Hyaluronidase enzyme core-5-fluorouracil-loaded chitosan-PEG-gelatin polymer nanocomposites as targeted and controlled drug delivery vehicles

This study examines the performance of novel hyaluronidase enzyme core-5-fluorouracil-loaded chitosan-polyethylene glycol-gelatin polymer nanocomposites, which were prepared using an ionic gelation technique, as targeted and controlled drug delivery vehicles. These hyaluronidase-loaded nanoparticles have recently been proposed as targeted and controlled drug delivery vehicle systems to tissues due to their ability to loosen the intercellular connective matrix of hyaluronic acid. The encapsulation efficiency and loading capacities of the nanoparticles demonstrated that these nanocomposites displayed sufficient binding ability, which depends on the pH and initial concentration of the drug. The cytotoxic effects of the chitosan-hyaluronidase-5-fluorouracil (CS-HYL-5-FU), chitosan-hyaluronidase-5-fluorouracil polyethylene glycol (CS-HYL-5-FU-PEG), and chitosan-hyaluronidase-5-fluorouracil polyethylene glycol-gelatin (CS-HYL-5-FU-PEG-G) nanoparticles were assessed using MTT assays, and the nanovectors were found to be less cytotoxic than the chemotherapeutic 5-FU after incubation for 3–12 h. The particle sizes of the CS-HYL-5-FU, CS-HYL-5-FU-PEG and CS-HYL-5-FU-PEG-G polymer composites were between 300 and 580 nm, as determined by a Zetasizer. Scanning electron microscopy (SEM) analysis indicated that the nanocomposites exhibit a clear, smooth surface and fine morphology. Linkages of the polymers, enzyme, and drug were confirmed by FTIR spectroscopy. Atomic fluorescence microscopy (AFM) analysis confirmed the size of the polymer composite nanoparticles. Therefore, this work established that the drug can be successfully encapsulated in chitosan-polyethylene glycol-gelatin-accompanied hyaluronidase nanoparticles with a homogeneous distribution. These nanoparticles can be potential carriers for targeted and controlled drug delivery to cancer cells.     

Hydrogel nanoparticles and nanocomposites for nasal drug/vaccine delivery

Over the past few years, nasal drug delivery has attracted more and more attentions, and been recognized as the most promising alternative route for the systemic medication of drugs limited to intravenous administration. Many experiments in animal models have shown that nanoscale carriers have the ability to enhance the nasal delivery of peptide/protein drugs and vaccines compared to the conventional drug solution formulations. However, the rapid mucociliary clearance of the drug-loaded nanoparticles can cause a reduction in bioavailability percentage after intranasal administration. Thus, research efforts have considerably been directed towards the development of hydrogel nanosystems which have mucoadhesive properties in order to maximize the residence time, and hence increase the period of contact with the nasal mucosa and enhance the drug absorption. It is most certain that the high viscosity of hydrogel-based nanosystems can efficiently offer this mucoadhesive property. This update review discusses the possible benefits of using hydrogel polymer-based nanoparticles and hydrogel nanocomposites for drug/vaccine delivery through the intranasal administration.     

Synthetic polymer systems in drug delivery

The development of synthetic polymers for applications in drug delivery is reviewed, with particular reference to polymers that can be activated to release a medicinal agent in vivo or that can respond to changes in environment to enhance the effectiveness of therapy. The mechanisms by which these polymers are designed to deliver drugs are highlighted, along with the challenges facing synthetic chemists and pharmaceutical scientists in designing new and more active therapeutic vehicles. Currently, synthetic materials with biomimetic properties are attracting growing attention as possible new dosage formulations and the potential applications of these increasingly sophisticated polymers in cell-specific drug targeting and in the emerging field of gene therapy are also considered. Finally, the potential development issues for delivery of therapeutics using active or 'smart' polymers are discussed with an analysis of the future trends in this rapidly expanding area of research.     

