Due to the adsorption of biomolecules, the control of the biodistribution of nanoparticles is still one of the major challenges of nanomedicine. Poly(2‐ethyl‐2‐oxazoline) (PEtOx) for surface modification of nanoparticles is applied and both protein adsorption and cellular uptake of PEtOxylated nanoparticles versus nanoparticles coated with poly(ethylene glycol) (PEG) and non‐coated positively and negatively charged nanoparticles are compared. Therefore, fluorescent poly(organosiloxane) nanoparticles of 15 nm radius are synthesized, which are used as a scaffold for surface modification in a grafting onto approach. With multi‐angle dynamic light scattering, asymmetrical flow field‐flow fractionation, gel electrophoresis, and liquid chromatography‐mass spectrometry, it is demonstrated that protein adsorption on PEtOxylated nanoparticles is extremely low, similar as on PEGylated nanoparticles. Moreover, quantitative microscopy reveals that PEtOxylation significantly reduces the non‐specific cellular uptake, particularly by macrophage‐like cells. Collectively, studies demonstrate that PEtOx is a very effective alternative to PEG for stealth modification of the surface of nanoparticles.
The design of drug delivery systems capable of efficiently delivering poorly soluble drugs to target sites still remains a major challenge. Such materials require several different functionalities; typically, these materials should be biodegradable and nontoxic, nonimmunogenic, responsive to their environment, and soluble in aqueous solution while retaining the ability to solubilize hydrophobic drugs. Here, a polypeptide‐polymer hybrid of elastin‐like polypeptides (ELPs) and poly(2‐oxazoline)s (POx) is reported. This paper describes the chemical synthesis, physical characteristics, and drug loading potential of these novel hybrid macromolecules. A novel method is introduced for terminal functionalization of POx with protected maleimide moieties. Following recovery of the maleimide group via a retro Diels–Alder reaction, the consecutive Michael addition of thiol‐functionalized ELPs yields the desired protein‐polymer conjugate. These conjugates form nanoparticles in aqueous solution capable of solubilizing the anti‐cancer drug paclitaxel with up to 8 wt% loading.
Polyelectrolyte block copolymer micelles assembled thin film is switched in response to local photocatalytic reactions on titanium dioxide, resulting in a layer of variable height, stiffness in response to visible light irradiation. Preosteoblasts migrate toward stiffer side of the substrates.
Glycodendrimers based on aromatic cores have an amphiphilic character and have been reported to generate supramolecuar assemblies in water. A new group of glycodendrimers with an aromatic rod‐like core were recently described as potent antagonists of DC‐SIGN‐mediated viral infections. A full characterization of the aggregation properties of these materials is presented here. The results show that these compounds exist mostly as monomers in water solution, in dynamic equilibrium with small aggregates (dimers or trimers). Larger aggregates observed by dynamic light scattering and transmission Electron Microscopy for some of the dendrimers are found to be portions of materials not fully solubilized and can be removed either by optimizing the dissolution protocol or by centrifugation of the samples.
The aim of this work is the preparation of an active nanovehicle for the effective administration of α‐tocopheryl succinate (α‐TOS). α‐TOS is loaded in the core of nanoparticles (NPs) based on amphiphilic pseudo‐block copolymers of N‐vinyl pyrrolidone and a methacrylic derivative of α‐TOS. These well‐defined spherical NPs have sizes below 165 nm and high encapsulation efficiencies. In vitro activity of NPs is tested in hypopharynx squamous carcinoma (FaDu) cells and nonmalignant epithelial cells, demonstrating that the presence of additional α‐TOS significantly enhances its antiproliferative activity; however, a range of selective concentrations is observed. These NPs induce apoptosis of FaDu cells by activating the mitochondria death pathway (via caspase‐9). Both loaded and unloaded NPs act via complex II and produce high levels of reactive oxygen species that trigger apoptosis. Additionally, these NPs effectively suppress the vascular endothelial growth factor (VEGF) expression of human umbilical vein endothelial cells (HUVECs). These results open the possibility to use this promising nanoformulation as an α‐TOS delivery system for the effective cancer treatment, effectively resolving the current limitations of free α‐TOS administration.
