d ‐Fructose modified poly(ε‐caprolactone)‐polyethylene glycol (PCL‐PEG‐Fru) diblock amphiphile is synthesized via Cu(I)‐catalyzed click chemistry, which self‐assembles with D‐α‐tocopheryl polyethylene glycol 1000 succinate (TPGS) into PCL‐PEG‐Fru/TPGS mixed micelles (PPF MM). It has been proven that glucose transporter (GLUT)5 is overexpressed in MCF‐7 cells other than L929 cells. In this study, PPF MM exhibit a significantly higher uptake efficiency than fructose‐free PCL‐PEG‐N3/TPGS mixed micelles in both 2D MCF‐7 cells and 3D tumor spheroids. Also, the presence of free d ‐fructose competitively inhibits the internalization of PPF MM in MCF‐7 cells other than L929 cells. PPF MM show selective tumor accumulation in MCF‐7 breast tumor bearing mice xenografts. Taken together, PPF MM represent a promising nanoscale carrier system to achieve GLUT5‐mediated cell specific delivery in cancer 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.
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.
The authors report a method to prepare cell‐laden, cell‐sized microparticles from various materials suitable for individual applications. The method includes a piezoelectric inkjetting technology and a horseradish peroxidase (HRP)‐catalyzed crosslinking reaction. The piezoelectric inkjetting technology enables production of cell‐laden, cell‐sized (20–60 μm) droplets from a polymer aqueous solution. The HRP‐catalyzed crosslinking of the polymer in the ejected solution enables production of spherical microparticles from various materials. Superior cytocompatibility of the microencapsulation method is confirmed from the viability and growth profiles of normal murine mammary gland epithelial cells.
A nanoassembled drug delivery system for anticancer treatment, formed by the host–guest interactions between paclitaxel (PTX) and β‐cyclodextrin (β‐CD) modified poly(acrylic acid) (PCDAA), is successfully prepared. After such design, the aqueous solubility of PTX is greatly increased from 0.34 to 36.02 μg mL?1, and the obtained PCDAA‐PTX nanoparticles (PCDAA‐PTX NPs) exhibit a sustained PTX release behavior in vitro. In vitro cytotoxicity finds that PCDAA‐PTX NPs can accumulate significantly in tumor cells and remain the pharmacological activity of PTX. The in vivo real‐time biodistribution of PCDAA‐PTX NPs is investigated using near‐infrared fluorescence imaging, indicating that the PCDAA‐PTX NPs can effectively target to the tumor site by the enhanced permeability and retention effect in H22 tumor‐bearing mice. Through in vivo antitumor examination, PCDAA‐PTX NPs exhibit superior efficacy in impeding the tumor growth compared to the commercially available Taxol®.
A unique l ‐cysteine conjugated antifouling amphiphilic conetwork (APCN) is synthesized through end‐crosslinking of well‐defined triblock copolymers poly(allyl methacrylate)‐b‐poly(ethylene glycol)‐b‐poly(allyl methacrylate) via a combination of reversible addition‐fragmentation chain transfer (RAFT) polymerization and thiol–ene “click” chemistry. The synthesized poly(ethylene glycol) macro‐RAFT agent initiates the polymerization of allyl methacrylate in a controlled manner. The vinyl pendant groups of the precursor partially conjugate with l ‐cysteine and the rest fully crosslink with mercaptopropyl‐containing siloxane via thiol–ene click chemistry under UV irradiation into APCNs, which show distinguished properties, that is, excellent biocompatibility, more than 39.6% water content, 101 barrers oxygen permeability, optimized mechanical properties, and more than 93% visible light transmittance. What's more, the resultant APCNs exhibit eminent resistance to protein adsorption, where the bovine serum albumin and lysozyme adsorption are decreased to 12 and 21 µg cm−2, respectively. The outstanding properties of APCNs depend on the RAFT controlled method, which precisely designs the hydrophilic/hydrophobic segments and eventually greatly improves the crosslinking efficiency and homogeneity. Meantime, the l ‐cysteine monolayer can effectively reduce the surface hydrophobicity and prevent protein adsorption, which exhibits the viability for antifouling surface over and under ophthalmic devices, suggesting a promising soft contact lens.
