Design and Synthesis of Lipidic Organoalkoxysilanes for the Self‐Assembly of Liposomal Nanohybrid Cerasomes with Controlled Drug Release Properties

This paper reports the facile design and synthesis of a series of lipidic organoalkoxysilanes with different numbers of triethoxysilane headgroups and hydrophobic alkyl chains linked by glycerol and pentaerythritol for the construction of cerasomes with regulated surface siloxane density and controlled release behavior. It was found that the number of triethoxysilane headgroups affected the properties of the cerasomes for encapsulation efficiency, drug loading capacity, and release behavior. For both water‐soluble doxorubicin (DOX) and water‐insoluble paclitaxel (PTX), the release rate from the cerasomes decreased as the number of triethoxysilane headgroups increased. The slower release rate from the cerasomes was attributed to the higher density of the siloxane network on the surface of the cerasomes, which blocks the drug release channels. In contrast to the release results with DOX, the introduction of one more hydrophobic alkyl chain into the cerasome‐forming lipid resulted in a slower release rate of PTX from the cerasomes due to the formation of a more compact cerasome bilayer. An MTT viability assay showed that all of these drug‐loaded cerasomes inhibited proliferation of the HepG2 cancer cell line. The fine tuning of the chemical structure of the cerasome‐forming lipids would foster a new strategy to precisely regulate the release rate of drugs from cerasomes.     

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.     

Surface modification of gold nanorods with synthetic cationic lipids

Colloidal gold nanorods (GNRs), which were passivated with cationic cerasome-forming lipids having triethoxysilyl groups, were obtained in the aqueous phase by sonication of the mixture of lipids and GNRs.     

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.     

Cerasome as an Organic-Inorganic Vesicular Nanohybrid: Characterization of Cerasome-Forming Lipids having a Single or a Dual Trialkoxysilyl Head

Morphological characterization of the organic-inorganic vesicular nanohybrids, Cerasomes, was performed in aqueous media from two aspects. Firstly, a novel Cerasome-forming lipid having two triethoxysilyl groups in the head moiety was synthesized and the physical property of the Cerasome was investigated. While the morphological stability of the Cerasomes, as evaluated from the vesicular collapse behavior against a micelle-forming nonionic surfactant, Triton-X 100, was extremely higher than that of the conventional phospholipid liposome, the stabilities were comparable to each other for the Cerasomes derived from the dual- and single-head lipids. On the other hand, the surface property of the Cerasome formed with the dual-head lipid more closely resembled the colloidal silica particles rather than that derived from the single-head lipid, as suggested by zeta-potential measurements. Secondly, the effect of the media pH on the morphological stability of the Cerasome formed with the single-head lipid was evaluated and appeared as a time difference in obtaining the morphological stability of the Cerasome. These morphological characteristics of the Cerasomes could be mainly owing to the development of the siloxane network on the vesicular surface.     

Preparation and characterization of a novel nanocomposite: silver nanoparticles decorated cerasome

In this study, a novel artificial hybrid vesicle, nano silver particles decorated cerasome were fabricated through sol–gel and self-assemble methods as well as in situ reduction. Samples were characterized in terms of hydrodynamic size and surface morphology via dynamic light scattering as well as scanning and transmission electron microscopies. Analysis through energy dispersive X-ray spectrometer proved the existence of silver particles. Due to the high morphological stability of cerasome, Silver nanoparticles with a size of about 5–10 nm can be deposited on the surface without any stabilizers. The UV spectra revealed a single symmetric extinction peak at 406 nm, confirming the spherical shape of the synthesized silver nanoparticles. Several reducing agents were screened before confirming sodium borohydride (NaBH₄). Comparison of different NaBH₄/lipid ratios (K_{NaBH4/cerasome-forming lipid}) was then carried out in order to ascertain its effect. Investigation of the stability of this hybrid vesicles was carried out, indicating that it can be stored at 4 °C for at least 3 months without any morphological change. Results demonstrated that this hybrid vesicle has excellent morphological stability, which impart it significant potential for various applications such as being an antibacterial material and a radio sensitization agent.     

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.     

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.     

