Preparation and characterization of a novel organic-inorganic nanohybrid "cerasome" formed with a liposomal membrane and silicate surface

A novel class of organic-inorganic hybrids, the so-called cerasomes, which have a bilayer vesicular structure and a silicate surface, has been synthesized by combination of sol-gel reaction and self-assembly of organoalkoxysilanes with a molecular structure analogous to lipids. We have synthesized two cerasome-forming organoalkoxysilanes, N-[N-(3-triethoxysilyl)propylsuccinamoyl]dihexadecylamine (1) and N,N-dihexadecyl-N (alpha)-[6-[(3-triethoxysilyl)propyldimethylammonio]hexanoyl]glycinamide bromide (2), and investigated the synthetic conditions of the cerasomes and their structural characteristics. For the proamphiphilic 1, the cerasome was obtained under restricted pH conditions where acid-catalyzed hydrolysis of the triethoxysilyl moiety proceeded without disturbing the vesicle formation. In contrast, the amphiphilic 2, additionally having a hydrophilic quaternary ammonium group, formed stable dispersions of the cerasome in a wide pH range. The hydrolysis behavior of the triethoxysilyl groups was monitored by (1)H NMR spectroscopy. Morphology of the cerasomes having the liposomal vesicular structure was confirmed by TEM observations. Extent of the development of siloxane networks through condensation among the silanol groups on the cerasome surface was evaluated by using MALDI-TOF-MS spectrometry. Formation of oligomers of the cerasome-forming lipids in the vesicle was clearly confirmed. Due to the siloxane network formation, the cerasome showed remarkably high morphological stability compared with a reference liposome, as evaluated by surfactant dissolution measurements.     

Encapsulation of Quantum Dots Inside Liposomal Hybrid Cerasome Using a One-Pot Procedure

A one-pot strategy for the fabrication of the quantum dots loaded cerasome has been successfully developed based on the condensation of dihexadecylamine and 3-isocyanatopropyltriethoxysilane, followed by spontaneous encapsulation and solubilization of hydrophobic quantum dots into the hybrid liposomal cerasomes in combination of self-assembly and sol-gel process. Fourier transform infrared spectroscopy and mass spectra prove the formation of the intermediate organoalkoxysilane with a lipid-like structure, which forms cerasome vesicles. After encapsulation into cerasome, quantum dots become well dispersed in aqueous solution. Such water-soluble QD cerasomes exhibit a better photostability and retain the luminescence property of the original hydrophobic quantum dots.     

Creation of magnetic cerasomes through electroless plating and their manipulation using external magnetic fields

Magnetic cerasome, an artificial cell membrane having ultrathin magnetic metal layers on the surface, was prepared through electroless plating of magnetic metal alloy onto an organic–inorganic vesicular nanohybrid “cerasome.” Morphological and functional characteristics of the magnetic cerasome were evaluated using various physical measurements: scanning and transmission electron microscopies, energy-dispersive X-ray spectroscopy, electron tomography, and vibrating sample magnetometry. The results proved that high morphological stability of the cerasome was important for constructing the magnetic lipid vesicle and that insertion of an alkylated metal ligand into the cerasome was essential to the magnetic metal alloy deposition on the cerasome surface. Fluorescence microscopic observations revealed that the magnetic cerasomes were collected reversibly on the slide glass surface and manipulated depending on external motion of a magnet. The potential use of the magnetic cerasomes as a novel vesicular nanohybrid is also described in this report.     

Recent advances in liposomal nanohybrid cerasomes as promising drug nanocarriers

Liposomes have been extensively investigated as possible carriers for diagnostic or therapeutic agents due to their unique properties. However, liposomes still have not attained their full potential as drug and gene delivery vehicles because of their insufficient morphological stability. Recently, a super-stable and freestanding hybrid liposomal cerasome (partially ceramic- or silica-coated liposome) has drawn much attention as a novel drug delivery system because its atomic layer of polyorganosiloxane surface imparts higher morphological stability than conventional liposomes and its liposomal bilayer structure reduces the overall rigidity and density greatly compared to silica nanoparticles. Cerasomes are more biocompatible than silica nanoparticles due to the incorporation of the liposomal architecture into cerasomes. Cerasomes combine the advantages of both liposomes and silica nanoparticles but overcome their disadvantages so cerasomes are ideal drug delivery systems. The present review will first highlights some of the key advances of the past decade in the technology of cerasome production and then review current biomedical applications of cerasomes, with a view to stimulating further research in this area of study.     

