Generic, anthracene-based hydrogel crosslinkers for photo-controllable drug delivery

Light‐responsive polymers with controllable, reversible crosslink mechanisms have the potential to create unique biomaterials with stimulus‐controlled swelling, degradation and diffusion properties useful in tissue engineering and drug delivery applications. Generic photodimerizing polyethylene glycol–anthracene macromolecules that may be grafted to various polymers to effectively control their crosslinking via a photodimerization mechanism have been developed. These generic crosslinkers were shown to effectively introduce photoresponsive properties into hyaluronate and alginate as model hydrophilic polymers. In vitro testing using human corneal epithelial cells was used to demonstrate cytocompatibility of the resulting photogels. The effective crosslinking density of the photogels could be increased resulting in a decrease in the release rate of small and large molecules from the photogels following exposure to 365 nm light. This tuneable crosslinking has the potential to manipulate the delivery rates of therapeutics resulting in control over treatment profiles and may lend itself to various applications, which may benefit from light induced changes in crosslinking.

     

Biodegradable thermo‐ and pH‐responsive hydrogels for oral drug delivery

In this article, novel smart hydrogels based on biodegradable pH sensitive poly(L ‐glutamic acid‐g‐2‐hydroxylethyl methacrylate) (PGH) chains and temperature‐sensitive hydroxypropylcellulose‐g‐acrylic acid (HPC‐g‐AA) segments were designed and synthesized. The influence of pH and temperature on the equilibrium swelling ratios of the hydrogels was discussed. The optical transmittance of the hydrogels was also changed as a function of temperature, which reflecting that the HPC‐g‐AA part of the hydrogels became hydrophobic at the temperature above the lower critical solution temperature (LCST). At the same time, the LCST of the hydrogels had a visible pH‐dependent behavior. Scanning electron microscopic analysis revealed the morphology of the hydrogels before and after enzymatic degradation. The biodegradation rate of the hydrogels was directly related to the PGH content and the pH value. The in vitro release of bovine serum albumin from the hydrogels were investigated. The release profiles indicated that both the HPC‐g‐AA and PGH contents played important roles in the drug release behaviors. These results show that the smart hydrogels seem to be of great promise in pH–temperature oral drug delivery systems. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis and characterization of star oligo/poly(2,2‐dimethyltrimethylene carbonate)s containing cholic acid moieties

Star oligo/poly(2,2‐dimethyltrimethylene carbonate)s containing cholic acid moieties were synthesized through the ring‐opening polymerization of 2,2‐dimethyltrimethylene carbonate (DTC) initiated by cholic acid with hydroxyl groups. Through the control of the feed ratio of the initiator cholic acid to the monomer DTC, a series of star oligomers/polymers with different molecular weights were obtained. The star oligomers/polymers were characterized with Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, combined size exclusion chromatography/multi‐angle laser light scattering analysis, wide‐angle X‐ray scattering, polarizing light microscopy, and differential scanning calorimetry. Compared with linear poly(2,2‐dimethyltrimethylene carbonate), these star oligo/poly(2,2‐dimethyltrimethylene carbonate)s had much faster hydrolytic degradation rates. With one of the star oligomers/polymers, a microsphere drug‐delivery system of a submicrometer size was fabricated with a very convenient ultrasonic dispersion method that did not involve toxic organic solvents. The in vitro drug release was studied. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6688‐6696, 2006     

Synthesis and characterization of a microsphere‐based coating for textiles with potential as an in situ bioactive delivery system

Proteinaceous microspheres have a wide range of biomedical applications, including their use as drug delivery systems. On the other hand, bioactive and antimicrobial textiles are promising substrates for medical care, in particular, as wound‐dressings. This work relates the development of a new process for the functionalization of textiles through the simultaneous formation and linkage of protein‐based microspheres onto textile fibers by sonochemical techniques. The microspheres developed by this process possess antimicrobial properties by themselves, but other may be incorporated by the encapsulation of various pharmaceutical formulations. This new type of microspheres and particularly their fixation onto textile materials encourage the development of textiles that can be used as delivery systems in a simple, fast, and non‐toxic process. Here it is reported the production of microspheres with a combination of bovine serum albumin (BSA), L ‐Cysteine (L ‐Cys), and n‐dodecane, using the ultrasound technology. The size distribution and morphology of the microspheres was determined as a function of several parameters such as irradiation time and BSA and L ‐Cys concentrations. The produced microspheres were analyzed using a laser light scattering size analyzer, an optical microscope and a scanning electron microscope. The new coating of BSA + L ‐Cys microspheres revealed a high stability and excellent antibacterial properties being a promising alternative to design textile‐based bioactive delivery systems with potential application in the development of textile‐based wound‐dressings. Copyright © 2011 John Wiley & Sons, Ltd.     