Size-selective shell cross-linked interior functionalized siloxane nanocages

A new structure, consisting of a shell cross-linked, 2 nm size siloxane nanocage containing propylamine groups tethered to the interior face of the shell was synthesized, starting with micelles of the surfactant molecule, (triethoxysilyl)propylcetylcarbamate. After hydrolysis of the ethoxysilyl groups and condensation and capping of the silanols to form a cross-linked, one-atom-layer-thick siloxane shell, the carbamate was converted to amine, releasing the cetyl group from the structure and resulting in the desired spherical nanocage. The intermediates in the synthesis process and the final structure were characterized by 1H and 29Si NMR, DLS, TEM, and mass spectroscopy. The amine groups tethered to the interior surface of the shell react readily with ninhydrin but do not interact with the larger ZnTPP, indicating molecular size selectivity by the cross-linked shell. The structure also exhibits confinement effect in the amine-catalyzed decarboxylation of acetoacetic acid, exhibiting higher activity and higher selectivity for acetal than (aminopropyl)triethoxysilane.     

Oligomeric Alkoxysilanes with Cagelike Hybrids as Cores: Designed Precursors of Nanohybrid Materials

Well‐defined alkoxysilane oligomers containing a cagelike carbosiloxane core were synthesized and used as novel building blocks for the formation of siloxane‐based hybrid networks. These oligomers were synthesized from the cagelike trimer derived from bis(triethoxysilyl)methane by silylation with mono‐, di‐, and triethoxychlorosilanes ((EtO)_nMe_3?nSiCl, n=1, 2, and 3). Hybrid xerogels were prepared by hydrolysis and polycondensation of these oligomers under acidic conditions. The structures of the products varied depending on the number of alkoxy groups (n). When n=2 and 3, microporous xerogels (BET surface areas of 820 and 510 m² g^?1, respectively) were obtained, whereas a nonporous xerogel was obtained when n=1. ²⁹Si NMR spectroscopic analysis suggested that partial rearrangement of the siloxane networks, which accompanied the cleavage of the Si–O–Si linkages, occurred during the polycondensation processes. By using an amphiphilic triblock copolymer surfactant as a structure‐directing agent, hybrid thin films with a 2D hexagonal mesostructure were obtained when n=2 and 3. These results provide important insight into the rational synthesis of molecularly designed hybrid materials by sol–gel chemistry.     

Fabrication of superhydrophobic surface from a supramolecular organosilane with quadruple hydrogen bonding

A supramolecular organosilane, 2-(3-(triethoxysilyl)propylaminocarbonylamino)-6-methyl-4[1H]pyrimidinone comprising quadruple hydrogen bonds has been synthesized in one step from commercially available starting materials. The synthesized supramolecular organosilane can be stabilized and phase-separated by dimerization via the linear array of quadruple hydrogen bonds in solution. This property of the supramolecular organosilane has been exploited to fabricate structuring materials having a superhydrophobic surface property. We have successfully generated the interconnected granular structure with adequate roughness for superhydrophobicity via sol-gel process.     

Effects of surfactants on foliar uptake of herbicides - a complex scenario

Novel organic–inorganic nanohybrids, each having an inorganic core covered with an asymmetric lipid-bilayer membrane, were prepared through two-step self-assembling of a Cerasome-forming organoalkoxysilane lipid, N-[N-(3-triethoxysilyl)propylsuccinamoyl]dihexadecylamine (1), as the inner layer with an appropriate bilayer-forming amphiphile, N,N-dihexadecyl-N-[6-(trimethylammonio)hexanoyl]alaninamide bromide (2), sodium N,N-dihexadecyl-N-(6-sulfohexanoyl)alaninamide (3), or dimyristoylphosphatidylcholine (DMPC; 4), as the outer layer on a monodispersed colloidal silica particle. The particle thus obtained was characterized by various physical measurements, such as FT-IR spectroscopy, transmission electron microscopy, differential scanning calorimetry, and zeta-potential measurements. These data strongly supported the successful formation of the asymmetric bilayer structure on the surface of the silica particle. The current method is widely applicable to various kinds of hybrids of inorganic particles with lipid membrane components.     

Reduction-responsive vesicles composed of dimethylaminopropyl octadecanamide and dithiodipropionic acid

Reduction-responsive vesicle was prepared by salt-bridging N-[3-(dimethylamino)propyl]-octadecanamide (DMAPODA, a cationic amphiphile) using 3,3′-dithiodipropionic acid (DTPA, a disulfide diacid compound). According to the transmission electron micrograph and the fluorescence quenching degree (53.2%), it could be said that vesicles were formed when the DMAPODA to DTPA molar ratio was 2:2. The DMAPODA/DTPA associate was considered to be a building block for vesicle formation because DTPA could electrostatically associate with DMAPODA and help the cationic amphiphile assemble into the vesicle. On a differential scanning calorimetric thermogram, the DMAPODA/DTPA vesicle showed two endothermic peaks at 50.6°C and 63.2°C. The peak found at the lower temperature was possibly due to the solid gel-to-liquid crystal phase transition of the vesicular membrane and the peak found at the higher temperature was considered to be due to the melting of DMAPODA, indicating that unassociated DMAPODA coexisted with DMAPODA/DTPA vesicles. The release of calcein enveloped in the vesicle was promoted by DL-dithiothreitol, possibly because DTPA can be broken by the reducing agent to form mercaptopropionic acids and the vesicle could be disintegrated and/or the vesicular membrane would become defective.     

