Liposome-templated supramolecular assembly of responsive alginate nanogels

Nanosized gel particles (nanogels) are of interest for a variety of applications, including drug delivery and single-molecule encapsulation. Here, we employ the cores of nanoscale liposomes as reaction vessels to template the assembly of calcium alginate nanogels. For our experiments, a liposome formulation with a high bilayer melting temperature (Tm) is selected, and sodium alginate is encapsulated in the liposomal core. The liposomes are then placed in an aqueous buffer containing calcium chloride, and the temperature is raised up to Tm. This allows permeation of Ca2+ ions through the bilayer and into the core, whereupon these ions gel the encapsulated alginate. Subsequently, the lipid bilayer covering the gelled core is removed by the addition of a detergent. The resulting alginate nanogels have a size distribution consistent with that of the template liposomes (ca. 120-200 nm), as confirmed by transmission electron microscopy and light scattering. Nanogels of different average sizes can be synthesized by varying the template dimensions, and the gel size can be further tuned after synthesis by the addition of monovalent salt to the solution.     

Molecular architecture of nanocapsules, bilayer-enclosed solid particles of Cisplatin

Cisplatin nanocapsules represent a lipid formulation of the anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) characterized by an unprecedented cisplatin-to-lipid ratio and exhibiting strongly improved cytotoxicity against tumor cells in vitro as compared to the free drug (Burger, K. N. J., et al. Nat. Med. 2002, 8, 81-84). Cisplatin nanocapsules are prepared by the repeated freezing and thawing of an equimolar dispersion of phosphatidylserine (PS) and phosphatidylcholine (PC) in a concentrated aqueous solution of cisplatin. Here, the molecular architecture of these novel nanostructures was elucidated by solid-state NMR techniques. 15N NMR and 2H NMR spectra of nanocapsules containing 15N- and 2H-labeled cisplatin, respectively, demonstrated that the core of the nanocapsules consists of solid cisplatin devoid of free water. Magic-angle spinning 15N NMR showed that approximately 90% of the cisplatin in the core is present as the dichloro species. The remaining 10% was accounted for by a newly discovered dinuclear Pt compound that was identified as the positively charged chloride-bridged dimer of cisplatin. NMR techniques sensitive to lipid organization, 31P NMR and 2H NMR, revealed that the cisplatin core is coated by phospholipids in a bilayer configuration and that the interaction between solid core and bilayer coat exerts a strong ordering effect on the phospholipid molecules. Compared to phospholipids in liposomal membranes, the motion of the phospholipid headgroups is restricted and the ordering of the acyl chains is increased, particularly in PS. The implications of these findings for the structural organization, the mechanism of formation, and the mode of action of cisplatin nanocapsules are discussed.     

含水核载牛血清白蛋白聚氰基丙烯酸丁酯微囊的制备及体外释放

利用界面乳液聚合方法制备了新型含水核载牛血清白蛋白 (BSA)的聚氰基丙烯酸丁酯 (PBCA)纳米微囊 .分别研究了纳米微囊的粒径及其分布 ,表面Zeta电势的变化 .并以牛血清白蛋白为模型药物考察了药物包裹率和载药量的变化以及载药纳米微囊在磷酸缓冲溶液中的体外释放行为 .结果表明 ,所制备的纳米微囊平均粒径为 2 0 0nm ,多分散度为 0 2 2 6;表面Zeta电势的变化证明了BSA是包裹于纳米微囊的内部而不是吸附在其表面 ;包裹率和载药量取决于水相中BSA的初始浓度 ,当BSA的浓度为 0 8mg mL时 ,包裹率和载药量分别为 3 5 %和 0 485× 1 0 - 9mol mg;药物的释放速率取决于纳米微囊的壁厚 ,通过调节壁厚可以达到控释的目的     

Self-assembly of stable monomolecular nucleic acid lipid particles with a size of 30 nm

