Enzyme immobilization is of high interest for industrial applications. However, immobilization may compromise enzyme activity or stability due to the harsh conditions which have to be applied. The authors therefore present a new and improved crosslinked layer‐by‐layer (cLbL) approach. Two different model enzymes (acid phosphatase and β‐galactosidase) are immobilized under mild conditions on biocompatible, monodisperse, sub‐micrometer poly(lactide‐co‐glycolide) (PLGA) particles. The resulting PLGA enzyme systems are characterized regarding their size, surface charge, enzyme activity, storage stability, reusability, and stability under various conditions such as changing pH and temperature. The developed and characterized cLbL protocol can be easily adapted to different enzymes. Potential future uses of the technology for biomedical applications are discussed. PLGA‐enzyme particles are therefore injected into the blood circulation of zebrafish embryos in order to demonstrate the in vivo stability and activity of the designed system.
Although chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western world, it remains incurable with conventional chemotherapeutic agents. Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is an antitumor candidate in cancer therapy. This study examines the proapoptotic effects of poly(propylene imine) (PPI) glycodendrimers modified with the maltotriose residues (PPI‐G4‐OS‐Mal‐III and PPI‐G4‐DS‐Mal‐III) on the TNF family in CLL cells. The combination of an understanding of the signaling pathways associated with CLL and the development of a molecular profiling is a key issue for the design of personalized approaches to therapy. Gene expression is determined with two‐color microarray 8 × 60K. The findings indicate that PPI‐G4‐OS/DS‐Mal‐III affect gene expression from the TRAIL apoptotic pathway and exert a strong effect on CLL cells comparable with fludarabine. Dendrimer‐targeted technology may well prove to bridge the gap between the ineffective treatment of today and the effective personalized therapy of the future.
Combined treatment is more effective than single treatment against most forms of cancer. In this work, doxorubicin loaded chitosan–W18O49 nanoparticles combined with the photothermal therapy and chemotherapy are fabricated through the electrostatic interaction between positively charged chitosan and negatively charged W18O49 nanoparticles. The in vitro and in vivo behaviors of these nanoparticles are examined by dynamic light scattering, transmission electron microscopy, cytotoxicity, near‐infrared fluorescence imaging, and tumor growth inhibition experiment. These nanoparticles have a mean size around 110 nm and show a pH sensitive drug release behavior. After irradiation by the 980 nm laser, these nanoparticles show more pronounced cytotoxicity against HeLa cells than that of free doxorubicin or photothermal therapy alone. The in vivo experiments confirm that their antitumor ability is significantly improved, resulting in superior efficiency in impeding tumor growth and extension of the lifetime of mice.
Using the third‐generation Grubbs catalyst, the living ring‐opening metathesis polymerization of ferrocene/cobalticenium copolymers is conducted with theoretical numbers of 25 monomer units for each block, and their redox and electrochemical properties allow using the Bard–Anson electrochemical method to determine the number of metallocenyl units in each block.
A multicomponent functional polymer is synthesized to support specific reactivity for successful conjugation with the vast array of functionality present in biological systems and the flexibility to conjugate biomolecules without requiring additional modification to install a terminal functional group. The multifunctional surface is realized using a novel coating composed of distinct N‐hydroxysuccinimide (NHS) ester and benzoyl functionalities, which can provide accessibility to both the NHS ester‐amine coupling reaction and the photochemically induced benzophenone crosslinking reaction, respectively. In addition, the multifunctional polymer is fabricated and transformed to form nanoscale colloids through the solvent displacement of a water/DMF system due to solubility characteristics of the resulting polymer with high polarity. A facile and efficient fabrication approach using the multifunctional nanocolloid is thus demonstrated to create a drug carrier by installing paclitaxel and folic acid for targeted cancer therapy.