Microparticulate systems composed of biodegradable polymers, such as poly(d ,l ‐lactic‐co‐glycolic acid) (PLGA), are widely used for controlled release of bioactive molecules. However, the acidic microenvironment within these microparticles, as they degrade, has been reported to perturb the configuration of most encapsulated proteins. In addition, these polymer particles are also reported to suffer from unrealistically slow and incomplete release of proteins. To address these drawbacks, hollow PLGA microparticles are fabricated through a novel one‐step oil‐in‐water emulsion solvent evaporation technique, by capitalizing on the osmotic property of an osmogen. The effects of fabrication parameters on particle size and morphology, i.e., volume space of hollow cavity and shell thickness, are also studied. These hollow microparticles are subsequently loaded with bovine insulin microcrystals. It is shown that insulin release profiles can be tuned by simply changing the amount of osmogen in the formulation. At the same time, these hollow microparticles are shown to be effective in maintaining the bioactivity of the encapsulated protein.
New macromolecules such as dendrimers are increasingly needed to drive breakthroughs in diverse areas, for example, healthcare. Here, the authors report hybrid antimicrobial dendrimers synthesized by functionalizing organometallic dendrimers with quaternary ammonium groups or 2‐mercaptobenzothiazole. The functionalization tunes the glass transition temperature and antimicrobial activities of the dendrimers. Electron paramagnetic resonance spectroscopy reveals that the dendrimers form free radicals, which have significant implications for catalysis and biology. In vitro antimicrobial assays indicate that the dendrimers are potent antimicrobial agents with activity against multidrug‐resistant pathogens such as methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus faecium as well as other microorganisms. The functionalization increases the activity, especially in the quaternary ammonium group‐functionalized dendrimers. Importantly, the activities are selective because human epidermal keratinocytes cells and BJ fibroblast cells exposed to the dendrimers are viable after 24 h.
A new methacrylic fructose glycomonomer is synthesized and copolymerized with N‐isopropyl acrylamide by reversible addition fragmentation chain transfer (RAFT) polymerization. By additional copolymerization of the analog mannose, glucose, and galactose glycomonomers, a set of glycopolymers is obtained which vary in the type of sugar attached to the polyacrylamide backbone. The glycopolymers are subsequently deprotected and characterized by size exclusion chromatography, FT‐IR and NMR spectroscopy, elemental analysis, as well as turbidimetry, revealing the thermoresponsive character of all synthesized glycopolymers. The deprotected glycopolymers are subsequently labeled with a Rhodamine B derivative, utilizing the thiol‐functionalities derived from the RAFT endgroups. As concluded from the ArlamaBlue assay, the glycopolymers are not cytotoxic. Finally, cellular uptake studies reveal a higher uptake of the fructose polymer into MDA?MB?231 breast cancer cells compared to the other glycopolymers, which demonstrates the high potential of fructosylated polymers for potential applications in the targeted treatment of breast cancer.
Biopolymers are an attractive class of compounds for being used in biomedical applications as they are widely available from biomass. Their drawback is the lack of mechanical stability and the ability to tune this properly. Covalent chemical cross‐linking is an often used approach but it limits usability due to legislation as well as the need of advanced and specialized knowledge by end users such as clinicians. Here, increased and tunable mechanical properties are achieved of alginate‐based hydrogels with non‐covalent approaches using linear polyethyleneimine (LPEI) as a polyelectrolyte rather than only multivalent metal ions (Ca2+). Gel stiffness increases with increasing LPEI content. Gel morphology changes from a thin fibrous mesh for alginate‐Ca2+ to thicker fibrous networks when LPEI is introduced. The gels are able to efficiently release encapsulated small molecular dyes and the gels are able to host cells. For the cell encapsulation human skin fibroblasts (HSkF) and human bone marrow‐derived mesenchymal stem cells (hBM‐MSC) are used. HSkF can be successfully incorporated without diminished viability while the matrix components and gel preparation method are not compatible with hBM‐MSC. The newly developed alginate‐based system is regarded as a potential candidate for wound dressing materials.