The design of efficient nucleic acid complexes is key to progress in genetic research and therapies based on RNA interference. For optimal transport within tissue and across extracellular barriers, nucleic acid carriers need to be small and stable. In this Article, we prepare and characterize mono-nucleic acid lipid particles (mono-NALPs). The particles consist of single short double-stranded oligonucleotides or single siRNA molecules each encapsulated within a closed shell of a cationic-zwitterionic lipid bilayer, furnished with an outer polyethylene glycol (PEG) shield. The particles self-assemble by solvent exchange from a solution containing nucleic acid mixed with the four lipid components DOTAP, DOPE, DOPC, and DSPE-PEG(2000). Using fluorescence correlation spectroscopy, we monitor the formation of mono-NALPs from short double-stranded oligonucleotides or siRNA and lipids into monodisperse particles of approximately 30 nm in diameter. Small angle neutron and X-ray scattering and transmission electron microscopy experiments substantiate a micelle-like core-shell structure of the particles. The PEGylated lipid shell protects the nucleic acid core against degradation by nucleases, sterically stabilizes the mono-NALPs against disassembly in collagen networks, and prevents nonspecific binding to cells. Hence, PEG-lipid shielded mono-NALPs are the smallest stable siRNA lipid system possible and may provide a structural design to be built upon for the development of novel nucleic acid delivery systems with enhanced biodistribution in vivo.     

The influence of high dielectric constant core on the activity of core-shell structure electrorheological fluid

The core-shell structural dielectric particles are applied widely in the electrorheological (ER) fluids. The properties of the dielectric core are critical factors influencing their ER activity. In this paper, we successfully synthesized two kinds of core-shell hydroxyl titanium oxalate (TOC) particles with SiO(2) and TiO(2) as core, respectively. The obtained core-shell structural SiO(2)-TOC and TiO(2)-TOC particles were well-dispersed spherical nanoparticles with ideal morphology and a narrow size distribution. Under DC electric fields, the TiO(2)-TOC ER fluid showed notable ER activity with a yield stress of about 96 kPa (at 4 kV/mm), which is 3 times of that SiO(2)-TOC ER fluid and outclassed the yield stress of the TOC ER fluid. The dielectric spectra indicated that the higher dielectric constant of TiO(2) core induces the stronger interaction between the neighboring particles, which contribute to the enhancement of ER activity.     

Heterogeneous and anomalous diffusion inside lipid tubules

Self-assembled lipid tubules with crystalline bilayer walls are promising candidates for controlled drug delivery vehicles on the basis of their ability to release preloaded biological molecules in a sustained manner. While a previous study has shown that the release rate of protein molecules from lipid tubules depends on the associated molecular mass, suggesting that the pertinent diffusion follows the well-known Stokes-Einstein relationship, only a few attempts have been made toward investigating the details of molecular diffusion in the tubule interior. Herein, we have characterized the diffusion rates of several molecules encapsulated in lipid tubules formed by 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC) using the techniques of fluorescence recovery after photobleaching (FRAP) and fluorescence correlation spectroscopy (FCS). Our results show that the mobility of these molecules depends not only on their positions in the DC8,9PC tubules but also on their respective concentrations. While the former indicates that the interior of the DC8,9PC tubules is heterogeneous in terms of diffusion, the latter further highlights the possibility of engineering specific conditions for achieving sustained release of a "drug molecule" over a targeted period of time. In addition, our FCS results indicate that the molecular diffusions inside the crystalline bilayer walls of the DC8,9PC tubules strongly deviate from the normal, stochastic processes, with features characterizing not only anomalous subdiffusions but also motions that are superdiffusive in nature.     

Novel core-shell lipid-chitosan and lipid-poloxamer nanocapsules: stability by hydration forces

In the last few years, a great attention has been paid to core-shell structured lipid nanocapsules. The interest of these colloids lies in their very promising applications as delivery systems of hydrophobic drugs or as DNA carriers. The aim of this work was to provide fuller knowledge concerning the physicochemical properties of these new colloidal particles, paying special attention to the role played by the constituting components. Our lipid nanocapsules were comprised of a triglyceride-lecithin core surrounded by a chitosan and/or poloxamer (Pluronic® F68) shell. Four different systems were formulated by varying the chitosan and poloxamer contents. We have estimated their shell composition from electrokinetic mobility measurements and stability studies. They revealed a high incorporation of chitosan to the shell, while Pluronic® F68 only presented a secondary role during the nanocapsule formation, providing final systems with low poloxamer content. In addition, the stability studies, performed not only on ideal solutions but also on simulated physiological fluids, revealed that hydration forces were crucial to maintain the integrity of these nanocapsules under physicochemical conditions similar to those found in real physiological fluids. Theoretical treatment of stability data has allowed us to determine the role that ions play on hydration forces when they act as counterions.     