In this study, double‐emulsion capsules (DECs) capable of concealing drug‐incorporated targeted‐supermolecules are developed to achieve “on‐demand” supermolecule release and enhanced sequential targeting for magneto‐chemotherapy. These water‐in‐oil‐in‐water DECs less than 200 nm in diameter are synthesized using a single component of PVA (polyvinyl alcohol) polymer and the magnetic nanoparticles, which are capable of encapsulating large quantities of targeted supermolecules composed of palitaxel‐incorporated beta‐cyclodextrin decorated by hyaluronic acid (HA, a CD44‐targeting ligand) in the watery core. The release profiles (slow, sustained and burst release) of the targeted supermolecules can be directly controlled by regulating the high‐frequency magnetic field (HFMF) and polymer conformation without sacrificing the targeting ability. Through an intravenous injection, the positive targeting of the supermolecules exhibited a 20‐fold increase in tumor accumulation via the passive targeting and delivery of DECs followed by positive targeting of the supermolecules. Moreover, this dual‐targeting drug‐incorporated supermolecular delivery vehicle at the tumor site combined with magneto‐thermal therapy suppressed the cancer growth more efficiently than treatment with either drug or supermolecule alone.
Current state‐of‐the‐art management of open spina bifida defects entails an open fetal surgery approach associated with significant morbidities. In an attempt to reduce these risks and provide for an earlier minimally invasive repair, it is aimed to develop and characterize an innovative alternative using a unique reverse thermal gel. This study focuses on characterization of the physical and biological properties of the polymer and its in vivo applicability. Based on the knowledge and benchmarking, the “ideal” biomaterial should have the following characteristics: stability in amniotic fluid, limited permeability, biocompatibility, biologically functional, nontoxic, ability to support cellular functions, and in vivo applicability. The results demonstrate that the polymer possesses a unique ultrastructure, is stable in amniotic fluid, possesses limited yet predictable permeability, biocompatible with cells exposed in neural tube defects, is nontoxic, and can support cellular migration. These characteristics make it a potential novel alternative to open fetal repairs.
Recombinant protein design allows modular protein domains with different functionalities and responsive behaviors to be easily combined. Inclusion of these protein domains can enable recombinant proteins to have complex responses to their environment (e.g., temperature‐triggered aggregation followed by enzyme‐mediated cleavage for drug delivery or pH‐triggered conformational change and self‐assembly leading to structural stabilization by adjacent complementary residues). These “smart” behaviors can be tuned by amino acid identity and sequence, chemical modifications, and addition of other components. A wide variety of domains and peptides have smart behavior. This review focuses on protein designs for self‐assembly or conformational changes due to stimuli such as shifts in temperature or pH.
Cell sorting is important for cell biology and regenerative medicine. A visible light‐responsive cell scaffold is produced using gold nanoparticles and collagen gel. Various kinds of cells are cultured on the visible light‐responsive cell scaffold, and the target cells are selectively detached by photoirradiation without any cytotoxicity. This is a new image‐guided cell sorting system.
A visible light and pH responsive anticancer drug delivery system based on polymer‐coated mesoporous silica nanoparticles (MSNs) has been developed. Perylene‐functionalized poly(dimethylaminoethyl methacrylates) sensitive to visible light and pH are electrostatically attached on the surface of MSNs to seal the nanopores. Stimulation of visible light and acid can unseal the nanopores to induce controlled drug release from the MSNs. More interestingly, the release can be enhanced under the combined stimulation of the dual‐stimuli. The synergistic effect of visible light and acid stimulation on the efficient release of anticancer drugs from the nanohybrids endows the system with great potential for cancer therapy.
The authors report on series of side‐chain smectic liquid crystal elastomer (LCE) cell scaffolds based on star block‐copolymers featuring 3‐arm, 4‐arm, and 6‐arm central nodes. A particular focus of these studies is placed on the mechanical properties of these LCEs and their impact on cell response. The introduction of diverse central nodes allows to alter and custom‐modify the mechanical properties of LCE scaffolds to values on the same order of magnitude of various tissues of interest. In addition, it is continued to vary the position of the LC pendant group. The central node and the position of cholesterol pendants in the backbone of ε‐CL blocks (alpha and gamma series) affect the mechanical properties as well as cell proliferation and particularly cell alignment. Cell directionality tests are presented demonstrating that several LCE scaffolds show cell attachment, proliferation, narrow orientational dispersion of cells, and highly anisotropic cell growth on the as‐synthesized LCE materials.