Chitosan: a potential polymer for colon-specific drug delivery system

Introduction: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties.

Areas covered: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug.

Expert opinion: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).     

Mathematical modeling of polymer erosion: consequences for drug delivery

Bioerodible polymers have been extensively used as carriers for drug delivery and as scaffolds for tissue engineering. The ability to model and predict erosion behavior can enable the rational design and optimization of biomaterials for various biomedical applications in vivo. This review examines critically the current approaches in mathematical modeling of the erosion of synthetic polymers. The models are classified broadly based on whether they use phenomenological, probabilistic, or empirical approaches. An analysis of the various physical, chemical, and biological factors affecting polymer erosion and the classes of bioerodible polymers to which these analyses have been applied are discussed. The key features and assumptions associated with each of the models are described, and information is provided on the limitations of the models and the various approaches. The review concludes with several directions for future models of polymer erosion.     

Chitosan: a potential polymer for colon-specific drug delivery system

INTRODUCTION: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties. AREAS COVERED: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug. EXPERT OPINION: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).     

Polymerized rosin: novel film forming polymer for drug delivery

Polymerized rosin (PR) a novel film forming polymer is characterized and investigated in the present study for its application in drug delivery. Films were produced by a casting/solvent evaporation method from plasticizer free and plasticizer containing solutions. Films prepared from different formulations were studied for their mechanical (tensile strength, percent elongation and Young's modulus), water vapour transmission and moisture absorption characteristics. Neat PR films were slightly brittle and posed the problem of breaking during handling. Hydrophobic plasticizers, dibutyl sebacate and tributyl citrate, improved the mechanical properties of free films with both the plasticizers showing significant effects on film elongation. Release of diclofenac sodium (model drug) from coated pellets was sustained with high coating levels. Concentration of plasticizer was found to affect the release profile. PR films plasticized with hydrophobic plasticizers could therefore be used in coating processes for the design of oral sustained delivery dosage forms.     

Exploiting EPR in polymer drug conjugate delivery for tumor targeting

Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue. PDCs offer added advantages of reduced deleterious effects of anticancer drugs and augmentation of its formulation capability (e.g. Solubility). There are now at least eleven PDCs that have entered phase I/II/III clinical trial as anticancer drugs. PDCs once entered into the tumor tissue, taking advantage of EPR, are endocytosed into the cell either by simple or receptor mediated endocytosis. Various polymeric carriers have been used with hydrolyzable linker arm for conjugation with bioactive moiety. The hydrolyzable linkages of PDC are broken down by acid hydrolyses of lysosomes and releases the drug. High concentrations of the chemotherapeutic agent are maintained near the nucleus, the target site. Passive targeting by PDCs is due to the physiological event of EPR, which is becoming one of the major thrust areas for targeting solid tumors.     

Mathematical models describing polymer dissolution: consequences for drug delivery

Polymer dissolution is an important phenomenon in polymer science and engineering that has found applications in areas like microlithography, controlled drug delivery, and plastics recycling. This review focuses on the modeling efforts to understand the physics of the drug release process from dissolving polymers. A brief review of the experimentally observed dissolution behavior is presented, thus motivating the modeling of the mechanism of dissolution. The main modeling contributions have been classified into two broad approaches - phenomenological models and Fickian equations, and anomalous transport models and scaling law-based approaches. The underlying principles and the important features of each approach are discussed. Details of the important models and their corresponding predictions are provided. Experimental results seem to be qualitatively consistent with the present picture.     