Cerasomes: Soft Interface for Redox Enzyme Electrochemical Signal Transmission

Anionic cerasomes, which consist of a liposomal lipid bilayer and a ceramic surface, were used as a soft interface for the construction of an integrated modified electrode to achieve the transmission of chemical information from a redox enzyme through electrical signals. The morphological properties of the cerasomes were systematically compared with those of two structural analogues, namely, liposomes and silica nanoparticles. The results indicated that the cerasomes combined the advantages of liposomes and silica nanoparticles. The lipid bilayer gave excellent biocompatibility, as in the case of liposomes, and high structural stability, similar to that of silica nanoparticles, was derived from the silicate framework on the cerasome surface. The performance at the electrochemical interface created by means of a combination of cerasomes and horseradish peroxidase on a glassy carbon electrode was much better than those achieved with liposomes or silica nanoparticles instead of cerasomes. The potential use of cerasomes in the construction of supramolecular devices for mediator‐free biosensing was evaluated.     

Hydrogen Peroxide and Glutathione Dual Redox‐Responsive Nanoparticles for Controlled DOX Release

Polymer nanoparticulate drug delivery systems that respond to reactive oxygen species (ROS) and glutathione (GSH) simultaneously at biologically relevant levels hold great promise to improve the therapeutic efficacy to cancer cells with reduced side effects of chemo drugs. Herein, a novel redox dual‐responsive amphiphilic block copolymer (ABP) that consists of a hydrophilic poly (ethylene oxide) block and a hydrophobic block bearing disulfide linked phenylboronic ester group as pendant is synthesized, and the DOX loaded nanoparticles (BSN‐DOX) based on ABPs with varied hydrophobic block length are fabricated for DOX delivery. The self‐immolative leaving reaction of phenylboronic ester triggered by extracellular ROS and the cleavage of disulfide linkages induced by intracellular GSH both lead to rapid DOX release from BSN‐DOX, resulting in an on‐demand DOX release. Moreover, BSN‐DOX show better tumor inhibition and lower side effects in vivo compared with free drug.     

Photodynamic Activity of C70 Caged within Surface‐Cross‐Linked Liposomes

[70]Fullerene (C₇₀) encapsulated into a surface‐cross‐linked liposome, a so‐called cerasome, was prepared by an exchange reaction incorporating C₇₀?γ‐cyclodextrin complexes into lipid membranes. Fullerene exchange in a cerasome‐incorporated C₇₀ (CIC₇₀), as well as in a lipid‐membrane‐incorporated C₇₀ (LMIC₇₀), was completed within 1 min with stirring at 25 °C. CIC₇₀ was more resistant to lysis than LMIC₇₀ towards lysing agents such as surfactants. Furthermore, the photodynamic activity of CIC₇₀ in HeLa cells was similar to that of LMIC₇₀, indicating that C₇₀ can act as a photosensitizing drug (PS) without release from cerasome membranes. Thus, in contrast with general drug‐delivery systems (DDSs), which require the drug to be released from the interior of liposomes, carriers for PSs for use in photodynamic therapy (PDT) do not necessarily need to release the drug. These results indicate that DDSs with high morphological stability can increase the residence time in blood and achieves tumor‐selective drug delivery by the enhanced permeability and retention (EPR) effect.     

