Injectable hydrogels for targeted delivering of therapeutic molecules for tissue engineering and disease treatment

Hydrogels are cross‐linked three‐dimensional polymeric networks that play a vital role in solving the pharmacological and clinical limitations of the existing systems due to their unique physical properties such as affinity for biological fluids, tunable porous nature, high water content, ease of preparation, flexibility, and biocompatibility. Hydrogel also mimics the living natural tissue, which opens several opportunities for its use in biomedical areas. Injectable hydrogel allows temporal control and exceptional spatial arrangements and can offset hitches with established hydrogel‐based drug delivery systems. Here, we review the recent development of injectable hydrogels and their significance in the delivery of therapeutics such as cells, genes, and drug molecules and how these innovatory systems can complement the current delivery systems.     

Interplay of chemical microenvironment and redox environment on thiol-disulfide exchange kinetics

The interplay between the chemical microenvironment surrounding disulfides and the redox environment of the media on thiol-disulfide exchange kinetics was examined by using a peptide platform. Exchange kinetics of up to 34 cysteine-containing peptides were measured in several redox buffers. The electrostatic attraction/repulsion between charged peptides and reducing agents such as glutathione was found to have a very pronounced effect on thiol-disulfide exchange kinetics (differences of ca. three orders of magnitude). Exchange kinetics could be directly correlated to peptide charge over the entire range examined. This study highlights the possibility of finely and predictably tuning thiol-disulfide exchange, and demonstrates the importance of considering both the local environment surrounding the disulfide and the nature of the major reducing species present in the environment for which their use is intended (e.g., in drug delivery systems, sensors, etc).     

Polymers for targeted and/or sustained drug delivery

Recent advances in the use of polymers for passive targeting of drugs attached or incorporated into polymeric species (enhanced permeability and retention, EPR) as well as active targeting of drugs by ligands or antibodies of receptors overexpressed on the surface of the targeted cells, is discussed in the present review. Examples of sustained, slow release of a drug incorporated into a polymeric matrix are cited. Drugs used for passive modes of targeting have been described in the context of polymer‐drug conjugates, drugs in the polymer coated liposomes, and drugs inserted into polymeric micelles. Active targeting of the drugs and their internalization by receptors, on the surface of the targeted cells, was also discussed. Release of the drugs inside cells, after are broken the environmentally sensitive links attaching them to polymeric platforms was described. Examples illustrate targeting drug by local heat generated by ultrasound, or by photodynamic treatment. Delivery modes of drugs incorporated into other nanoparticles and the concept of prodrugs have been investigated. Copyright © 2008 John Wiley & Sons, Ltd.     

Glucocorticoid-loaded core-cross-linked polymeric micelles with tailorable release kinetics for targeted therapy of rheumatoid arthritis

Polymerizable and hydrolytically cleavable dexamethasone (DEX, red dot in picture) derivatives were covalently entrapped in core-cross-linked polymeric micelles that were prepared from a thermosensitive block copolymer (yellow and gray building block). By varying the oxidation degree of the thioether in the drug linker, the release rate of DEX could be controlled. The DEX-loaded micelles were used for efficient treatment of inflammatory arthritis in two animal models.     

Design and synthesis of a series of novel, cationic liposaccharide derivatives as potential penetration enhancers for oral drug delivery

Oral delivery remains a challenge for a number of drug candidates with low absorption profile (poor membrane permeability, lack of stability, solubility issues or susceptibility to enzymatic degradation) and various methodologies have been investigated to overcome it. The approach presented here consists of associating, by ion-pairing, a hydrophilic, ionizable model drug to a series of synthetic counter-ionic entities with a controlled degree of lipophilicity in order to enhance its penetration of biomembranes and offer some protection against in situ degradation, while preserving its biologically active chemical structure. We report herein the synthesis of a series of positively charged potential penetration enhancers designed from d-glucose, 2-aminododecanoic acid, and additional lipophilic amino acids, and converted afterward into quaternary ammoniums in an optimized, innovative one-step reaction. Each liposaccharide derivative synthesized was fully characterized and their ability to generate micelles in solution was assessed by isothermal titration calorimetry.     

Highly porous, water-soluble, superparamagnetic, and biocompatible magnetite nanocrystal clusters for targeted drug delivery

Magnetic particles have become very promising materials for drug delivery. However, preparation of magnetite particles with high surface area, biocompatibility, strong magnetic response, and suitable particle size still remains a major challenge. In this report, magnetite nanocrystal clusters with high surface areas were fabricated through a solvothermal process by introducing ammonium acetate as a porogen and trisodium citrate as a surface modification agent. The porosity, which was controlled by the reactant concentration, has been investigated in detail. The surface area of the nanocrystal clusters was as high as 141 m(2) g(-1). Ibuprofen, as a model drug, was entrapped into the magnetite carriers. The interfacial interaction between the carboxylic groups on the drug molecules and the carboxylate groups on the carriers enhanced the loading efficiency. Low cytotoxicity in MCF-7 cell and in vitro constant drug release behavior combined with the high drug loading efficiency and high saturation magnetization values demonstrated the potential of the as-synthesized magnetite materials in targeted drug release systems.     