UV-photocrosslinking of inulin derivatives to produce hydrogels for drug delivery application

In this work, INU, a natural polysaccharide, has been chemically modified in order to obtain new photocrosslinkable derivatives. To reach this goal, INU has been derivatized with MA thus obtaining four samples (INU-MA derivatives) as a function of the temperature and time of reaction. An aqueous solution of the derivative INU-MA1 was irradiated by using a UV lamp with an emission range from 250 to 364 nm and without using photoinitiators. The obtained hydrogel showed a remarkable water affinity but it underwent a partial degradation in simulated gastric fluid. To overcome this drawback, INU-MA1 was derivatized with SA thus obtaining the INU-MA1-SA derivative designed to produce a hydrogel showing a low swelling and an increased chemical stability in acidic medium. Ibuprofen, as a model drug, was loaded by soaking into INU-MA1 and INU-MA1-SA hydrogels and its release from these matrices was evaluated in simulated gastrointestinal fluids. INU-MA1 hydrogel showed the ability to quickly release the entrapped drug thus indicating its potential as a matrix for an oral formulation. INU-MA1-SA hydrogel showed a pH-responsive drug delivery. Therefore it is a promising candidate for controlled drug release in the intestinal tract.     

Polymer Micro‐ and Nanocapsules as Biological Carriers with Multifunctional Properties

The design and development of multifunctional polymer capsules with controlled chemical composition and physical properties has been the focus of academic and industrial research in recent years. Especially in the biomedical field, the formulation of novel polymer‐based encapsulation systems for the early‐stage disease diagnostic and effective delivery of bioactive agents represent one of the most rapidly advancing areas of science. The stimuli‐responsive release of cargo molecules from the carrier gains remarkable attention for in vitro and in vivo delivery of contrast agents, genes, and pharmaceutics. In this Review, the current status and the challenges of different polymer‐based micro‐ and nanocapsule formulations are considered, emphasizing on their potential biological application as carriers for specific drug targeting and controlled release upon applying of external stimulus.     

Synthesis of pH‐responsive photocrosslinked hyaluronic acid‐based hydrogels for drug delivery

Photocrosslinked hyaluronic acid/poly(vinyl alcohol)‐styrylpyridinium (HA/PVA‐SbQ) hydrogels were synthesized for controlled antitumor drug delivery. The photocrosslinking reaction was rapid, and the time required for completely converting into the insoluble hydrogels was less than 500 s on exposure to 5 mW/cm² UV light irradiation. The resulting hydrogels exhibited sensitivity to the pH value of the surrounding environment. Scanning electron microscopic analysis revealed that the morphology and the pore size of the hydrogels could be controlled by changing the ratio of HA and PVA‐SbQ in the formulations. Paclitaxel (PTX)‐loaded hydrogel could also be formed rapidly by UV irradiation of a mixed solution of HA/PVA‐SbQ and PTX. Release profiles of PTX from the hydrogels showed pH‐dependent and sustained manner. Moreover, our data revealed that PTX released from the HA hydrogels remained biologically active and had the capability to kill cancer cells. In contrast, control groups of HA hydrogels without PTX did not exhibit any cytotoxicity. This study demonstrates the feasibility of using HA‐based hydrogels as a potential carrier for chemotherapeutic drugs for cancer treatments. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Reducible polyethylenimine hydrogels with disulfide crosslinkers prepared by michael addition chemistry as drug delivery carriers: Synthesis,properties, and in vitro release

