for the delivery of the PEGylated conjugates.     

Studies on pectins as potential hydrogel matrices for controlled-release drug delivery

Polymeric hydrogels are widely used as controlled-release matrix tablets. In the present study, we investigated high-methoxy pectins for their potential value in controlled-release matrix formulations. The effects of compression force, ratio of drug to pectin, and type of pectin on drug release from matrix tablets were also investigated. The results of the in vitro release studies show that the drug release from compressed matrix tablets prepared from pectin can be modified by changing the amount and the type of pectin in the matrix tablets. However, compression force did not significantly affect the drug release. The mechanisms controlling release rate were discussed with respect to drug diffusion through the polymer matrices, but may be more complex.     

温敏性高分子水凝胶制备及灭火性能研究

采用自由共聚的方法合成了一种温敏性水凝胶,分析了不同质量分数凝胶的低临界溶解温度(LCST)和粘度变化,分别采用水、浙江大学胶体灭火剂B和温敏性水凝胶对1A堆垛进行灭火实验,通过辐射热探头和热电偶分别对灭火过程中的辐射热和温度变化进行采集,结果表明在相同的供给强度下,温敏性水凝胶灭火剂的灭火时间最短,消耗的灭火剂用量最少,灭火后所产生的水渍损失最小,而且灭火后火场残留物易于清理,通过对灭火过程中的危险气体进行检测,结果表明没有额外毒害气体产生。     

Development of pH sensitive polyacrylamide grafted pectin hydrogel for controlled drug delivery system

In the present study an attempt was made to graft polyacrylamide on pectin. The grafted polymer was characterized by FTIR spectroscopy, differential scanning calorimetry and X-ray diffraction. Rheological property of pectin solution was compared with the product solution. The grafted polymer was cross-linked with varying amount of glutaraldehyde. The swelling properties of the cross-linked product were also studied. The salicylic acid, an antipyretic drug, was incorporated in the cross-linked gel as a model drug and the drug release studies were done in a modified Franz’s diffusion cell. The effect of cross-linking density on the release property of salicylic acid was studied through the cross-linked product. The product showed better film forming property and gelling property than pectin. The comparative rheological properties of pectin and grafted copolymer indicated change in the property of the product. FTIR studies indicated incorporation of amide group. Differential scanning calorimetry and XRD suggested formation of a new polymer. Swelling study indicated pH dependent swelling of the cross-linked hydrogel. Salicylic acid release indicated pH dependent release from the hydrogel.     

PAA/PVA互穿网络水凝胶膜的制备和药物输送研究

采用自由基溶液聚合和连续的互穿网络技术,以氧化还原引发体系为引发剂、化学交联聚丙烯酸(PAA)和聚乙烯醇(PVA)制备了一系列PAA/PVA水凝胶膜.ATR-FTIR光谱表明,网络组成之间形成了新的相互作用的氢键,DSC分析表示网络组成具有良好的热力学相容性.膜在各种介质中的溶胀性质表明:因PAA的亲水性强于PVA,溶胀比随PAA的增多而提高.以阳离子化合物结晶紫为模板药物考察了在不同的pH缓冲溶液中的释放行为,结果表明,药物的释放能力可以通过改变体系的pH值加以调控.     

Characterization and cytocompatibility of thermosensitive hydrogel embedded with chitosan nanoparticles for delivery of bone morphogenetic protein-2 plasmid DNA

A novel injectable chitosan thermosensitive hydrogel was designed as a target multi-effect scaffold for endogenous repair of the periodontium. The hydrogel complex was designed by embedding chitosan nanoparticles (CSn) loaded with bone morphogenetic protein-2 plasmid DNA (pDNA-BMP2) into a chitosan (CS)-based hydrogel with α,β-glycerophosphate (α,β-GP), termed CS/CSn(pDNA-BMP2)-GP. Characterization, the in vitro release profile for pDNA-BMP2, and cytocompatibility to human periodontal ligament cells (HPDLCs), were then conducted. The average diameter of the CSn(pDNA-BMP2) was 270.1 nm with a polydispersity index (PDI) of 0.486 and zeta potential of +27.0 mv. A DNase I protection assay showed that CSn could protect the pDNA-BMP2 from nuclease degradation. Encapsulation efficiency and loading capacity of CSn(pDNA-BMP2) were more than 80 and 30 %, respectively. The sol–gel transition time was only 3 min when CSn(pDNA-BMP2) was added into the CS/α,β-GP system. Scanning electron microscopy showed that CSn(pDNA-BMP2) was randomly dispersed in a network with regular holes and a porous structure. Weighting method showed the swelling ratio and degradation was faster in medium of pH 4.0 than pH 6.8. An in vitro pDNA-BMP2 release test showed that the cumulative release rate of pDNA-BMP2 was much slower from CS/CSn-GP than from CSn in identical release media. In release media with different pH, pDNA-BMP2 release was much slower at pH 6.8 than at pH 4.0. Three-dimensional culture with HPDLCs showed good cell proliferation and the Cell-Counting Kit-8 assay indicated improved cell growth with the addition of CSn(pDNA-BMP2) to CS/α,β-GP. In summary, the CS/CSn(pDNA-BMP2)-GP complex system exhibited excellent biological properties and cytocompatibility, indicating great potential as a gene delivery carrier and tissue regeneration scaffold for endogenous repair of the periodontium.