Facile construction of multivalent targeted drug delivery system from Boltorn® series hyperbranched aliphatic polyester and folic acid

The conjugation of PAMAM dendrimer and folic acid is a well‐studied multivalent targeted drug delivery system, but it is expensive and difficult to be synthesized. To construct an inexpensive and well‐defined multivalent targeted drug delivery system, a cheap carrier — Boltorn® series hyperbranched aliphatic polyester — was proposed as the nanodevice to carry fluorescein, folic acid, and methotrexate. The construction follows a facile route: (1) synthesizing the carrier — a hybrid hyperbranched polymer with acyclic hydroxyls and cyclic carbonate, (2) linking fluorescein to the hyperbranched polymer via the acyclic hydroxyls, (3) opening the ring of the cyclic carbonate with the amino group of folic acid, and (4) attaching the drug methotrexate to the resulting hydroxyls by ring‐opening reaction. In this route, the peripheral hydroxyls of the hyperbranched polymer are divided into two groups and reacted with three reagents in sequence to form the desired multivalent targeted drug delivery system. Copyright © 2009 John Wiley & Sons, Ltd.     

Comparison of tungsten coil electrothermal vaporization and thermospray sample introduction methods for flame furnace atomic absorption spectrometry

Flame furnace atomic absorption spectrometry (FF-AAS) is a newly developed flame atomic absorption spectrometric technique based on arranging a flame furnace onto the top of the flame burner head. In this fundamental investigation, 25 elements were carefully tested by using either thermospray FF-AAS or tungsten coil electrothermal vaporization FF-AAS, of which 15 volatile and semi-volatile elements (Cd, Tl, Ag, Pb, Zn, Hg, Cu, Sb, Bi, Te, In, As, Se, Sn and Au) exhibited better limits of detection compared to those by conventional FAAS; however, non-volatile or refractory elements (Fe, Co, Ni, Cr, Mn, Pd, Pt, Al, Be and V) showed inferior sensitivities by the proposed methods.     

Preparation of Pixantrone/Poly(γ‐glutamic acid) Nanoparticles through Complex Self‐Assembly for Oral Chemotherapy

A facile and green approach is reported to construct pixantrone/poly(γ‐glutamic acid) nanoparticles (PIX/γ‐PGA NPs) as an oral drug delivery system through the complex self‐assembly of polyelectrolyte γ‐PGA and the anticancer drug pixantrone dimaleate (PDM). The complex self‐assembly behavior is investigated in detail. The results demonstrate that PDM can interact with γ‐PGA to conveniently form NPs and the size of NPs can be controlled by adjusting the solution volume ratio of PDM to γ‐PGA. These NPs illustrate their pH‐dependent release behavior, efficient cellular uptake and enhanced drug efficacy through an in vitro release study, flow cytometry, CLSM analysis and the MTT assay. In summary, PIX/γ‐PGA NPs may serve as a promising oral drug delivery system for cancer therapy.

     

Penetration Process of a Hydrated Deep Eutectic Solvent Through the Stratum Corneum and its Application as a Protein Penetration Enhancer

The penetration mechanism of choline chloride-glycerol deep eutectic solvent (DES) through the stratum corneum (SC) as a potential solvent for a novel enhancer of protein penetration into the skin was investigated in a wide and small angle X-ray diffraction study. We found that DES penetrated through intercellular lipids but not the corneocytes. DES seemed to extract a portion of lipids of the short lamellae in the SC. Hydrated DES with a DES to water weight ratio of 9 to 1 (9DES-1H₂O) showed the strongest interaction with the lipids in the SC compared with water, DES, and hydrated DESs with another weight ratio of DES to water (DES : water=8 : 2). In a skin penetration test with a fluorescently labelled lysozyme, 9DES-1H₂O increased the amount of penetration through the SC by two-fold compared with HEPES buffer.     

Ultrasound-Triggered Release of Ibuprofen from a Chitosan-Mesoporous Silica Composite- a Novel Approach for Controlled Drug Release

Summary: In this work, an attempt was made to synthesize a novel Chitosan-Mesoporous silica (CS-MS) hybrid composite to design a drug delivery system based on ultrasound triggered stimuli-responsive smart release. The in-vitro drug release properties of both the Mesoporous Silica (MS) and Chitosan (CS) hybrids were investigated. Ibuprofen (Ibu) was used as a model drug. The results from powder X-Ray diffraction (XRD) patterns, and BET N₂ adsorption isotherms exhibited that MS can accommodate drug molecules into the lumen of the channels and pores. Drug release, stimulated by temperature and pH of the release media was also investigated. We studied the Ultrasound (US) triggered release of Ibu in a simulated body fluid (pH 7.4). The results exhibited that US can be used as a non-invasive technique for drug release from polymeric materials. The enhancing effect of ultrasound on drug release is due to the Cavitation effect, without causing any significant destruction on the polymer morphology.     