Polyisobutylene‐paclitaxel conjugates with pendant carboxylic acids and polystyrene chains: Towards multifunctional stent coatings with slow drug release

Drug‐eluting stents are used in the treatment of atherosclerosis, where the incorporation of anti‐proliferative or anti‐inflammatory drugs decreases the rate of restenosis, the recurrence of artery narrowing. However, these stents can suffer from limitations such as drug depletion and delamination of the drug‐eluting coating from the stent surface. Described here is an approach aimed at addressing these issues. Starting from a maleic anhydride adduct of polyisobutylene (PIB) prepared from butyl rubber, ring opening using paclitaxel (PTX) or a combination of PTX and polystyrene (PS) afforded covalent conjugates of PTX and PIB or PIB‐PS graft copolymers bearing pendant carboxylic acids. When coated on stainless steel, the drug release was slower than that from a control coating that ressembles a clinical formulation comprising a physical mixture of a PS‐PIB‐PS triblock copolymer (SIBS) and PTX. The PTX conjugates also exhibited enhanced adhesion to stainless steel and increased tensile strength in comparison with the starting rubber. Cytotoxicity assays indicated that the materials did not leach toxic levels of PTX into cell culture media. Nevertheless, they were capable of inhibiting the adhesion and proliferation of C2C12 cells on their surfaces. These properties are advantageous for the potential application of the materials as stent coatings. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2209–2219     

Amphiphilic block poly(propylene carbonate)‐block‐allyloxypolyethyleneglycol copolymer based shell cross‐linked micelles for controlled release of drug

Amphiphilic block poly(propylene carbonate)‐block‐allyloxypolyethyleneglycol (PPC‐b‐APEG) copolymer was synthesized by the click chemistry, and its structure were characterized. PPC‐b‐APEG can self‐assemble into micelles without emulsifier in water. Shell cross‐linked micelles were obtained by the reaction of the allyloxy groups, which were exposed on the outer of the PPC‐b‐APEG micelles, and N‐vinylpyrrolidone (NVP). The morphology and size of the micelles before and after cross‐link reactions were characterized. The research result shows that the shell cross‐linking could improve the stability of micelles. The particle size of uncross‐linked micelle was about 800 nm. The size of cross‐linked micelles increased with increasing amount of cross‐linking degree. To better evaluate the release behavior of PPC‐b‐PEG copolymer, doxorubicin (DOX)‐loaded micelles were synthesized using DOX as the model drug. Results showed that the DOX releasing rate decreased with increasing of NVP. The shell cross‐linking do decrease the burst release behaviours of DOX and reduce the DOX release rate.     

Micelles from amphiphilic block copolyphosphates for drug delivery

Amphiphilic block copolyphosphates (PEP-b-PIPPs) are synthesized by two-step ROP of cyclic phosphate monomers with different pedant groups. They can spontaneously self-assemble into approximately spherical micelles ranging in size between 89 and 198 nm in water. A typical hydrophobic anti-cancer drug DOX is encapsulated into the micelles. The release rate of DOX slows down with increasing hydrophobic block length of PIPP. DOX-loaded micelles are investigated for the proliferation inhibition of Hela cells and the DOX dose required for 50% cellular growth inhibition is found to be 0.8 μg mL(-1). It is demonstrated that PEP-b-PIPP micelles can be used as a safe and promising drug delivery system.     

Hollow‐Core Magnetic Colloidal Nanocrystal Clusters with Ligand‐Exchanged Surface Modification as Delivery Vehicles for Targeted and Stimuli‐Responsive Drug Release

The fabrication of hierarchical magnetic nanomaterials with well‐defined structure, high magnetic response, excellent colloidal stability, and biocompatibility is highly sought after for drug‐delivery systems. Herein, a new kind of hollow‐core magnetic colloidal nanocrystal cluster (HMCNC) with porous shell and tunable hollow chamber is synthesized by a one‐pot solvothermal process. Its novelty lies in the “tunability” of the hollow chamber and of the pore structure within the shell through controlled feeding of sodium citrate and water, respectively. Furthermore, by using the ligand‐exchange method, folate‐modified poly(acrylic acid) was immobilized on the surface of HMCNCs to create folate‐targeted HMCNCs (folate‐HMCNCs), which endowed them with excellent colloidal stability, pH sensitivity, and, more importantly, folate receptor‐targeting ability. These assemblages exhibited excellent colloidal stability in plasma solution. Doxorubicin (DOX), as a model anticancer agent, was loaded within the hollow core of these folate‐HMCNCs (folate‐HMCNCs‐DOX), and drug‐release experiments proved that the folate‐HMCNCs‐DOX demonstrated pH‐dependent release behavior. The folate‐HMCNCs‐DOX assemblages also exhibited higher potent cytotoxicity to HeLa cells than free doxorubicin. Moreover, folate‐HMCNCs‐DOX showed rapid cell uptake apart from the enhanced cytotoxicity to HeLa cells. Experimental results confirmed that the synthesized folate‐HMCNCs are smart nanovehicles as a result of their improved folate receptor‐targeting abilities and also because of their combined pH‐ and magnetic‐stimuli response for applications in drug delivery.     