To simultaneously control inflammation and facilitate dentin regeneration, a copolymeric micelle‐in‐microsphere platform is developed in this study, aiming to simultaneously release a hydrophobic drug to suppress inflammation and a hydrophilic biomolecule to enhance odontogenic differentiation of dental pulp stem cells in a distinctly controlled fashion. A series of chitosan‐graft‐poly(lactic acid) copolymers is synthesized with varying lactic acid and chitosan weight ratios, self‐assembled into nanoscale micelle‐like core–shell structures in an aqueous system, and subsequently crosslinked into microspheres through electrostatic interaction with sodium tripolyphosphate. A hydrophobic biomolecule either coumarin‐6 or fluocinolone acetonide (FA) is encapsulated into the hydrophobic cores of the micelles, while a hydrophilic biomolecule either bovine serum albumin or bone morphogenetic protein 2 (BMP‐2) is entrapped in the hydrophilic shells and the interspaces among the micelles. Both hydrophobic and hydrophilic biomolecules are delivered with distinct and tunable release patterns. Delivery of FA and BMP‐2 simultaneously suppresses inflammation and enhances odontogenesis, resulting in significantly enhanced mineralized tissue regeneration. This result also demonstrates the potential for this novel delivery system to deliver multiple therapeutics and to achieve synergistic effects.
Three‐dimensional hydrogel supports for mesenchymal and neural stem cells (NSCs) are promising materials for tissue engineering applications such as spinal cord repair. This study involves the preparation and characterization of superporous scaffolds based on a copolymer of 2‐hydroxyethyl and 2‐aminoethyl methacrylate (HEMA and AEMA) crosslinked with ethylene dimethacrylate. Ammonium oxalate is chosen as a suitable porogen because it consists of needle‐like crystals, allowing their parallel arrangement in the polymerization mold. The amino group of AEMA is used to immobilize RGDS and SIKVAVS peptide sequences with an N‐γ‐maleimidobutyryloxy succinimide ester linker. The amount of the peptide on the scaffold is determined using 125I radiolabeled SIKVAVS. Both RGDS‐ and SIKVAVS‐modified poly(2‐hydroxyethyl methacrylate) scaffolds serve as supports for culturing human mesenchymal stem cells (MSCs) and human fetal NSCs. The RGDS sequence is found to be better for MSC and NSC proliferation and growth than SIKVAVS.
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.
A bioinspired adhesive material, polydopamine (pDA), was employed as an interfacial glue to stably immobilize human neural stem cells (hNSCs) on the external surface of biodegradable polycaprolactone (PCL) microspheres, thereby serving as versatile key systems that can be used for cell carriers. The pDA decoration on the PCL microspheres has been resulted in robust hNSC immobilization as well as proliferation on their curved surfaces. The pDA coating has transformed the hydrophobic PCL systems toward water‐friendly and sticky characteristics, thereby resulting in full dispersion in aqueous solution and stable adherence onto a wet biological surface. Adeno‐associated virus, a safe gene vector capable of effectively regulating cell behaviors, can be decorated on the PCL surfaces and delivered efficiently to hNSCs adhered to the microsphere exteriors. These distinctive multiple benefits of the sticky pDA microspheres can provide core technologies that can boost the therapeutic effects of cell therapy approaches.
Cell‐free approaches to in situ tissue engineering require materials that are mechanically stable and are able to control cell‐adhesive behavior upon implantation. Here, the development of mechanically stable grafts with non‐cell adhesive properties via a mix‐and‐match approach using ureido‐pyrimidinone (UPy)‐modified supramolecular polymers is reported. Cell adhesion is prevented in vitro through mixing of end‐functionalized or chain‐extended UPy‐polycaprolactone (UPy‐PCL or CE‐UPy‐PCL, respectively) with end‐functionalized UPy‐poly(ethylene glycol) (UPy‐PEG) at a ratio of 90:10. Further characterization reveals intimate mixing behavior of UPy‐PCL with UPy‐PEG, but poor mechanical properties, whereas CE‐UPy‐PCL scaffolds are mechanically stable. As a proof‐of‐concept for the use of non‐cell adhesive supramolecular materials in vivo, electrospun vascular scaffolds are applied in an aortic interposition rat model, showing reduced cell infiltration in the presence of only 10% of UPy‐PEG. Together, these results provide the first steps toward advanced supramolecular biomaterials for in situ vascular tissue engineering with control over selective cell capturing.
Hyaluronic acid nanogel (HyA‐AT) is a redox sensitive crosslinkable nanogel, obtained through the conjugation of a thiolated hydrophobic molecule to the hyaluronic acid chain. Engineered nanogel was studied for its biocompatibility, including immunocompatibility and hemocompatability. The nanogel did not compromise the metabolic activity or cellular membrane integrity of 3T3, microvascular endothelial cells, and RAW 264.7 cell lines, as determined by the 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide and lactate dehydrogenase release assays. Also, we didn't observe any apoptotic effect on these cell lines through the Annexin V‐FITC test. Furthermore, the nanogel cell internalization was analyzed using murine bone marrow derived macrophages, and the in vivo and ex vivo biodistribution of the Cy5.5 labeled nanogel was monitored using a non‐invasive near‐infrared fluorescence imaging system. The HyA‐AT nanogel exhibits fairly a long half‐live in the blood stream, thus showing potential for drug delivery applications.