Competitive Affinity Release for Long‐Term Delivery of Antibodies from Hydrogels

With increased clinical use of antibodies, long‐term delivery strategies are needed to decrease injection frequency and improve health outcomes. A three‐component drug‐delivery system was developed for competitive affinity release of a streptavidin–antibody conjugate from agarose–desthiobiotin hydrogels via controlled dissolution of sparingly soluble biotin derivatives. The antibody conjugate was localized in the hydrogel through streptavidin–desthiobiotin complexation. Dissolution of sparingly soluble biotin derivatives disrupts streptavidin–desthiobiotin complexation for controlled release of the antibody conjugate. Release was tuned by altering the total biotin derivative concentration without further hydrogel or antibody modification. First‐order tunable release of bioactive Avastin, a therapeutic anti‐VEGF antibody, was demonstrated from a non‐cytotoxic system for over 100 days.     

Block copolymer micelles conjugated with anti‐EGFR antibody for targeted delivery of anticancer drug

Antiepidermal growth factor receptor antibody (anti‐EGFR antibody) was conjugated with the block copolymer micelle based on poly(ethylene glycol) (PEG) and poly(ε‐caprolactone) (PCL) for active targeting to EGFR overexpressing cancer cells. Doxorubicin (DOX) was encapsulated in the core of the block copolymer (MePEG‐b‐PCL) micelle (DOX‐micelle). The mean diameters of the DOX‐micelle and the anti‐EGFR‐PEG‐b‐PCL copolymer micelles loaded with DOX (DOX‐anti‐EGFR‐micelle) were about 25 and 31 nm, respectively. The RKO human colorectal cancer cells expressing moderate degree of EGFR were incubated with free DOX, DOX‐micelle, or DOX‐anti‐EGFR‐micelle to study the distribution of DOX in the cells. When cells were incubated with free DOX, moderate degree of DOX fluorescence was observed in the nuclei. In the cells treated with DOX‐micelle, the DOX fluorescence intensity in the cytoplasm was much greater than that in the nuclei. On the other hand, the nuclei of the cells treated with DOX‐anti‐EGFR‐micelle exhibited DOX fluorescence intensity similar to that in the cytoplasm. The cytotoxicity of DOX‐anti‐EGFR‐micelle to induce apoptosis in RKO cells was significantly greater than that of free DOX or DOX‐micelle. These results demonstrated that the presence of anti‐EGFR antibody on the DOX‐micelle surface (DOX‐anti‐EGFR‐micelle) increased the internalization of the DOX‐micelle and nuclear accumulation of DOX, and enhanced the DOX‐induced cell death. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7321–7331, 2008     

Deep eutectic solvents as both active fillers and monomers for frontal polymerization

The deep eutectic solvents (DESs) based on the mixtures of a variety of ammonium salts and hydrogen bond donors containing acrylic acids and acrylamides are capable of sustaining frontal polymerization (FP). The selection of ammonium salt affects the reactivity and allows FP at relatively low temperature but with full conversion. Also, full conversion allows us to use these polymers for biomedical applications (e.g., drug delivery systems) as the unreactive ammonium salts can be released from the resulting polymer without by‐products. We call these components “active fillers,” which can be ammonium salts with biological or pharmaceutical importance. For instance, we prepared poly(acrylic acid) loaded with lidocaine hydrochloride (a common anesthetic), the release of which was found to occur in a controlled fashion. The ammonium salts also create a sufficiently high viscosity to suppress buoyancy‐driven convection without additional materials. The DES here described played an all‐in‐one role, providing the monomer, the active filler, and the polymerization medium for FPs. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Electrospinning nanofibers of microbial polyhydroxyalkanoates for applications in medical tissue engineering

Differently to most chemically synthesized medical materials, polyhydroxyalkanoates (PHAs) are intracellular carbon and energy storage granules, which is a family of natural bio-polymers synthesized by microorganism's materials. Due to excellent biocompatibility reasonable biodegradability and versatile material difference, PHAs are well medical biomaterials candidates for applications in tissue engineering and drug delivery, including commercial PHB, PHBV, PHBHHx, PHBVHHx, P34HB and few uncommercial PHAs. Electrospinning nanofibers with the size of 10–10,000 nm can improve the mechanical properties and decrease the crystallinity of PHA, meanwhile simulate the structure and function of native extracellular matrix of cells. Hence, PHAs electrospinning nanofibers as engineered scaffolds have been widely used for tissue engineering scaffolds in cardiovascular, vascular, nerve, bone, cartilage and skin; also, as carriers for application in drug delivery system. In this review, we highlight the extraction and properties of medical PHAs from natural or engineered microorganism, and microstructure, current manufacturing techniques and medical applications of electrospinning nanofibers of PHAs. Moreover, the current challenges and prospects of PHAs electrospinning nanofibers are discussed rationally, providing an insight into developing vibrant fields of PHAs electrospinning nanofibers-based biomedicine.