A Versatile and Robust Vesicle Based on a Photocleavable Surfactant for Two‐Photon‐Tuned Release

A small amphiphile that contains a coumarin unit and alkynyl groups, as a two‐photon‐cleavable segment and polymerizable groups, respectively, was designed and synthesized. The amphiphile showed a critical aggregation concentration of about 4.6×10^?5 M and formed a vesicle‐type assembly. The formed vesicles were stabilized by in situ “click” polymerization without altering their morphology. Hydrophobic and hydrophilic guests can be encapsulated within the vesicle membrane and inside the aqueous core of the vesicle, respectively. The loaded guests can be released from the vesicle by using UV or near‐IR stimuli, through splitting up the amphiphilic structure of the amphiphile. Distinguished dose‐controlled photorelease of the polymeric vesicle is achieved with the maintenance of vesicular integrity, which makes the guest release dependent on the amount of cleavage of the amphiphilic structure during irradiation. This study provides a potential strategy for the development of versatile and stable drug‐delivery systems that offer sustained and photo‐triggered release.     

Intracellular injection of phospholipids directly alters exocytosis and the fraction of chemical release in chromaffin cells as measured by nano-electrochemistry

Using a nano-injection method, we introduced phospholipids having different intrinsic geometries into single secretory cells and used single cell amperometry (SCA) and intracellular vesicle impact electrochemical cytometry (IVIEC) with nanotip electrodes to monitor the effects of intracellular incubation on the exocytosis process and vesicular storage. Combining tools, this work provides new information to understand the impact of intracellular membrane lipid engineering on exocytotic release, vesicular content and fraction of chemical release. We also assessed the effect of membrane lipid alteration on catecholamine storage of isolated vesicles by implementing another amperometric technique, vesicle impact electrochemical cytometry (VIEC), outside the cell. Exocytosis analysis reveals that the intracellular nano-injection of phosphatidylcholine and lysophosphatidylcholine decreases the number of released catecholamines, whereas phosphatidylethanolamine shows the opposite effect. These observations support the emerging hypothesis that lipid curvature results in membrane remodeling through secretory pathways, and also provide new evidence for a critical role of the lipid localization in modulating the release process. Interestingly, the IVIEC data imply that total vesicular content is also affected by in situ supplementation of the cells with some lipids, while, the corresponding VIEC results show that the neurotransmitter content in isolated vesicles is not affected by altering the vesicle membrane lipids. This suggests that the intervention of phospholipids inside the cell has its effect on the cellular machinery for vesicle release rather than vesicle structure, and leads to the somewhat surprising conclusion that modulating release has a direct effect on vesicle structure, which is likely due to the vesicles opening and closing again during exocytosis. These findings could lead to a novel regulatory mechanism for the exocytotic or synaptic strength based on lipid heterogeneity across the cell membrane.

Amperometry and intracellular vesicle impact electrochemical cytometry with nanotip electrodes were used to monitor the effects on exocytosis and vesicular storage after nano-injection of phospholipids with different geometries into secretory cells.     

Polymerization behavior and gel properties of ethane,ethylene and acetylene-bridged polysilsesquioxanes

Soluble bridged polysilsesquioxanes with a range of molecular weight were synthesized from bis(triethoxysilyl)ethane, ethylene, and acetylene (BTES-E1, -E2, and -E3) via hydrolysis and polycondensation reaction by adjusting the water amount. Polymerization behavior of these three trialkoxysilanes was investigated by monitoring the reaction progress by GPC, and ²⁹Si NMR spectrometry of the resulting polymers, poly(BTES-E1), poly(BTES-E2), and poly(BTES-E3), showing that BTES-E1 generated cyclic oligomers at the early stage. In contrast, polymerization of BTES-E2 and BTES-E3 provided no detectable amounts of cyclic oligomers, but afforded linear polymers only. Bulk gels were also prepared by curing the polymers. The gel from poly(BTES-E3) exhibited high thermal stability derived from the rigid acetylene spacer with respect to thermogravimetric analysis. On the other hand, the polymer film of BTES-E1 showed the highest pencil hardness index among the polymers, indicating the tight siloxane network of poly(BTES-E1).     