This blinded controlled prospective randomized study investigates the biocompatibility of polypyrrole (PPy) polymer that will be used for intracranial triggered release of anti‐epileptic drugs (AEDs). Three by three millimeters PPy are implanted subdurally in six adult female genetic absence epilepsy rats from Strasbourg. Each rat has a polymer implanted on one side of the cortex and a sham craniotomy performed on the other side. After a period of seven weeks, rats are euthanized and parallel series of coronal sections are cut throughout the implant site. Four series of 15 sections are histological (hematoxylin and eosin) and immunohistochemically (neuron‐specific nuclear protein, glial fibrillary acidic protein, and anti‐CD68 antibody) stained and evaluated by three investigators. The results show that implanted PPy mats do not induce obvious inflammation, trauma, gliosis, and neuronal toxicity. Therefore the authors conclude the PPy used offer good histocompatibility with central nervous system cells and that PPy sheets can be used as intracranial, AED delivery implant.
Using colloidal polyacrylamide (PAAm) microgels as carriers, a novel strategy for covalent immobilization of enzymes maintained in hydrated microenvironment on/in a macroporous surface‐functionalized hydrophobic polyvinylidene fluoride (PVDF) membrane is developed. The PAAm microgels are synthesized by inverse miniemulsion polymerization, and first the parameters are investigated which are suited to obtain particles in the desired size range, 100–200 nm, with narrow size distribution. Amino functions are then imparted to the microgels applying the Hofmann reaction. The modification is confirmed by Fourier‐transform infrared spectroscopy analysis, ninhydrin test, and elemental analysis. In addition, functionalized microgels are characterized by dynamic light scattering. The amino‐functionalized PAAm microgels are then immobilized on pre‐modified PVDF membrane having aldehyde functionalities on the surface. Afterward, unreacted aldehyde groups still present on the membrane where quenched by ethanolamine and the enzyme lipase from Candida rugosa (LCR) is subsequently immobilized on the microgels loaded PVDF membrane via glutaraldehyde cross‐linking, exploiting the free amino groups on immobilized microgels. Catalytic efficiency of LCR immobilized by this strategy is evaluated using para‐nitrophenyl palmitate as substrate and compared with LCR directly immobilized on PVDF membrane without microgels. Results show that LCR immobilized by means of microgels exhibits better performance with a 2.3‐fold higher specific biocatalytic activity.
Polydimethylsiloxane (PDMS) constitutes an interesting material for a variety of biomedical applications, especially as intraocular lenses (IOLs), for its excellent transparency. In this work, a photoreversible PDMS‐coumarin network, whose shape and properties can be adjusted postoperatively in a noninvasive manner, is developed. The synthesis of PDMS‐coumarin is achieved by amidation of a coumarin acid chloride derivative with amine‐functionalized PDMSs. Under exposure of λ > 300 nm, these polymers can be cured by dimerization of coumarin. The cured polymers can be uncrosslinked via photocleavage of cyclobutane dimers upon illumination at λ < 290 nm. The diffusion of linear PDMSs in a crosslinked network and the controlled shape modification are studied, which demonstrate that these polymers are good candidates for adjustable IOL application. IOL disks prepared from these materials show high hydrophobicity and good transparency. In vitro cytotoxicity, lens epithelial cell adhesion assays, and rabbit host reaction against implanted disks demonstrate the biocompatibility of the polymer.