This study reports the structural transition of electrospun poly(ε‐caprolactone) (PCL)/poly[(propylmethacryl‐heptaisobutyl‐polyhedral oligomeric silsesquioxane)‐co‐(methyl methacrylate)] (POSS‐MMA) blends, from PCL‐rich fibers, to bicontinuous PCL core/POSS‐MMA shell fibers, to POSS‐MMA‐rich fibers with a discontinuous PCL inner phase. A ternary phase diagram depicting the electrospinnability of PCL/POSS‐MMA solutions is constructed by evaluating the morphological features of fibers electrospun from solutions with various concentrations and PCL/POSS‐MMA blend ratios. X‐ray diffraction, Raman spectroscopy, and differential scanning calorimetry are further used to characterize the electrospun PCL/POSS‐MMA hybrid fibers. These physicochemical characterization results are thoroughly discussed to understand the internal structures of the hybrid fibers, which are directly correlated to the phase separation behavior of the electrospun solutions. The current study provides further insight into the complex phase behavior of POSS‐copolymer‐based systems, which hold great potential for a broad spectrum of biomedical applications.
Adhesion and proliferation of cells are often suppressed in rigid hydrogels as gel stiffness induces mechanical stress to embedded cells. Herein, the composite hydrogel systems to facilitate high cellular activities are described, while maintaining relatively high gel stiffness. This unusual property is obtained by harmonizing gelatin‐poly(ethylene glycol)‐tyramine (GPT, semisynthetic polymer) and gelatin‐hydroxyphenyl propionic acid conjugates (GH, natural polymer) into hydrogels. A minimum GH concentration of 50% is necessary for cells to be proliferative. GPT is utilized to improve biological stability (>1 week) and gelation time (<20 s) of the hydrogels. These results suggest that deficiency in cellular activity driven by gel stiffness could be overcome by finely tuning the material properties in the microenvironments.
Complementary nucleobase‐functionalized polymeric micelles, a combination of adenine‐thymine (A‐U) base pairs and a blend of hydrophilic–hydrophobic polymer pairs, can be used to construct 3D supramolecular polymer networks; these micelles exhibit excellent self‐assembly ability in aqueous solution, rapid pH‐responsiveness, high drug loading capacity, and triggerable drug release. In this study, a multi‐uracil functionalized poly(ε‐caprolactone) (U‐PCL) and adenine end‐capped difunctional oligomeric poly(ethylene glycol) (BA‐PEG) are successfully developed and show high affinity and specific recognition in solution owing to dynamically reversible A‐U‐induced formation of physical cross‐links. The U‐PCL/BA‐PEG blend system produces supramolecular micelles that can be readily adjusted to provide the desired critical micellization concentration, particle size, and stability. Importantly, in vitro release studies show that doxorubicin (DOX)‐loaded micelles exhibit excellent DOX‐encapsulated stability under physiological conditions. When the pH value of the solution is reduced from 7.4 to 5.0, DOX‐loaded micelles can be rapidly triggered to release encapsulated DOX, suggesting these polymeric micelles represent promising candidate pH‐responsive nanocarriers for controlled‐release drug delivery and pharmaceutical applications.
Biodegradable self‐assembled polymeric nanoparticles (NPs) composed of poly(6‐O‐methacryloyl‐D‐galactopyranose)‐b‐poly(L‐lactide)‐b‐poly(6‐O‐methacryloyl‐D‐galactopyranose) (PMAGP‐b‐PLA‐b‐PMAGP) are prepared as carriers for the hydrophobic anticancer drug paclitaxel (PTX), to achieve target delivery to hepatoma cells. PTX can be encapsulated by the NPs with various molar ratios of L‐lactide (LA) and 6‐O‐methacryloyl‐D‐galactopyranose (MAGP) during the process of self‐assembly, and the resulting NPs exhibit high drug loading efficacy and substantial stability in aqueous solution. The size, size distribution, and morphology of the NPs are characterized using a Zetasizer Nano ZS and transmission electron microscopy. The hemolysis assay and cell cytotoxicity assay indicate that the polymeric NPs are biocompatible and non‐toxic. The cellular uptake assay demonstrates that the galactose‐containing NPs can be selectively recognized and subsequently accumulate in HepG2 cells. All of these results demonstrate that galactose‐containing polymeric NPs are potential carriers for hepatoma‐targeted drug delivery and liver cancer therapy in clinical medicine.