Stabilized vesicles consisting of small amphiphiles for stepwise photorelease via UV light

A small amphiphile consisting of hydrophilic tetraethylene glycol monoacrylate and hydrophobic alkyl chain which were connected by an o-nitrobenzyl unit, a photolabile group, was designed and synthesized. The critical aggregate concentration of the synthesized amphiphile was determined to be about 3 × 10(-5) M by the fluorescence probe technique. Nanosized vesicles were prepared and stabilized by in-situ radical polymerization without altering the morphology. The polymeric vesicle was highly stable which retained vesicular shape under dilution or UV irradiation. Hydrophobic guests can be encapsulated within the vesicle membrane and released out of the vesicle by UV stimulus through splitting the amphiphilic structure of the amphiphile. Distinguished dose-controlled photorelease of the polymeric vesicle is achieved due to the maintenance of the vesicular shape integrity which makes the guest release depend on the cleavage amount of amphiphilic structure during UV irradiation. This study provides a promising strategy to develop stable drug delivery systems for sustained and phototriggered release.     

Chemical tailoring of porous silica xerogels: local structure by vibrational spectroscopy

Monolithic porous silica xerogels were synthesized by the sol-gel process, and their local structure was analysed by vibrational spectroscopy. The silica alcogels were prepared by a two-step hydrolytic polycondensation of tetraethoxysilane (TEOS) in isopropanol, with a water/TEOS molar ratio of 4. The hydrolysis step was catalysed by hydrochloric acid (HCl), with different HCl/TEOS molar ratios (ranging from 0.0005 to 0.009), and the condensation step was catalysed by ammonia (NH(3)), with different NH(3)/HCl molar ratios (ranging from 0.7 to 1.7). After appropriate ageing, the alcogels were washed with isopropanol and subcritically dried at atmospheric pressure. The diffuse reflectance infrared Fourier transform (DRIFT) spectra were analysed in terms of the main siloxane rings that form the silica particles, taking into account the splitting of the nu(as)Sibond;Obond;Si mode into pairs of longitudinal and transverse optic components, by long-range Coulomb interactions. It was proven that the proportion of residual silanol groups (which correlates with hydrophilicity), and the fraction of siloxane 6-rings (which correlates with porosity) may be tailored by adequate catalytic conditions, mostly by the hydrolysis pH. This was explained in terms of the reactions' mechanisms taking place in the two-step sol-gel process followed.     

Polycondensation of trialkoxysilane monomers accelerated by neighboring group participation of urea moiety

(Phenylaminomethyl)trimethoxysilane (= α‐amino‐siloxane) was treated with various isocyanates to obtain a series of siloxanes having urea moieties (= α‐urea‐siloxanes). Their hydrolysis‐condensation reactions were monitored with ²⁹Si NMR, to reveal that they exhibited much higher reactivity than a urea‐siloxane derived from [3‐(phenylamino)propyl]trimethoxysilane (= γ‐amino‐siloxane). When compared with the derivation of the γ‐amino‐siloxane into the corresponding γ‐urea‐siloxane, those of the α‐amino‐siloxane into the corresponding α‐urea‐siloxanes were accompanied by much larger shifts of the ²⁹Si NMR signal toward a higher magnetic field. These results suggested that the location of the urea moiety in the α‐urea‐siloxanes was favorable to its intramolecular coordination to the silicon atom to exhibit its “neighboring group participation” that promoted transformation of the tetravalent silicon center into the pentavalent one, which is more electrophilic to make the siloxanes more susceptive to undergo the hydrolysis and condensation reactions. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6654–6659, 2008     

Gemini peptide lipids with ditopic ion-recognition site. Preparation and functions as an inducer for assembling of liposomal membranes

Gemini amphiphiles having two peptide lipid units and a spacer group connected at the polar heads were synthesized. A gemini peptide lipid bearing l-histidyl residues, hydrophobic double-chain segments, and a tri(oxyethylene) spacer performed as an inducer of the reversible assembling of liposomal membranes through ditopic ion recognition toward transition metal ions and alkali metal ions. The vesicular assembling behavior induced by the gemini peptide lipids was sensitive to the structural difference in the amino acid residue and the spacer group of the lipids.