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.
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.
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.
The development of delivery systems efficiently uptaken by cells is of due importance since sites of drug action are generally localized in subcellular compartments. Herein, naked and core–shell polymeric nanoparticles (NPs) have been produced from poly(lactic‐co‐glycolic acid)—PLGA, poly(ethylene oxide)‐b‐poly(ε‐caprolactone)—PEO‐b‐PCL, and poly(ethylene oxide)‐b‐poly(lactic acid)—PEO‐b‐PLA. The nanostructures are characterized and the cellular uptake behavior is evaluated. The data evidence that cellular uptake is enhanced as the length of the hydrophilic PEO‐stabilizing shell reduces and that high negative surface charge restricts cellular uptake. Furthermore, NPs of higher degree of hydrophobicity (PEO‐b‐PCL) are more efficiently internalized as compared to PEO‐b‐PLA NPs. Accordingly, taking into account our recent published results 1 and the findings of the current investigation, there should be a compromise regarding protein fouling and cellular uptake as resistance to nonspecific protein adsorption and enhanced cellular uptake are respectively directly and inversely related to the length of the PEO‐stabilizing shell.
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.
Stem cell transplantations for spinal cord injury (SCI) have been studied extensively for the past decade in order to replace the damaged tissue with human pluripotent stem cell (hPSC)‐derived neural cells. Transplanted cells may, however, benefit from supporting and guiding structures or scaffolds in order to remain viable and integrate into the host tissue. Biomaterials can be used as supporting scaffolds, as they mimic the characteristics of the natural cellular environment. In this study, hPSC‐derived neurons, astrocytes, and oligodendrocyte precursor cells (OPCs) are cultured on aligned poly(ε‐caprolactone) nanofiber platforms, which guide cell orientation to resemble that of spinal cord in vivo. All cell types are shown to efficiently spread over the nanofiber platform and orient according to the fiber alignment. Human neurons and astrocytes require extracellular matrix molecule coating for the nanofibers, but OPCs grow on nanofibers without additional treatment. Furthermore, the nanofiber platform is combined with a 3D hydrogel scaffold with controlled thickness, and nanofiber‐mediated orientation of hPSC‐derived neurons is also demonstrated in a 3D environment. In this work, clinically relevant materials and substrates for nanofibers, fiber coatings, and hydrogel scaffolds are used and combined with cells suitable for developing functional cell grafts for SCI repair.
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 phase behavior of a dendritic amphiphile containing a Newkome‐type dendron as the hydrophilic moiety and a cholesterol unit as the hydrophobic segment is investigated at the air–liquid interface. The amphiphile forms stable monomolecular films at the air–liquid interface on different subphases. Furthermore, the mineralization of calcium phosphate beneath the monolayer at different calcium and phosphate concentrations versus mineralization time shows that at low calcium and phosphate concentrations needles form, whereas flakes and spheres dominate at higher concentrations. Energy‐dispersive X‐ray spectroscopy, X‐ray photoelectron spectroscopy, and electron diffraction confirm the formation of calcium phosphate. High‐resolution transmission electron microscopy and electron diffraction confirm the predominant formation of octacalcium phosphate and hydroxyapatite. The data also indicate that the final products form via a complex multistep reaction, including an association step, where nano‐needles aggregate into larger flake‐like objects.
Multi‐micelle aggregation (MMA) mechanism is widely acknowledged to explicate large spherical micelles self‐assembly, but the process of MMA during self‐assembly is hard to observe. Herein, a novel kind of strong, regular microspheres fabricated from self‐assembly of amphiphilic anthracene‐functionalized β‐cyclodextrin (CD‐AN) via Cu(I)‐catalyzed azide‐alkyne click reactions is reported. The obtained CD‐AN amphiphiles can self‐assemble in water from primary core–shell micelles to secondary aggregates with the diameter changing from several tens nm to around 600–700 nm via MMA process according to the images of scanning electron microscopy, transmission electron microscopy, and atomic force microscopy as well as the dynamic light scattering measurements, followed by further crosslinking through photo‐dimerization of anthracene. What merits special attention is that such photo‐crosslinked self‐assemblies are able to disaggregate reversibly into primary nanoparticles when changing the solution conditions, which is benefited from the designed regular structure of CD‐AN and the rigid ranging of anthracene during assembly, thus confirming the process of MMA.