The marine sulfated polysaccharide fucoidan displays superior ability to induce platelet aggregation compared to other sulfated polysaccharides. As such, it is an attractive tool for studying molecular and cellular responses in activated platelets. The heterogeneous structure, however, poses a problem in such applications. This study describes the synthesis of sulfated α‐l ‐fucoside‐pendant poly(methacryl amides) with homogeneous structures. By using both thiol‐mediated chain transfer and reversible addition‐fragmentation chain transfer polymerization techniques, glycopolymers with different chain lengths are obtained. These glycopolymers show platelet aggregation response and surface changes similar to those of fucoidan, and cause platelet activation through intracellular signaling as shown by extensive protein tyrosine phosphorylation. As the platelet activating properties of the glycopolymers strongly mimic those of fucoidan, this study concludes these fucoidan‐mimetic glycopolymers are unique tools for studying molecular and cellular responses in human blood platelets.
Herein, a kind of dual acid‐sensitive nanoparticles based on monomethoxy poly(ethylene glycol)‐imine‐β‐cyclodextrin is constructed by a facile phenylboronic acid‐cross‐linked way. The data of dynamic light scattering and transmission electron microscope reveal the cross‐linked nanoparticles have improved stability. The cross‐linked nanoparticles could easily self‐assemble and load the anticancer drug at neutral pH condition. However, when the drug‐loaded nanoparticles are delivered to extracellular tumor sites (pH ≈6.8), the surface of the nanoparticles would be amino positively charged and easily internalized by tumor cell due to the cleavage of the acid‐labile benzoic–imine. Subsequently, with the acidity in subcellular compartments significantly increasing (such as the endosome pH ≈5.3), the loaded drug would fast release from the endocytosis carriers due to the hydrolysis of boronate ester. These features suggest that these dual acid‐sensitive cross‐linked nanoparticles not only possess excellent biocompatibility but also can efficiently load and deliver anticancer drug into tumor cells to enhance the inhibition of cellular proliferation, outlining a favorable platform as drug carriers.
Multivalent aptamer–siRNA conjugates containing multiple mucin‐1 aptamers and BCL2‐specific siRNA are synthesized, and doxorubicin, an anthracycline anticancer drug, is loaded into these conjugates through intercalation with nucleic acids. These doxorubicin‐incorporated multivalent aptamer–siRNA conjugates are transfected to mucin‐1 overexpressing MCF‐7 breast cancer cells and their multidrug‐resistant cell lines. Doxorubicin‐incorporated multivalent aptamer–siRNA conjugates exert promising anticancer effects, such as activation of caspase‐3/7 and decrease of cell viability, on multidrug‐resistant cancer cells because of their high intracellular uptake efficiency. Thus, this delivery system is an efficient tool for combination oncotherapy with chemotherapeutics and nucleic acid drugs to overcome multidrug resistance.
Carbon nanotube (CNT)‐hydrogel nanocomposites are beneficial for various biomedical applications, such as nerve regeneration, tissue engineering, sensing, or implant coatings. Still, there are impediments to developing nanocomposites, including attaining a homogeneous CNT‐polymer dispersion or patterning CNTs on hydrogels. While few approaches have been reported for patterning CNTs on polymeric substrates, these methods include high temperature, high vacuum or utilize a sacrificial layer and, hence, are incompatible with hydrogels as they lead to irreversible collapse in hydrogel structure. In this study, a novel two‐step method is designed to transfer CNTs onto hydrogels. First, dense CNTs are grown on quartz substrates. Subsequently, hydrogel solutions are deposited on the quartz‐grown CNTs. Upon gelation, the hydrogel with transferred CNTs is peeled from the quartz. Successful transfer is confirmed by scanning electron microscopy and indirectly by cell attachment. The efficient transfer is attributed to π‐interactions pregelation between the polymers in solution and the CNTs.
The present study delves into a combined bio‐nano‐macromolecular approach for bone tissue engineering. This approach relies on the properties of an ideal scaffold material imbued with all the chemical premises required for fostering cellular growth and differentiation. A tannic acid based water dispersible hyperbranched polyurethane is fabricated with bio‐nanohybrids of carbon dot and four different peptides (viz. SVVYGLR, PRGDSGYRGDS, IPP, and CGGKVGKACCVPTKLSPISVLYK) to impart target specific in vivo bone healing ability. This polymeric bio‐nanocomposite is blended with 10 wt% of gelatin and examined as a non‐invasive delivery vehicle. In vitro assessment of the developed polymeric system reveals good osteoblast adhesion, proliferation, and differentiation. Aided by this panel of peptides, the polymeric bio‐nanocomposite exhibits in vivo ectopic bone formation ability. The study on in vivo mineralization and vascularization reveals the occurrence of calcification and blood vessel formation. Thus, the study demonstrates carbon dot/peptide functionalized hyperbranched polyurethane gel for bone tissue engineering application.