Preparation of Hybrid Nanocapsules

Hybrid nanoparticles with a polystyrene core and a hybrid copolymer shell were used to produce hybrid nanocapsules by dissolving the polystyrene core from the previously elaborated core-shell particles. Following previous works, the core-shell particles were prepared by emulsion polymerization of styrene and subsequent addition of γ-methacryloxy propyl trimethoxy silane (MPS) to produce the shell by copolymerization reaction of MPS with the residual styrene. Core extraction was performed by diluting the core-shell particles in an excess of tetrahydrofuran (THF). Two procedures were investigated to separate the dissolved polymer chains from the nanocapsules. In the first procedure, the polymer was isolated by successive centrifugation and redispersion in THF, whereas in the second procedure, the free polymer chains were removed by dialysis. The polymer molecular weight was optimized in order to promote dissolution of the polymer chains and allow them to diffuse through the shell.     

同轴电喷-去模板法制备具有金属基质蛋白酶响应性的纳米载体

通过化学键偶联的形式在聚乳酸(PLA)分子链中引入了可被金属基质蛋白酶(MMP-2)特异性降解的多肽peptide(GPLGIAGQ)单元,得到具有金属基质蛋白酶响应性的聚合物PLA-b-peptide-b-PLA.通过同轴电喷方法制备得到以PLA-b-peptide-b-PLA和抗肿瘤药物DOX的混合物作为内核,亲水性聚乙二醇(PEG)作为外壳的,具有核-壳结构的载药微球.其中水溶性的PEG壳层可在水环境中迅速脱除,将载药微球的尺寸从微米级减小到纳米尺度,可以达到药物载体系统在输运的循环过程中的尺寸递减.制备的纳米载体可在金属基质蛋白酶存在的环境中,响应性释放所包载的抗肿瘤药物,实现药物的控制释放.     

从层层组装的核壳粒子到医学/生物化学诊断和药物输送*

层层组装的核壳型粒子由于具有尺度和组成的剪裁优点近年来得到了广泛的研究,它们为技术应用如医学/生物化学诊断和药物输送提供了新的机遇.本文综述了基于层层自组装和胶体模板以及采用各种化学和物理方法直接除去核制备磁性复合核壳粒子和空腔球体.给出了核壳粒子在药物输送、生物检测与标记应用的一些实例.     

pH值和前驱体用量对核壳结构PSt/SiO2复合微球结构形态的影响

首先通过无皂乳液聚合法制得表面含羧基、粒径为360 nm的单分散聚苯乙烯(PSt)种子乳液,并在EtOH/H2O混合介质中用γ-氨丙基三乙氧基硅烷(KH-550)对其进行改性,制得表面含有活性硅乙氧基并带有正电荷的改性PSt乳胶粒,然后再加入原硅酸乙酯(TEOS)进行共水解与共缩聚反应,制备出了核壳结构PSt/SiO2...     

Enhanced In Vitro Antitumor Efficacy and Strong Anti‐Cell‐Migration Activity of a Hydroxycamptothecin‐Encapsulated Magnetic Nanovehicle

A 10‐hydroxycamptothecin‐encapsulated magnetic nanovehicle (HEMN) was fabricated by coencapsulating Fe₃O₄ nanoparticles and 10‐hydroxycamptothecin (HCPT) into a micelle core self‐assembled from the amphiphilic copolymer methoxy‐poly(ethylene glycol)–poly(d,l ‐lactide‐co‐glycolide) through a facile dialysis method. A satisfactory drug‐loading content of (9.03±0.67) % and a relatively high encapsulation efficiency of (53.52±6.46) % were achieved. In vitro drug release was performed by membrane dialysis and a pH‐dependent release behavior was observed. In comparison with free HCPT dissolved in dimethylsulfoxide, HEMNs showed a greatly improved in vitro antitumor efficacy against three different human cancer cell lines—HeLa, A549, and HepG2—and lower IC₅₀ values were measured. The mechanism of cell death was investigated, and it was clearly demonstrated that the apoptosis process was triggered. An in vitro wound‐healing assay and a transwell assay indicated that HEMNs exerted much stronger activity in inhibiting HeLa cell migration. The cellular uptake of HEMNs in a desired area can be significantly enhanced by an external magnetic field. These results demonstrate HCPT‐encapsulated magnetic nanovehicles might have important potential in clinical applications for inhibiting tumor metastasis and for targeted drug delivery.     