Recently, polymer drug conjugates (PDCs) have attracted considerable attention in the treatment of cancer. In this work, a simple strategy has been developed to make PDCs of an antitumor alkylating agent, chlorambucil, using a biocompatible disulphide linker. Chlorambucil‐based chain transfer agent was used to prepare various homopolymers and block copolymers in a controlled fashion via reversible addition–fragmentation chain transfer polymerization. Chlorambucil conjugated block copolymer, poly(polyethylene glycol monomethyl ether methacrylate)‐b‐poly(methyl methacrylate), formed nanoaggregates in aqueous solutions, which are characterized by dynamic light scattering and field emission‐scanning electron microscopy. Finally, the simplicity of the design is exemplified by performing a release study of chlorambucil under reducing condition by using D,L‐dithiothreitol.
Furfuryl glycidyl ether (FGE) represents a highly versatile monomer for the preparation of reversibly cross‐linkable nanostructured materials via Diels–Alder reactions. Here, the use of FGE for the mid‐chain functionalization of a P2VP‐b‐PEO diblock copolymer is reported. The material features one furan moiety at the block junction, P2VP68‐FGE‐b‐PEO390, which can be subsequently addressed in Diels–Alder reactions using maleimide‐functionalized counterparts. The presence of the FGE moiety enables the introduction of dyes as model labels or the formation of hetero‐grafted brushes as shell on hybrid Au@Polymer nanoparticles. This renders P2VP68‐FGE‐b‐PEO390, a powerful tool for selective functionalization reactions, including the modification of surfaces.
In this study, heparin‐mimicking hydrogel thin films are covalently attached onto poly(ether sulfone) membrane surfaces to improve anticoagulant property. The hydrogel films display honeycomb‐like porous structure with well controlled thickness and show long‐term stability. After immobilizing the hydrogel films, the membranes show excellent anticoagulant property confirmed by the activated partial thromboplastin time values exceeding 600 s. Meanwhile, the thrombin time values increase from 20 to 61 s as the sodium allysulfonate proportions increase from 0 to 80 mol%. In vitro investigations of protein adsorption and blood‐related complement activation also confirm that the membranes exhibit super‐anticoagulant property. Furthermore, gentamycin sulfate is loaded into the hydrogel films, and the released drug shows significant inhibition toward E. coli bacteria. It is believed that the surface attached heparin‐mimicking hydrogel thin films may show high potential for the applications in various biological fields, such as blood contacting materials and drug loading materials.
The present review focuses on the recent progress made in thin film orientation of semi‐conducting polymers with particular emphasis on methods using epitaxy and shear forces. The main results reported in this review deal with regioregular poly(3‐alkylthiophene)s and poly(dialkylfluorenes). Correlations existing between processing conditions, macromolecular parameters and the resulting structures formed in thin films are underlined. It is shown that epitaxial orientation of semi‐conducting polymers can generate a large palette of semi‐crystalline and nanostructured morphologies by a subtle choice of the orienting substrates and growth conditions.
Colorectal peritoneal carcinomatosis (CRPC) is a common systemic metastasis of intra‐abdominal cancers. Intraperitoneal chemotherapy against CRPC is at present the preferred treatment. The aim of this study is to develop a novel hydrogel drug delivery system through the combination of 5‐fluorouracil (5‐FU) loaded polymeric micelles and cisplatin (DDP) in biodegradable thermosensitive chitosan (CS) hydrogel. The prepared CS hydrogel drug is a free‐flowing solution at room temperature and forms a stationary gel at body temperature. Therefore, a CRPC mouse model is established to investigate the antitumor activity of CS hydrogel drug system. The results suggest that intraperitoneal administration of CS hydrogel drug can inhibit tumor growth and metastasis, and prolong survival time compared with other groups, thus improving the chemotherapeutic effect. Ki‐67 immunohistochemical analysis reveals that tumors in the CS hydrogel drug group has lower cell proliferation in contrast to other groups (P < 0.001). Furthermore, hematoxylin‐eosin staining of liver and lung tissue indicates that the CS hydrogel drug has also a certain inhibitory effect on colorectal cancer metastasis to the liver and lung. Hence, the work highlights the potential clinical applications of the CS hydrogel drug.