Photo‐crosslinking and self‐healing have received considerable attention for the design of intelligent materials. A novel photostimulated, self‐healing, and cytocompatible hydrogel system is reported. A coumarin methacrylate crosslinker is synthesized to modify the polyacrylamide‐based hydrogels. With the [2+2] cyclo‐addition of coumarin moieties, the hydrogels exhibit excellent self‐healing capacity when they are exposed to light with wavelengths at 280 and 365 nm, respectively. To enhance cell compatibility, a poly (amidoamine) crosslinker is also synthesized. Variations in light exposure times and irradiation wavelengths are found to alter the self‐healing property of the hydrogels. The hydrogels are shown to induce a regular cellular pattern. The hydrogels are used to regulate bone marrow stromal cells differentiation. The relative mRNA expressions are recorded to monitor the osteogenic differentiation of the cells.
The actinomycetes, Gram‐positive filamentous bacteria, are the most prolific source of natural occurring antibiotics. At an industrial level, antibiotics from actinomycete strains are produced by means of submerged fermentations, where one of the major factors negatively affecting bioproductivity is the pellet‐shaped biomass growth. The immobilization of microorganisms on properly chosen supports prevents cell–cell aggregation resulting in improving the biosynthetic capability. Thus, novel porous biopolymer‐based devices are developed by combining melt mixing and particulate leaching. In particular, polycaprolactone (PCL), polyethylene glycol (PEG), and sodium chloride (NaCl) with different grain sizes are used to prepare PCL/PEG/NaCl blends in the melt. These blends are then leached to obtain PCL‐based porous membranes that are used as solid support for the growth of Streptomyces coelicolor, a model streptomycete used to produce various antibiotics including the blue colored actinorhodin (ACT). Thereafter, the effect of the devices' characteristics on the bacterial growth and on the production ACT is evaluated. The results showed that ACT production is strongly dependent on the pore size distribution of the device. Moreover, membranes with pores ranging from 90 to 110 μm are able to offer a potential improvement in volumetric productivity of ACT if compared to conventional submerged liquid culture.
Furoxans, or 1,2,5‐oxadiazole‐N‐oxides, are a class of nitric oxide (NO)‐donating compounds that release NO in response to thiol‐containing molecules. In this study, polymeric micelles bearing furoxan moieties are prepared from an amphiphilic block copolymer consisting of a hydrophobic furoxan‐bearing block and a hydrophilic poly(N‐acryloylmorpholine) block. The block copolymer is prepared using a combination of the reversible addition–fragmentation chain transfer polymerization and the copper‐catalyzed Huisgen cycloaddition techniques. The block copolymers form spherical micelles with a diameter of 50 nm by self‐assembly in water. The micelles release NO in response to cysteine and show improved stability against hydrolytic decomposition. Furthermore, the micelles show a synergistic anti‐proliferative effect with ibuprofen in human colon cancer cells.
A stable polymeric network that mimics the highly polyanionic extracellular cartilage matrix still remains a great challenge. The main aim of this study is to present the synthesis of dendritic polyglycerol sulfate (dPGS)‐based in situ forming hydrogels using strain promoted azide‐alkyne cycloaddition reactions. A real time rheological study has been used to characterize the hydrogel properties. The viability of encapsulated human chondrocytes in the different hydrogels are monitored using live‐dead staining. Furthermore, type I and II collagen gene have been analyzed. Hydrogels with elastic moduli ranging from 1 to 5 kPa have been prepared by varying the dPGS amount. The chondrocyte viability in dPGS hydrogels is found to be higher than in pure PEG and alginate‐based hydrogels after 21 d. The higher cell viability in the dPGS engineered hydrogels can be explained by the fact that dPGS can interact with different proteins responsible for cell growth and proliferation.
Phospholipid‐detergent conjugates are proposed as fusogenic carriers for gene delivery. Eleven compounds are prepared and their properties are investigated. The ability of the conjugates to promote fusion with a negatively charged model membrane is determined. Their DNA delivery efficiency and cytotoxicity are assessed in vitro. Lipoplexes are administered in the mouse lung, and transgene expression Indeterminate inflammatory activity are measured. The results show that conjugation of 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine (DOPC) with C12E4 produces a carrier that can efficiently deliver DNA to cells, with negligible associated toxicity. Fusogenicity of the conjugates shows good correlation with in vitro transfection efficiency and crucially depends on the length of the polyether moiety of the detergent. Finally, DOPC‐C12E4 reveals highly potent for in vivo DNA delivery and favorably compares to GL67A, the current golden standard for gene delivery to the airway, opening the way for further promising developments.
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