Design of a core-shelled polymer cylinder for potential programmable drug delivery

A cylindrical dosage form comprising a laminated composite polymer core and a hydrophobic polycarbonate coating was proposed for programmable drug delivery. In the core, poly[(ethyl glycinate) (benzyl amino acethydroxamate) phosphazene] was synthesized as drug-loaded layers for its strong pH-sensitive degradation (eroded after 1.5 days at pH 7.4 and more than 20 days at pH 5.0 and 6.0). Poly(sebacic anhydride)-b-polyethylene glycol or poly(sebacic anhydride-co-trimellitylimidoglycine)-b-poly(ethylene glycol) was selected as isolating layers for their good processing properties at room temperature and suitable erosion duration. The in vitro drug release studies of these devices were conducted under physiological conditions (pH 7.4). The results revealed that the model drugs (brilliant blue, FITC-dextran, myoglobin) could be released in typical pulsatile manner. Moreover, the duration time of drug release (24-40 h) and the lag time (18-118 h) could be separately regulated by the mass of polyphosphazene and the type or mass of polyanhydride. In this experiment, the cooperative effect of polyanhydrides and pH-sensitive degradable polyphosphazene was specially demonstrated, which offers a new idea to develop a programmable drug delivery system for single dose vaccine and other related applications.     

Rheological and biopharmaceutical investigation of polymer drug delivery systems

Drug release of watersoluble active agent (ephedrine hydrochloride) and water-insoluble ones (griseofulvine, salicylic acid, sulfadimidine) from hydrogels containing different polymers was investigated. The rheological behaviour of polymer matrices was characterized by flow curves and viscosity curves. These hydrogels were not thixotropic systems, unlike more authors' statement. The values of rheological constants increase exponentially with concentration of polymers. The liberation of active agents can be characterized by a multiplicative function. The constant of viscosity vs. concentration function was determined and it was called as characteristic of structure formation. A linear relationship between constant of structure formation and drug liberation was demonstrated.     

Novel anionic polymer as a carrier for CNS delivery of anti-Alzheimer drug

Natural and plant-based polymers could be used for control release of drugs and also helps in targeting drug to the site of action. The main objective of present work was to check the feasibility of plant-based, namely, mango gum polymeric nanoparticles (NPs) as a carrier for central nervous system (CNS) delivery using model drug donepezil (DZP). The NPs were prepared by modified ionic gelation method and emulsion cross-linking method. Zeta sizer results showed that the diameter of NPs was about 90–130?nm. The polymeric DZP-loaded NPs were almost spherical in shape, as revealed by transmission electron microscopy (TEM). On increasing concentration of NPs suspension from 50?μg/ml to 5000?μg/ml there was no significant increase in % hemolysis. In vivo studies showed that brain targeting was achieved. So on the basis of above results, the extracted water soluble fraction of mango gum is a suitable candidate for brain delivery in the form of nanoformulations.     

Eudraginated polymer blends: a potential oral controlled drug delivery system for theophylline

Sustained release (SR) dosage forms enable prolonged and continuous deposition of the drug in the gastrointestinal (GI) tract and improve the bioavailability of medications characterized by a narrow absorption window. In this study, a new strategy is proposed for the development of SR dosage forms for theophylline (TPH). Design of the delivery system was based on a sustained release formulation, with a modified coating technique and swelling features aimed to extend the release time of the drug. Different polymers, such as Carbopol 71G (CP), sodium carboxymethylcellulose (SCMC), ethylcellulose (EC) and their combinations were tried. Prepared matrix tablets were coated with a 5 % (m/m) dispersion of Eudragit (EUD) in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for micromeritic properties, drug concentration and in vitro drug release. It was found that the in vitro drug release rate decreased with increasing the amount of polymer. Coating with EUD resulted in a significant lag phase in the first two hours of dissolution in the acidic pH of simulated gastric fluid (SGF) due to decreased water uptake, and hence decreased driving force for drug release. Release became faster in the alkaline pH of simulated intestinal fluid (SIF) owing to increased solubility of both the coating and matrixing agents. The optimized formulation was subjected to in vivo studies in rabbits and the pharmacokinetic parameters of developed formulations were compared with the commercial (Asmanyl(?)) formulation. Asmanyl(?) tablets showed faster absorption (t(max) 4.0 h) compared to the TPH formulation showing a t(max) value of 8.0 h. The C(max) and AUC values of TPH formulation were significantly (p < 0.05) higher than those for Asmanyl(?), revealing relative bioavailability of about 136.93 %. Our study demonstrated the potential usefulness of eudraginated polymers for the oral delivery of the sparingly soluble drug theophylline.     