The development of stimuli‐responsive polymeric nanocarriers could significantly enhance drug bioavailability due to improved pharmacokinetics and biodistribution. However, in the drug delivery process, the poor cell uptake of drug‐loaded carriers has greatly limited the therapeutic efficiency for anti‐cancer applications. Herein, 2,3‐dimethylmaleic anhydride (DMMA) is engineered into the well‐defined biodegradable amphiphilic block copolymer poly(D,L‐lactide)‐block‐poly(2‐aminoethyl methacrylate) (PLA‐b‐PAEMA) to construct a tumor‐acidity activated nanocarrier (PLA‐b‐PAEMA/DMMA) for potential tumor therapy. After the loading of positively charged DOX·HCl into the negatively charged corona structure through electrostatic attraction, this carrier is expected to prolong the blood circulation time and smartly convert surface charge from negative to positive for enhanced tumor cell uptake and targeted drug release. Furthermore, this carrier exhibits additional cytotoxicity for tumor cells after the tumor‐acidity activated surface charge‐conversion from negative to positive. Thus, this smart carrier is a feasible candidate for potential cancer therapy.
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.
In this contribution, amphiphilic star copolymers (H40‐star‐PCL‐a‐PEG) with an H40 hyperbranched polyester core and poly(ε‐caprolactone)‐a‐poly(ethylene glycol) copolymer arms linked with acetal groups are synthesized using ring‐opening polymerization and a copper (I)‐catalyzed alkyne‐azide cycloaddition click reaction. The acid‐cleavable acetal groups between the hydrophilic and hydrophobic segments of the arms endow the amphiphilic star copolymers with pH responsiveness. In aqueous solution, unimolecular micelles can be formed with good stability and a unique acid degradability, as is desirable for anticancer drug carriers. For the model drug of doxorubicin, the in vitro release behavior, intracellular release, and inhibition of proliferation of HeLa cells show that the acid‐cleavable unimolecular micelles with anticancer activity can be dissociated in an acidic environment and efficiently internalized by HeLa cells. Due to the acid‐cleavable and biodegradable nature, unimolecular micelles from amphiphilic star copolymers are promising for applications in intracellular drug delivery for cancer chemotherapy.
Polymer‐protein conjugates are biohybrid macromolecules derived from covalently connecting synthetic polymers with polypeptides. The resulting materials combine the properties of both worlds: chemists can engineer polymers to stabilize proteins, to add functionality, or to enhance activity; whereas biochemists can exploit the specificity and complexity that Nature has bestowed upon its macromolecules. This has led to a wealth of applications, particularly within the realm of biomedicine. Polymer‐protein conjugation has expanded to include scaffolds for drug delivery, tissue engineering, and microbial inhibitors. This feature article reflects upon recent developments in the field and discusses the applications of these hybrids from a biomaterials standpoint.
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.
The structural evolution in poly(styrene‐b‐butadiene) (P(S‐b‐B)) diblock copolymer thin films during solvent vapor treatment is investigated in situ using time‐resolved grazing‐incidence small‐angle X‐ray scattering (GISAXS). Using incident angles above and below the polymer critical angle, structural changes near the film surface and in the entire film are distinguished. The swelling of the film is one‐dimensional along the normal of the substrate. During swelling, the initially perpendicular lamellae tilt within the film to be able to shrink. In contrast, at the film surface, the lamellae stay perpendicular, and eventually vanish at the expense of a thin PB wetting layer. During the subsequent drying, the perpendicular lamellae reappear at the surface, and finally, PS blocks protrude. By modeling, the time‐dependent height of the protrusions can be quantitatively extracted.
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