Stimuli‐responsive nanocarriers with the ability to respond to tumorous heterogeneity have been extensively developed for drug delivery. However, the premature release during blood circulation and insufficient intracellular drug release are still a significant issue. Herein, three disulfide bonds are introduced into the amphiphilic poly(ethylene glycol)‐polycaprolactone copolymer blocks to form triple‐sensitive cleavable polymeric nanocarrier (tri‐PESC NPs) to improve its sensitivity to narrow glutathione (GSH) concentration. The tri‐PESC NPs keep intact during blood circulation due to the limited cleaving of triple‐disulfide bonds, whereas the loaded drug is efficiently released at tumor cells with the increased concentration of GSH. In vitro studies of doxorubicin‐loaded tri‐PESC NPs show that the nanocarriers achieve sufficient drug release in cancerous cells and inhibit the tumor cells growth, though they only bring minimum damage to normal cells. Therefore, the tri‐PESC NPs with triple‐sensitive cleavable bonds hold great promise to improve the therapeutic index in cancer therapy.
The strand material in extrusion‐based bioprinting determines the microenvironments of the embedded cells and the initial mechanical properties of the constructs. One unmet challenge is the combination of optimal biological and mechanical properties in bioprinted constructs. Here, a novel bioprinting method that utilizes core–shell cell‐laden strands with a mechanically robust shell and an extracellular matrix‐like core has been developed. Cells encapsulated in the strands demonstrate high cell viability and tissue‐like functions during cultivation. This process of bioprinting using core–shell strands with optimal biochemical and biomechanical properties represents a new strategy for fabricating functional human tissues and organs.
Pulmonary air leaks are medical complications of thoracic surgery for which fibrin sealant is the main treatment. In this study, innovative sealants based on hydrophobically modified Alaska pollock‐derived gelatin (hm‐ApGltn) and a poly(ethylene)glycol‐based 4‐armed cross‐linker (4S‐PEG) have been developed and their burst strengths have been evaluated using fresh rat lung. The developed sealants show higher lung burst strength compared with the nonmodified original ApGltn (Org‐ApGltn)‐based sealant and a commercial fibrin sealant. The maximum burst strength of the hm‐ApGltn‐based sealant is 1.6‐fold higher than the Org‐ApGltn‐based sealant (n = 5, p < 0.05), and 2.1‐fold higher than the commercial fibrin sealant (n = 5, p < 0.05). Cell culture experiments show that modification of ApGltn with cholesteryl or stearoyl groups effectively enhances anchoring to the cell surface. In addition, binding constants between hm‐ApGltn and extracellular matrix proteins such as fibronectin and fibrillin are increased. Therefore, the new hm‐ApGltn/4S‐PEG‐based sealant has the potential for applications in thoracic surgery.
Polydopamine‐based coatings are fabricated via an electric field‐accelerating and ‐directing codeposition process of polydopamine with charged polymers such as polycations, polyanions, and polyzwitterions. The coatings are uniform and smooth on various substrates, especially on those adhesion‐resistant materials including poly(vinylidene fluoride) and poly(tetrafluoroethylene) membranes. Moreover, this electric field‐directed deposition method can be applied to facilely prepare Janus membranes with asymmetric chemistry and wettability.
A novel PEGylation polypeptide, poly(ethylene glycol)‐b‐poly(l ‐lysine)‐b‐poly(l ‐cysteine) (PEG‐PLL‐PCys) triblock copolymer is synthesized via the sequential ring‐opening polymerization of amino acid N‐carboxyanhydrides initiated by methoxypolyethylene glycol amine (mPEG‐NH2, M w is 2 kDa). Subsequently, the obtained polypeptide is partially conjugated with fluorocarbon chains via disulfide exchange reaction. PLL segment can condense plasmid DNA through an electrostatic force to form a complex core, PEG segment surrounding the complex like a corona can prevent the complex from precipitation and reduce the adsorption of serum, while PCys segment with fluorocarbon can enhance the cellular uptake and the stability of the formed polyplex micelles in physiological conditions. Experiment results exhibit that the fluorinated polypeptides have low cytotoxicity and good gene transfection efficiency even in the presence of 50% fetal bovine serum.
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