Degradable hydrogels crosslinked with disulfide bonds were prepared by Michael addition between amine groups of branched polyethylenimine and carbon–carbon double bonds of N,N′‐bis(acryloyl)cystamine. The influences of the chemical composition of the resulted hydrogels on their properties were examined in terms of morphology, surface area, swelling kinetics, and degradation. The hydrogels were uniformly crosslinked and degraded into water‐soluble polymers in the presence of the reducing agent of dithiothreitol, which improved the control over the release of encapsulated drug. The degradation of hydrogels can trigger the release of encapsulated molecules, as well as facilitate the removal of empty vehicles. Results obtained from in vitro drug release suggested that the disulfide crosslinked hydrogels exhibited an accelerated release of encapsulated drug in dithiothreitol‐containing PBS buffer solution. Moreover, the drug release rate decreased gradually with increasing crosslinking density. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4074–4082, 2009     

Synthesis and characterization of a biodegradable ABC triblock terpolymer as co‐delivery carrier of doxorubicin and DNA

This study is aimed to develop a well‐defined ABC triblock terpolymer, poly(ethylethylene phosphate)‐block‐poly(ε‐caprolactone)‐block‐poly[2‐(dimethylamino)ethyl methacrylate] (PEEP‐b‐PCL‐b‐PDMAEMA), for co‐encapsulating anticancer drug doxorubicin (DOX) and DNA to form polyplexes. The terpolymer is first synthesized via a combination of ring‐opening polymerization and atom‐transfer radical polymerization techniques, and characterized by ¹H NMR and gel permeation chromatography. Subsequently, the self‐assembly behavior of the terpolymer and the micelles loaded with DOX or DNA are investigated by dynamic light scattering, ζ potential, transmission electron microscopy, and gel retardation assay, respectively. In vitro release study reveals that much more DOX is released at pH 5.0 than that at pH 7.4 in the same period. The simultaneous delivery of DOX and green fluorescent protein (GFP)‐labeled DNA is studied by a fluorescence microscope and the results demonstrate that both drug and GFP–DNA can be efficiently delivered into HeLa cells. This system presents a practical and promising carrier for the co‐delivery of drugs and genes. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3005–3016     

Influence of Solute Charge and Hydrophobicity on Partitioning and Diffusion in a Genetically Engineered Silk‐Elastin‐Like Protein Polymer Hydrogel

The influence of solute hydrophobicity and charge on partitioning and diffusion in physically crosslinked networks of a genetically engineered SELP polymer was investigated. A series of fluorescent dyes were used to assess the impact of solute charge and hydrophobicity on release behavior. The mechanism of solute release from the SELP hydrogel appeared to vary as a function of dye hydrophobicity. The extent of FITC attachment to amine‐terminated G4 dendrimers influenced SELP hydrogel partitioning more than dendrimer diffusion properties. Results suggest the possibility of controlling solute release from SELP hydrogels by modifying the hydrophobicity and surface charge of drugs and drug/polymer conjugates as well as the possibility of “designing‐in” solute‐specific interactions.

     

Redox‐ and pH‐Responsive Cysteamine‐Modified Poly(aspartic acid) Showing a Reversible Sol–Gel Transition

Synthesis and characterization of a pH‐ and redox‐sensitive hydrogel of poly(aspartic acid) are reported. Reversible gelation and dissolution are achieved both in dimethylformamide and in aqueous medium via a thiol‐disulphide interconversion in the side chain of the polymers. Structural changes are confirmed by Raman microscopy and rheological measurements. Injectable aqueous solutions of thiolated poly(aspartic acid) can be converted into mechanically stable gels by oxidation, which can be useful for drug encapsulation and targeted delivery. Reduction‐facilitated release of an entrapped drug from disulphide cross‐linked hydrogels is studied.

     

A New Approach for in vitro Imaging of Breast Cancer Cells by Anti‐Metadherin Targeted PVA‐Pyrene

Poly(vinyl alcohol)‐pyrene‐anti‐metadherin (PVA‐Py‐(Anti‐MTDH)), a novel antibody based water soluble probe containing both fluorescent and target sites in the structure for in vitro imaging of breast cancer cells is reported here. Since breast cancer cells have an excess of MDTH protein expressed on the surface, a PVA‐Py prepared by “Click chemistry” approach is targeted by Anti‐MTDH antibody and applied to the MCF‐7 cell line. After characterization, the designed architecture was evaluated in terms of cell incorporation efficiency and compared with a non‐targeted structure (PVA‐Py). Atomic force microscopy (AFM) and fluorescence microscopy images of cells after incubation of the probe molecules were also obtained to monitor the interaction of the probes with the cancerous cells.