Preparation and properties of poly(N‐isopropylacrylamide)/poly(N‐isopropylacrylamide) interpenetrating polymer networks for drug delivery

A novel poly(N‐isopropylacrylamide) (PNIPA)/PNIPA interpenetrating polymer network (IPN) was synthesized and characterized. In comparison with conventional PNIPA hydrogels, the shrinking rate of the IPN hydrogel increased when gels, swollen at 20 °C, were immersed in 50 °C water. The phase‐transition temperature of the IPN gel remained unchangeable because of the same chemical constituent in the PNIPA gel. The reswelling kinetics were slower than those of the PNIPA hydrogel because of the higher crosslinking density of the IPN hydrogel. The IPN hydrogel had better mechanical strength because of its higher crosslinking density and polymer volume fraction. The release behavior of 5‐fluorouracil (5‐Fu) from the IPN hydrogel showed that, at a lower temperature, the release of 5‐Fu was controlled by the diffusion of water molecules in the gel network. At a higher temperature, 5‐Fu inside the gel could not diffuse into the medium after a burst release caused by the release of the drug on the surface of the gel. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 1249–1254, 2004     

Synthesis of well‐defined star‐shaped poly(ε‐caprolactone)/poly(ethylbene glycol) amphiphilic conetworks by combination of ring opening polymerization and “click” chemistry

Well‐defined star‐shaped hydrophobic poly(ε‐caprolactone) (PCL) and hydrophilic poly(ethylene glycol) (PEG) amphiphilic conetworks (APCNs) have been synthesized via the combination of ring opening polymerization (ROP) and click chemistry. Alkyne‐terminated six arm star‐shaped PCL (6‐s‐PCLx‐C?CH) and azido‐terminated PEG (N₃‐PEG‐N₃) are characterized by ¹H NMR and FT‐IR. The swelling degree of the APCNs is determined both in water and organic solvent. This unique property of the conetworks is dependent on the nanophase separation of hydrophilic and hydrophobic phases. The morphology and thermal behaviors of the APCNs are investigated by SEM and DSC respectively. The biocompatibility is determined by water soluble tetrazolium salt reagents (WST‐1) assay, which shows the new polymer networks had good biocompatibility. Through in vitro release of paclitaxel (PTX) and doxorubicin (DOX), the APCNs is confirmed to be promising drug depot materials for sustained hydrophobic and hydrophilic drugs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 407–417     

Photo‐ and pH‐Responsive Polycarbonate Block Copolymer Prodrug Nanomicelles for Controlled Release of Doxorubicin

Photo/pH dual‐responsive amphiphilic diblock copolymers with alkyne functionalized pendant o‐nitrobenzyl ester group are synthesized using poly(ethylene glycol) as a macroinitiator. The pendant alkynes are functionalized as aldehyde groups by the azide‐alkyne Huisgen cycloaddition. The anticancer drug doxorubicin (DOX) molecules are then covalently conjugated through acid‐sensitive Schiff‐base linkage. The resultant prodrug copolymers self‐assemble into nanomicelles in aqueous solution. The prodrug nanomicelles have a well‐defined morphology with an average size of 20–40 nm. The dual‐stimuli are applied individually or simultaneously to study the release behavior of DOX. Under UV light irradiation, nanomicelles are disassembled due to the ONB ester photocleavage. The light‐controlled DOX release behavior is demonstrated using fluorescence spectroscopy. Due to the pH‐sensitive imine linkage the DOX molecules are released rapidly from the nanomicelles at the acidic pH of 5.0, whereas only minimal amount of DOX molecules is released at the pH of 7.4. The DOX release rate is tunable by applying the dual‐stimuli simultaneously. In vitro studies against colon cancer cells demonstrate that the nanomicelles show the efficient cellular uptake and the intracellular DOX release, indicating that the newly designed copolymers with dual‐stimuli‐response have significant potential applications as a smart nanomedicine against cancer.     