Rattle-type hollow CaWO4:Tb(3+)@SiO2 nanocapsules as carriers for drug delivery

Rattle-type hollow nanocapsules are among of the most promising candidates as drug carriers owing to their huge inner space and multifunctional material combination. In this paper, rattle-type hollow CaWO(4):Tb(3+)@SiO(2) nanocapsules with a diameter of 100-110 nm and a wall thickness around 10 nm were fabricated. The hollow silica nanospheres were used as nano-reactors and the luminescent core of CaWO(4):Tb(3+) was post-filled into the nano-reactors by a vacuum nano-casting route combined with a Pechini-type sol-gel method. Subsequently, doxorubicin hydrochloride (DOX), a model of an anti-cancer drug, is loaded into the CaWO(4):Tb(3+)@SiO(2) nanocapsules and their cell cytotoxicity, cancer cell uptake and drug release behavior are investigated in vitro. The prepared multifunctional inorganic nanocapsules show a loading capacity for DOX as high as 124 mg g(-1) and sustained-release properties. The release profile of the drug from DOX-loaded nanocapsules can last over five days. Besides, the blank CaWO(4):Tb(3+)@SiO(2) shows very low cytotoxicity against cancer cell lines (HeLa cell) while the DOX-loaded nanocapsules exhibit relatively high efficiency for killing of HeLa cells. The rapid cancer cell uptake process is observed by confocal laser scanning microscopy. The results indicate that a rattle-type hollow CaWO(4):Tb(3+)@SiO(2) nanocapsule has the potential to be used as drug carrier in therapy. Moreover, it is possible to extend the synthetic strategy in this study to other rattle-type multifunctional composites to meet various demands.     

Core-shell lipid-polymer nanoparticles as a promising ocular drug delivery system to treat glaucoma

Nowadays,tremendous researches have been focused on the core-shell lipid-polymer nanoparticles(LPNs) due to the advantages of both liposomes and polymer nanoparticles.In this work,LPNs were applied to encapsulate brinzolamide(Brz-LPNs) for achieving sustained drug release,improving drug corneal permeation and enhancing drug topical therapeutic effect.The structure of Brz-LPNs was composed of poly(lactic-co-glycolic) acid(PLGA) nanocore which encapsulated Brz(Brz-NPs) and lipid shell around the core.Brz-LPNs were prepared by a modified thin-film dispersion method.With the parameters optimization of Brz-LPNs,optimal Brz-LPNs showed an average particle size of151.23±1.64 nm with a high encapsulation efficiency(EE) of 86.7%±2.28%.The core-shell structure of Brz-LPNs were confirmed by transmission electronic microscopy(TEM).Fourier transformed infrared spectra(FTIR) analysis proved that Brz was successfully entrapped into Brz-LPNs.Brz-LPNs exhibited obvious sustained release of Brz,compared with AZOPT^■ and Brz-LPs.Furthermore,the corneal accumulative permeability of Brz-LPNs significantly increased compared to the commercial available formulation(AZOPT^■) in vitro.Moreover,Brz-LPNs(1 mg/mL Brz) showed a more sustained and effective intraocular pressure(IOP) reduction than Brz-LPs(1 mg/mL) and AZOPT^■(10 mg/mL Brz) in vivo.In conclusion,Brz-LPNs,as promising ocular drug delivery systems,are well worth developing in the future for glaucoma treatment.     

Core-shell nanoparticles: characterization and study of their use for the encapsulation of hydrophobic fluorescent dyes

Core-shell nanocapsules intended to be used as drug scavengers were prepared using a surfactant mixture containing octadecyltrimethoxysilane (OTMS) as a reactive amphiphile, to form spherical templates. A siloxane shell was grown on the surface of the templates by reacting tetramethoxysilane (TMOS) with the silanol groups obtained after the hydrolysis and condensation of OTMS. Dynamic light scattering (DLS) showed that particles with diameters in the range of 100-200 nm were obtained, with core and shell sizes controlled by varying component compositions. Atomic force microscopy (AFM) was used to study the effect of the silica coating of the templates on their robustness after deposition on a substrate. Subsequently, we present studies on the encapsulation of two hydrophobic fluorescent dyes, which are sensors of polarity and rigidity. Steady-state fluorescence spectroscopy was used to examine the fluorescence response of the dyes before and after shell growth. Changes in the emission of the encapsulated dyes were related to changes in the polarity and rigidity of the microenvironment where the dyes were located and correlated to the AFM results. Finally, dye-free core-shell particles were used to sequester the dyes from aqueous suspensions. Fluorescence of the sequestered species was compared to the dye-loaded particles to determine the final fate of the fluorophores in the nanoparticles.     