     

Design of a poly(L‐histidine)‐carbohydrate conjugate for a new pH‐sensitive drug carrier

A poly(L ‐histidine) (PLH)‐carbohydrate conjugate has been synthesized as a new macromolecule extracting pH‐dependent properties of PLH with imidazole groups. Because of poor water solubility at physiological pH, the application of PLH with a pK_a around 6.0 has been limited in spite of the native possession of the pH‐dependent property change at endosomal pH. Although the PLH modified with aliphatic primary amino groups suddenly precipitated out of the aqueous medium above pH 6.0 as a result of the deprotonation of the imidazole groups, the water solubility of PLH was improved at physiological pH by the conjugation of the aminated PLH with hydrophilic maltopentaose. The resulting PLH‐maltopentaose conjugates and metalloporphyrins formed the complexes which varied their assembling structure below pH 6.0. The PLH‐maltopentaose would be the fundamental compound for designing various drug carriers with the pH sensitivity at endosomal pH. Copyright © 2004 John Wiley & Sons, Ltd.     

Dual thermo‐ and pH‐sensitive network‐grafted hydrogels formed by macrocrosslinker as drug delivery system

Dual thermo‐ and pH‐sensitive network‐grafted hydrogels made of poly(N,N‐dimethylaminoethyl methacrylate) (PDMAEMA) network and poly(N‐isopropylacrylamide) (PNIPAM) grafting chains were successfully synthesized by the combination of atom transfer radical polymerization (ATRP), reversible addition‐fragmentation chain transfer (RAFT) polymerization, and click chemistry. PNIPAM having two azide groups at one chain end [PNIPAM‐(N₃)₂] was prepared with an azide‐capped ATRP initiator of N,N‐di(β‐azidoethyl) 2‐chloropropionylamide. Alkyne‐pending poly(N,N‐dimethylaminoethyl methacrylate‐co‐propargyl acrylate) [P(DMAEMA‐co‐ProA)] was obtained through RAFT copolymerization using dibenzyltrithiocarbonate as chain transfer agent. The subsequent click reaction led to the formation of the network‐grafted hydrogels. The influences of the chemical composition of P(DMAEMA‐co‐ProA) on the properties of the hydrogels were investigated in terms of morphology and swelling/deswelling kinetics. The dual stimulus‐sensitive hydrogels exhibited fast response, high swelling ratio, and reproducible swelling/deswelling cycles under different temperatures and pH values. The uptake and release of ceftriaxone sodium by these hydrogels showed both thermal and pH dependence, suggesting the feasibility of these hydrogels as thermo‐ and pH‐dependent drug release devices. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Self‐immolative dendrimers as novel drug delivery platforms

Self‐immolative dendrimers were recently developed and introduced as a potential platform for a single‐triggered multi‐prodrug. These unique structural dendrimers can release all of their tail units through domino‐like chain fragmentation, which is initiated by a single cleavage at the dendrimer core. The incorporation of drug molecules as the tail units and an enzyme substrate as the trigger generates a multi‐prodrug unit that is activated with a single enzymatic cleavage. We have demonstrated several examples of self‐immolative dendritic prodrug systems and have shown significant advantages with respect to the appropriate monomeric prodrug. We anticipate that single‐triggered, dendritic prodrugs will be exploited to further improve selective chemotherapeutic approaches in cancer therapy. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 1569–1578, 2006     

Designing responsive microgels for drug delivery applications

Microgels based on thermally responsive polymers have been widely investigated in the context of controlled release applications, with increasing recent interest on developing a clearer understanding of what physical, chemical, and biological parameters must be considered to rationally design a microgel to deliver a specific drug at a specific rate in a specific physiological context. In this contribution, we outline these key design parameters associated with engineering responsive microgels for drug delivery and discuss several recent examples of how these principles have been applied to the synthesis of microgels or microgel-based composites. Overall, we suggest that in vivo assessment of these materials is essential to bridge the existing gap between the fascinating properties observed in the lab and the practical use of microgels in the clinic. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3027–3043     