Overcoming drug resistance is a major challenge for cancer therapy. Tumor necrosis factor α‐related apoptosis‐inducing ligand (TRAIL) is a potent therapeutic as an activator of apoptosis, particularly in tumor but not in healthy cells. However, its efficacy is limited by the resistance of tumor cell populations to the therapeutic substance. Here, we have addressed this limitation through the development of a controlled release system, matrix‐metalloproteinase (MMP)‐sensitive and arg‐gly‐asp‐ser (RGDS) peptide functionalized poly (ethylene‐glycol) (PEG) particles which are synthesized via visible‐light‐induced water‐in‐water emulsion polymerization. Quinacrine (QC), a recently discovered TRAIL sensitizer drug, is loaded into the hydrogel carriers and the influence of this system on the apoptosis of a malignant type of brain cancer, glioblastoma multiforme (GBM), has been investigated in detail. The results suggest that MMP‐sensitive particles are cytocompatible and superior to promote TRAIL‐induced apoptosis in GBM cells when loaded with QC. Compared to QC and TRAIL alone, combination of QC‐loaded PEG hydrogel and TRAIL demonstrates synergistic apoptotic inducing behavior. Furthermore, QC‐loaded particles, but not QC or PEG‐hydrogels alone, enhance apoptosis as is measured through expression of apoptosis‐related genes. This system is promising to significantly improve the efficacy of chemotherapeutic drugs and suggests a combination treatment for GBM therapy.
Affinity‐based cell separation is label‐free and highly specific, but it is difficult to efficiently and gently release affinity‐captured cells due to the multivalent nature of cell‐material interactions. To address this challenge, we have developed a platform composed of a capture substrate and a cell‐releasing molecular trigger. The capture substrate is functionalized with a cell‐capture antibody and a coiled‐coil A . The cell‐releasing molecular trigger B ‐PEG (polyethylene glycol), a conjugate of a coiled‐coil B and polyethylene glycol, can drive efficient and gentle release of the captured cells, because A / B heterodimerization brings B ‐PEG to the substrate and PEG chains adopt extended conformations and break nearby multivalent antibody‐biomarker interactions. No enzymes or excessive shear stress are involved, and the released cells have neither external molecules attached nor endogenous cell‐surface molecules cleaved, which is critical for the viability, phenotype, and function of sensitive cells.
Poly(amido amine)s' (PAAs) versatility are nearly unique among stepwise polymers. Different functional groups can be easily introduced into these polymers to add functionality such as cell internalization, charge‐shift, bioreducibility, “stealth” properties, and targeting moieties, while maintaining the bulk structural integrity of these polymers. The poly(amido amine)s are used as a unique research platform to elucidate their complex structure–function relationship. It is shown that guanidinium group, carboxyl group, disulfide bond, alkyl chain, branching, acetyl groups, benzoyl groups, and quaternary nicotinamide moieties can influence many steps of gene delivery, such as DNA condensation, cellular uptake, endosomal escape, nuclear entry, and finally gene expression. The authors systematically discuss the structure–function correlations of PAAs for gene delivery, and elaborate how the properties of polymers can be adjusted by changing the polymeric structure.
This study presents a molecular model for the amplitude‐dependent dynamic moduli of polymer melts reinforced with nanoparticles. This study shows that intense strain‐thinning reported in experimental studies of polymer nanocomposites can be attributed to disentanglement of bulk polymer chains from those strongly adsorbed to the surface of nanoparticles. This flow‐induced relaxation is what is frequently termed as convective constraint release and is similar to the cohesive slip of polymer melt at solid interfaces.
Aggregation‐caused quenching (ACQ) is a general phenomenon that is faced by traditional fluorescent polymers. Aggregation‐induced emission (AIE) is exactly opposite to ACQ. AIE molecules are almost nonemissive in their molecularly dissolved state, but they can be induced to show high fluorescence in the aggregated or solid state. Incorporation of AIE phenomenon into polymer design has yielded various polymers with AIE characteristics. In this review, the recent progress of AIE polymers for biological applications is summarized.
Graphene oxide (GO) has received increasing attention in bioengineering fields due to its unique biophysical and electrical properties, along with excellent biocompatibility. The application of GO nanoparticles (GO‐NPs) to engineer self‐renewal and differentiation of human fetal neural stem cells (hfNSCs) is reported. GO‐NPs added to hfNSC culture during neurosphere formation substantially promote cell‐to‐cell and cell‐to‐matrix interactions in neurospheres. Accordingly, GO‐NP‐treated hfNSCs show enhanced self‐renewal ability and accelerated differentiation compared to untreated cells, indicating the utility of GO in developing stem cell therapies for neurogenesis.
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