Novel polymer micelles prepared from chitosan grafted hydrophobic palmitoyl groups for drug delivery

Chitosan-based polymer micelles have a splendid outlook for drug delivery owing to the interesting properties, abundance, and low cost of chitosan. A new method of preparation of water-soluble N-palmitoyl chitosan (PLCS) which can form micelles in water is developed in this paper. The preparation of PLCS was carried out by swollen chitosan coupling with palmitic anhydride in dimethyl sulfoxide (DMSO). The degree of substitution (DS) of PLCS was in the range of 1.2-14.2%, and the critical aggregation concentration (CAC) of PLCS micelles was in the range of 2.0 x 10(-3) to 37.2 x 10(-3) mg/mL. The properties of PLCS micelles such as encapsulation capacity and controlled release ability of hydrophobic model drug ibuprofen (IBU) were evaluated. Experimental results indicated that the loading capacity (LC) of PLCS was approximately 10%. The drug release strongly depended on pH and temperature: low pH and high temperature accelerated drug release markedly. Moreover, the IR, 1H NMR, and TEM of PLCS, IBU-loaded PLCS, and a PLCS-IBU physical mixture have been measured to show that IBU is loaded by PLCS micelles.     

Responsive polymer conjugates for drug delivery applications: recent advances in bioconjugation methodologies

Abstract

Protein–polymer conjugates have achieved tremendous attention in the last few years, since their importance in diverse fields including drug delivery, biotechnology and nanotechnology. Over the past few years, numerous chemical strategies have been developed to conjugate different synthetic polymers onto proteins and great progress has been made. Currently, there are a handful of therapeutic polymer conjugates that have been approved by the FDA, while many hundreds of products are under extensive clinical trials and preclinical development phases. In this way, the development of novel techniques for conjugation, especially living radical polymerisation (LRP) has greatly enhanced the potential to broaden the scope of therapeutic conjugates. As a consequence, versatile techniques have developed, such as the ‘grafting from’ approach, which allows modifications of biomacromolecules at the atomic level, and subsequently preparing well-defined stimuli-responsive conjugates. These strategies present a unique perspective for therapy expansion of a new generation of ‘smart’ products with proprieties that can be finely controlled and tuned rather than just enhanced. This article highlights recent advances in the synthesis and application of protein–polymer conjugates by controlled radical polymerisation techniques, with special emphasis on stimuli-responsive conjugates on new applications in biomedical and pharmaceutical areas.     

胞内酶敏感肿瘤靶向递药体系的合成及应用

目的利用对乳腺癌肿瘤细胞MDA-MB-435内特有酶豆蛋白酶(legumain)敏感的多肽(AANL)连接阿霉素(DOX)构建具有胞内特异性释药功能的纳米递药系统,并对AANL在含有legumain环境下的断裂效率进行研究。方法将DOX用AANL修饰得到AANL-DOX(AD),再将AD连接至4-arm PEG上,最后将细胞穿膜肽(TAT)连接至4-arm PEG-AD上,制备出TAT-PEG-AD并自组装形成纳米粒(TPAD)。核磁表征TAT-PEG-AANL-DOX;粒度分析仪和透射电镜测定纳米粒的粒径及外观形貌;模拟体内、肿瘤微环境和胞内环境通过动态透析法研究legumain对AANL的断裂效率并模拟DOX的药物控释效率;细胞毒性研究TPAD对MDA-MB-435细胞的毒性作用。结果核磁共振氢谱证实TAT-PEG-AANL-DOX合成成功;测定TPAD的粒径为126.3 nm;透射电镜(TEM)观察纳米粒结构圆整,粒径为80 nm;24 h的累积释药量为82.2%;体外细胞毒性研究表明,TPAD对MDA-MB-435细胞有较好的杀伤作用,其效果接近游离DOX的细胞毒性。结论利用legumain敏感多肽连接DOX制备具有胞内特异性释药功能的纳米粒,能够有效实现肿瘤细胞内晚期内涵体和溶酶体精准释药,提高抗肿瘤药物的生物利用度,值得进一步研究。     