Hybrid alginate beads with thermal‐responsive gates for smart drug delivery

Polysaccharide‐based thermo‐responsive material was prepared by grafting PNIPAAm onto hybrid alginate beads, in which a biomineralized polyelectrolyte layer was constructed aiming to enhance the mechanical strength and ensure higher graft efficiency. XPS results demonstrated that the incorporation of PNIPAAm to the hybrid beads was successful, and the PNIPAAm‐grafted beads were more hydrophilic than the ungrafted ones as indicated by their swelling behavior. The drug release behaviors revealed that the grafted beads were both thermo‐ and pH‐sensitive, and the PNIPAAm existed in the pores of the alginate beads acted as the “on–off” gates: the pores of the beads were covered by the stretched PNIPAAm to delay the drug release at 25°C and opened to accelerate the drug release at 37°C because of the shrinking of PNIPAAm molecules. This paper would be a useful example of grafting thermo‐responsive polymers onto biodegradable natural polymer substrate. The obtained beads provide a new mode of behavior for thermo‐responsive “smart” polysaccharide materials, which is highly attractive for targeting drug delivery system and chemical separation. Copyright © 2010 John Wiley & Sons, Ltd.     

Poly(DL‐Lactide‐co‐ε‐Caprolactone)/Poly(Acrylic Acid) Composite Implant for Controlled Delivery of Cationic Drugs

Poly(DL‐lactide‐co‐ε‐caprolactone)/poly(acrylic acid) implantable composite reservoirs for cationic drugs are synthesized by sequentially applying photoirradiation and liquid phase inversion. The chemical composition and microstructure of reservoirs are characterized with Fourier transform infrared spectroscopy‐attenuated total reflection (FTIR‐ATR) and scanning electron microscopy (SEM), respectively. Drug loading and release properties are investigated using methylene blue as the drug model. Biocompatibility of reservoirs is examined through a series of in vitro tests and an in vivo experiment of subcutaneous implantation in Dark Agouti rats. Reservoirs show good ion‐exchange capacity, high water content, and fast reversible swelling with retained geometry. Results of drug loading and release reveal excellent loading efficiency and diffusion‐controlled release during 2 weeks. Biocompatibility tests in vitro demonstrate the lack of implant proinflammatory potential and hindered adhesion of L929 cells on the implant surface. Implants exhibit low acute toxicity and elicit a normal acute foreign body reaction that reaches the early stages of fibrous capsule formation after 7 days.     

Self‐Rolled Polymer Tubes: Novel Tools for Microfluidics,Microbiology, and Drug‐Delivery Systems

Recent work on the fabrication of tubular microstructures via self‐rolling of thin, bilayer polymer films is reviewed. A bending moment in the films arises due to the swelling of one component of the bilayer in a selective solvent. The inner diameters of the tubes vary from hundreds of nanometers to dozens of micrometers. The position of the tubes on the substrate and their length can be preset by photolithographic patterning of the bilayer. Prior to rolling, the bilayers can be exposed to different methods of surface functionalization, providing opportunities for engineering the microtube inner surfaces for use in microfluidic circuits and “microbiological” applications. The self‐rolling approach is promising for the development of novel drug‐ and cell‐delivery systems, as well as for tissue engineering.     

Konjac glucomannan‐graft‐acrylic acid hydrogels containing azo crosslinker for colon‐specific delivery

In this article, the synthesis and characterization of novel hydrogel systems designed for colon‐targeting drug delivery are reported. The gels were composed of konjac glucomannan, copolymerized with acrylic acid, and crosslinked by the aromatic azo agent bis(methacryloylamino)‐azobenzene. The influence of various parameters on the dynamic and equilibrium swelling ratios (SRs) of the hydrogels was investigated. It is shown that the SR was inversely proportional to the grafting degree of acrylic acid and the content of bis(methacryloylamino)‐azobenzene. The dependence of SR on the pH indicates that obtained hydrogels are potential for drug delivery to colon. It was possible to modulate the degree of swelling and the pH sensitivity of the gels by changing crosslinking density of the polymer. The main chain of hydrogels can be degraded by β‐glycosidase which is abundant in colon. They can be in vitro degraded for 73% in a month by Cereflo® and 86% in 20 days by Mannaway25L. We have also prepared the hydrogels that loaded with bovine serum albumin about 1.5%, 3%, 9%, and 20% by weight. In vitro release of model drug bovine serum albumin was studied in the presence of Mannaway25L or Fungamyl®800L in pH 7.4 phosphate buffer at 37 °C. The drug release can be controlled by the biodegradation of the hydrogels. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4370–4378, 2004