具有pH-响应性的聚天冬氨酸类载药胶束的制备和释放能力研究

通过大分子引发剂ω-氨基-α-甲氧基聚乙二醇引发N-羧基-α-氨基环内酸酐开环聚合和水合肼侧基改性,制备了一系列聚乙二醇-聚氨基酸类三嵌段共聚物.其中聚氨基酸链段包括具有酰肼基的聚天冬氨酸衍生物(PAHy),以及疏水性的聚丙氨酸链段.引入具有pH响应性的腙键键合阿霉素,利用键合阿霉素与游离阿霉素之间的π-π叠合作用,在聚合物自组装形成胶束过程中通过化学键合+物理包埋的方式充分负载药物.该胶束以聚丙氨酸链段为核心,以PEG链段为冠层,以PAHy链段为包裹药物的壳层.载药胶束的粒径在170 nm左右.研究不同pH值条件下载药胶束的药物释放能力,随环境pH值的降低药物的释放速率显著增加.     

Interfacial self-organization of bolaamphiphiles bearing mesogenic groups: relationships between the molecular structures and their self-organized morphologies

This article discusses the relationship between the molecular structure of bolaamphiphiles bearing mesogenic groups and their interfacial self-organized morphology. On the basis of the molecular structures of bolaamphiphiles, we designed and synthesized a series of molecules with different hydrophobic alkyl chain lengths, hydrophilic headgroups, mesogenic groups, and connectors between the alkyl chains and the mesogenic group. Through investigating their interfacial self-organization behavior, some experiential rules are summarized: (1) An appropriate alkyl chain length is necessary to form stable surface micelles; (2) different categories of headgroups have a great effect on the interfacial self-organized morphology; (3) different types of mesogenic groups have little effect on the structure of the interfacial assembly when it is changed from biphenyl to azobenzene or stilbene; (4) the orientation of the ester linker between the mesogenic group and alkyl chain can greatly influence the interfacial self-organization behavior. It is anticipated that this line of research may be helpful for the molecular engineering of bolaamphiphiles to form tailor-made morphologies.     

Influence of the polymer structure over self‐assembly and thermo‐responsive properties: The case of PEG‐b‐PCL grafted copolymers via a combination of RAFT and ROP

During the last years, the field of drug delivery has experienced a growing interest toward the so‐called thermo‐responsive polymers: synthetic materials that, due to the specific hydrophilic–lipophilic balance of their repeating units, exhibit a lower critical solution temperature (LCST) in water associated to a characteristic coil–globule transition. In this work, thermo‐responsive amphiphilic block copolymers are synthesized via reversible addition‐fragmentation transfer (RAFT) polymerization starting from thermo‐responsive monomers and a hydrophobic biodegradable macromonomer, oligo(caprolactone)methacrylate (CL₃MA), produced via ring opening polymerization (ROP). The obtained copolymers exhibit an interesting self‐assembly behavior leading to nanoparticles (NPs) as long as temperature is kept below the LCST. Otherwise, once this value is overcome, the destabilization of the NPs causes the formation of hydrophobic superstructures that enhance the release of an entrapped lipophilic drug. This characteristic behavior has been systematically studied and related to the copolymer structure. In particular, the self‐assembly behavior as well as temperature‐triggered NP destabilization have been related to the relative length of the two blocks constituting the copolymers and to their hydrophilic–lipophilic balance (HLB). Finally, the efficacy of the thermo‐responsive triggered drug release has been tested in the case of Paclitaxel (PTX). © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2919–2931     