Development and evaluation of pulsatile drug delivery system using novel polymer

The aim of the present investigation was to develop a pulsatile drug delivery system based on an insoluble capsule body filled with theophylline microspheres and sealed with a swellable novel polymer plug isolated from the endosperm of seeds of higher plant Delonix regia family-Fabaceae. Theophylline microspheres were prepared by solvent evaporation method using Eudragit S 100. The swellable plugs of varying thickness and hardness were prepared by direct compression, which were then placed in the capsule opening. The drug delivery system was designed to deliver the drug at such a time when it was needed most to offer convenience to the chronic patients of asthma. Formulated dosage forms were evaluated for an in vitro drug release study, which showed that the release might be consistent with a release time expected to deliver the drug to the colon depending on the thickness and hardness of the hydrogel plug. Thus, thickness and hardness of the novel polymeric plug plays an important role in controlling the drug release from the formulated drug delivery system.     

Development of buccal drug delivery systems based on a thiolated polymer

The purpose of the present study was to investigate the benefit of thiolated polymers (thiomers) for the development of buccal drug delivery systems. L-Cysteine was thereby covalently attached to polycarbophil (PCP) mediated by a carbodiimide. The resulting conjugate displayed 140.5+/-8.4 microM thiol groups per gram polymer. Disintegration studies were carried out with tablets based on unmodified polymer and conjugated polymer, respectively. Due to the formation of disulfide bonds within the thiolated polymer, the stability of matrix-tablets based on this polymer was strongly improved. Additionally tensile studies were carried out, which were in good correlation with further results obtained by mucoadhesion studies, using the rotating cylinder method. These results showed that tablets based on thiolated PCP remained attached on freshly excised porcine mucosa 1.8 times longer than the corresponding control. Moreover, the enzyme inhibitory properties of polymers were evaluated as well. Thiolated PCP increased the stability of the synthetic substrate for aminopeptidase N-leu-p-nitroanilide (N-leu-pNA) and the model drug leucin-enkephalin (leu-enkephalin) against enzymatic degradation on buccal mucosa. Due to the use of thiolated polymers also a controlled drug release for leu-enkephalin was guaranteed over a time period for more than 24 h. Results of the present studies suggest that thiolated polymers represent a very useful tool for buccal delivery of peptide drugs.     

In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery

Microneedles (MNs) system for transdermal drug delivery has the potential to improve therapeutic efficacy, proving an approach that is more convenient and acceptable than traditional medication systems. This study systematically researched dissolving polymer MNs fabricated from various common FDA-approved biocompatible materials, including gelatine, chitosan, hyaluronic acid (HA) and polyvinyl alcohol (PVA). Upon application of MN patches to the porcine cadaver skin, the MNs effectively perforated the skin and delivered drugs to subcutaneous tissue on contact with the interstitial fluid. Both the in vitro and in vivo drug release tests showed the similar trends but different release rates among the prepared MNs. Interestingly, the drug-release kinetics of PVA MNs were able to be altered by changing the molecular weight. To evaluate the feasibility using the proposed MNs for treating diabetes, an in vivo insulin absorption study in diabetic mice was performed. The results showed different insulin release properties of MNs fabricated from various kinds of polymer, leading to different decrease in blood glucose levels. We made a systematic and comprehensive study of some drug-loaded polymer MNs, and anticipated that dissolving polymer MNs have potential to improve therapeutic efficacy through controlled drug release.