Metal–Organic‐Framework‐Templated Polyelectrolyte Nanocapsules for the Encapsulation and Delivery of Small‐Molecule–Polymer Conjugates

Herein, we report a strategy for exploiting nanoscale metal–organic frameworks (nano‐MOFs) as templates for the layer‐by‐layer (LbL) assembly of polyelectrolytes. Because small‐molecule drugs or imaging agents cannot be efficiently encapsulated by polyelectrolyte nanocapsules, we investigated two promising and biocompatible polymers (comb‐shaped polyethylene glycol (PEG) and hyperbranched polyglycerol‐based PEG) for the conjugation of model drugs and imaging agents, which were then encapsulated inside the nano‐MOF‐templated nanocapsules. Furthermore, we also systemically explored the release kinetics of the encapsulated conjugates, and examined how the encapsulation and/or release processes could be controlled by varying the composition and architecture of the polymers. We envision that our nano‐MOFs‐templated nanocapsules, through combining with small‐molecule–polymer conjugates, will represent a new type of delivery system that could open up new opportunities for biomedical applications.     

Preparation of pH-Responsive Doxorubicin Nanocapsules by Combining High-gravity Antisolvent Precipitation with In-situ Polymerization for Intracellular Anticancer Drug Delivery

Owing to the low pH value in tumor and cancer cells, drug delivery systems based on pH-responsive polymer nanocarriers have been extensively explored for anticancer chemotherapy. Herein, we developed a pH-responsive doxorubicin(DOX) nanocapsule(named as DNanoCapsule) prepared by combining in-situ polymerization technique with high-gravity antisolvent precipitation technique through an amphiphilic polymerized surface ligand. DNanoCapsules show an obvious spherical core-shell structure with a single DOX nanoparticle encapsulated in the polymer layer. Dissolution rate studies prove that the DNanoCapsules have robust drug-release profiles under acidic environments due to the division of the pH-sensitive cross-linker, which triggers the collapse of the polymer layer. The in vitro investigations demonstrated that the DNanoCapsules exhibited high cellular uptake efficiency and cytotoxicity for both HeLa and MCF-7 cancer cells. Therefore, this work may provide a promising strategy to design and develop various stimuli-responsive drug nanocapsules for the treatment of cancer or other diseases.     

新型SiO2/SiO2核壳型固定相的制备与评价

采用层层自组装的方法,以微米多孔硅胶小球为核,将硅胶纳米粒子多层包覆,制备了核壳型SiO2/SiO2硅胶小球.透射电子显微镜表明这种硅胶小球具有明显的核壳结构,氮气吸附实验证明该硅胶小球是典型的介孔材料,具有良好的介孔结构和窄的孔径分布.将其作为基质制备碳十八键合核壳型SiO2/SiO2色谱固定相,该固定相的碳含量与未...     

Novel Methods of Enhanced Retention in and Rapid, Targeted Release from Liposomes

Liposomes are single bilayer capsules with distinct interior compartments in which hydrophilic drugs, imaging agents, diagnostics, etc. can be sequestered from the exterior environment. The polar parts of the individual lipids face the water compartments, while the hydrophobic parts of the lipid provide a barrier in which hydrophilic or charged molecules are poorly soluble. Hydrophobic molecules can be dissolved within the bilayer. The bilayers are typically from 3 - 6 nm thick and the liposome can range from about 50 nm - 50 microns in diameter. The question asked in this review is if any one bilayer, regardless of its composition, can provide the extended drug retention, long lifetime in the circulation, active targeting to specific tissues and rapid and controllable drug release at the site of interest. As an alternative, we review methods of self-assembling multicompartment lipid structures that provide enhanced drug retention in physiological environments. We also review methods of externally targeting and triggering drug release via the near infrared heating of gold nanoshells attached to or encapsulated within bilayer vesicles.     

A Multi-crosslinking Nanocapsule-Based Serial-Stimuli-Responsive Leakage-Free Drug-Delivery System In Vitro

As some stimuli utilized in conventional drug delivery systems can also be found in normal cells, it is inevitable that encapsulated drugs escape from carriers into normal cells. Based on mutual interactions among proteins, polyphenol compounds, and metal ions, we developed a serial-stimuli-responsive drug delivery system. With multi-crosslinking structure, nanocapsules can maintain the integrity of the framework, even with a certain amount of stimuli present, and eventually reach tumor cells to initiate apoptosis, and protect normal cells from being damaged. Meanwhile, the fluorescence of DOX will be quenched when encapsulated in nanocapsules. This property means that the DOX that is released from nanocapsules can be monitored in real-time based on the recovery of fluorescence. These versatile nanocapsules exhibit great potentials to treat cancer.