Hydrophobic siloxane paper coatings: the effect of increasing methyl substitution

Paper is an organic material widely used in cultural heritage and mainly composed of cellulose mixed with lignin, hemicellulose and small amounts of additives. This paper deals with siloxane coatings on pure cellulose paper, applied by sol–gel dipping in sols prepared with different siloxane precursors (tetraethoxysilane, methyl triethoxysilane, dimethyl diethoxysilane, trimethyl monoethoxysilane). The coated samples were characterized using various techniques (Fourier Transform Infrared Spectroscopy FT-IR, Nuclear Magnetic Resonance NMR and Scanning Electron Microscopy and Energy Dispersive Spectroscopy SEM–EDS), measuring their mechanical properties, flame resistance and contact angles, and a colorimetric test. The coated samples’ behavior was more hydrophobic the higher the methyl number of siloxane precursor, regardless of the coating’s thickness. Increasing the thickness improved the mechanical and thermal properties. The thickest coatings were obtained using a double coating process and a basic catalyst for the hydrolysis step, but this latter condition facilitated the formation of surface agglomerates, which make the paper too stiff and yellow.     

Paclitaxel‐Loaded Polylactide/Polyethylene Glycol Fibers with Long‐Term Antitumor Activity as a Potential Drug Carrier for Local Chemotherapy

Local application of anticancer agents prolongs the presence time and increases the concentration of drug in the target place and therefore may reduce serious side effects compared to drug systemic administration. The preparation of fibrous materials of polylactide (PLA) and polyethylene glycol (PEG) loaded with paclitaxel (PTX, 1 or 10 wt%) is presented. Scanning electron microscopy proves that PTX is homogeneously incorporated into the fibers. The addition of PEG of various molecular weights (6, 20, or 35 kDa) ensures the release of significantly higher amounts of hydrophobic PTX in a prolonged release time compared to the fibers containing PTX only. Present PLA‐PEG fibrous carriers can serve as a drug depot for PTX since they exhibit significant toxicity for cancer cell lines in several‐day experiment. They are promising for local recurrence therapy, where the initial release is efficient to kill tumor cells and continued release can prevent their subsequent proliferation.     

Synthesis of self-assemble pH-responsive cyclodextrin block copolymer for sustained anticancer drug delivery

Well-defined p H-responsive poly(ε-caprolactone)-graft-β-cyclodextrin-graft-poly(2-(dimethylamino)ethylmethacrylate)-co-poly(ethylene glycol) methacrylate amphiphilic copolymers(PCL-g-β-CD-g-P(DMAEMA-co-PEGMA)) were synthesized using a combination of atom transfer radical polymerization(ATRP),ring opening polymerization(ROP) and "click" chemistry.Successful synthesis of polymers was confirmed by Fourier transform infrared spectroscopy(FTIR),proton nuclear magnetic resonance(1H-NMR),and gel permeation chromatography(GPC).Then,the polymers could selfassemble into micelles in aqueous solution,which was demonstrated by dynamic light scattering(DLS) and transmission electron microscopy(TEM).The p H-responsive self-assembly behavior of these copolymers in water was investigated at different p H values of 7.4 and 5.0 for controlled doxorubicin(DOX) release,and these results revealed that the release rate of DOX could be effectively controlled by altering the p H,and the release of drug loading efficiency(DLE) was up to 88%(W/W).CCK-8 assays showed that the copolymers had low toxicity and possessed good biodegradability and biocompatibility,whereas the DOX-loaded micelles remained with high cytotoxicity for He La cells.Moreover,confocal laser scanning microscopy(CLSM) images revealed that polymeric micelles could actively target the tumor site and the efficient intracellular DOX release from polymeric micelles toward the tumor cells further confirmed the anti-tumor effect.The DOX-loaded micelles could easily enter the cells and produce the desired pharmacological action and minimize the side effect of free DOX.These results successfully indicated that p H-responsive polymeric micelles could be potential hydrophobic drug delivery carriers for cancer targeting therapy with sustained release.