Highly Efficient Gating of Electrically Actuated Nanochannels for Pulsatile Drug Delivery Stemming from a Reversible Wettability Switch

Many ion channels in the cell membrane are believed to function as gates that control the water and ion flow through the transitions between an inherent hydrophobic state and a stimuli‐induced hydration state. The construction of nanofluidic gating systems with high gating efficiency and reversibility is inspired by this hydrophobic gating behavior. A kind of electrically actuated nanochannel is developed by integrating a polypyrrole (PPy) micro/nanoporous film doped with perfluorooctanesulfonate ions onto an anodic aluminum oxide nanoporous membrane. Stemming from the reversible wettability switch of the doped PPy film in response to the applied redox potentials, the nanochannels exhibit highly efficient and reversible gating behaviors. The optimized gating ratio is over 10⁵, which is an ultrahigh value when compared with that of the existing reversibly gated nanochannels with comparable pore diameters. Furthermore, the gating behavior of the electrically actuated nanochannels shows excellent repeatability and stability. Based on this highly efficient and reversible gating function, the electrically actuated nanochannels are further applied for drug delivery, which achieves the pulsatile release of two water‐soluble drug models. The electrically actuated nanochannels may find potential applications in accurate and on‐demand drug therapy.     

环糊精-药物复合纳米粒子的制备及其控制释放研究进展

从直接法、小分子键合、星形、树枝状和超支化环糊精大分子胶束及水凝胶、超分子组装7方面论述了环糊精-药物纳米复合体的制备,认为扩散控制、溶胀控制和化学控制是环糊精-药物纳米复合体主要的释放机理。结合释放机理,指出具有超分子结构的复合体系可望成为智能靶向释放领域的主导。     

Magnetic Targeting Nanocarriers Combined with Focusing Ultrasound for Enhanced Intracerebral Hemorrhage Therapy

Intracerebral hemorrhage (ICH) remains a significant cause of morbidity and mortality around the world, and surgery is still the most direct and effective way to remove ICH. However, the potential risks brought by surgery, such as normal brain tissue damage, post-operative infection, and difficulty in removing deep hematoma, are still the main problems in the surgical treatment of ICH. Activation of the peroxisome proliferator-activated receptor gamma (PPARγ) is reported to show a good therapeutic effect in hematoma clearance. Herein, a magnetic targeting nanocarrier loaded with a PPARγ agonist (15d-PGJ2-MNPs) is synthesized, which could be magnetically targeted and enriched in the area of the hematoma after intravenous injection. Subsequent application of focusing ultrasound (FUS) could enhance drug diffusion, which activates the PPARγ receptors on macrophages around the hematoma for better hematoma clearance. The 15d-PGJ2-MNP treatment alleviates brain injury, accelerates hematoma clearance, attenuates neuroinflammation, reduces brain edema and significantly improves the deficits in sensory and motor function and spatial learning ability in the ICH mouse model. This work proposes an effective magnetic targeting plus FUS method to treat ICH, highlighting its great potential in the treatment of hemorrhagic stroke.     

Zn2+‐Triggered Drug Release from Biocompatible Zirconium MOFs Equipped with Supramolecular Gates

A new theranostic nanoplatform, comprising of monodisperse zirconium metal‐organic frameworks (MOFs) as drug carriers and carboxylatopillar[5]arene‐based supramolecular switches as gating entities, is constructed, and controlled drug release triggered by bio‐friendly Zn²⁺ ions (abundant in synaptic vesicles) and auxiliary thermal stimulus is realized. This on‐command drug delivery system exhibits large pore sizes for drug encapsulation, excellent biodegradability and biocompatibility, extremely low cytotoxicity and premature drug release, and superior dual‐stimuli responsiveness, opening a new avenue in targeted drug delivery and controlled release of therapeutic agents, especially in the treatment of central nervous system diseases.     

Magneto‐Controllable Capture and Release of Cancer Cells by Using a Micropillar Device Decorated with Graphite Oxide‐Coated Magnetic Nanoparticles

Aiming to highly efficient capture and analysis of circulating tumor cells, a micropillar device decorated with graphite oxide‐coated magnetic nanoparticles is developed for magneto‐controllable capture and release of cancer cells. Graphite oxide‐coated, Fe₃O₄ magnetic nanoparticles (MNPs) are synthesized by solution mixing and functionalized with a specific antibody, following by the immobilization of such modified MNPs on our designed micropillar device. For the proof‐of‐concept study, a HCT116 colorectal cancer cell line is employed to exam the capture efficiency. Under magnetic field manipulation, the high density packing of antibody‐modified MNPs on the micropillars increases the local concentration of antibody, as well as the topographic interactions between cancer cells and micropillar surfaces. The flow rate and the micropillar geometry are optimized by studying their effects on capture efficiency. Then, a different number of HCT116 cells spiked in two kinds of cell suspension are investigated, yielding capture efficiency >70% in culture medium and >40% in blood sample, respectively. Moreover, the captured HCT116 cells are able to be released from the micropillars with a saturated efficiency of 92.9% upon the removal of applied magnetic field and it is found that 78% of the released cancer cells are viable, making them suitable for subsequent biological analysis.     

X‐ray‐Controlled Bilayer Permeability of Bionic Nanocapsules Stabilized by Nucleobase Pairing Interactions for Pulsatile Drug Delivery

The targeted and sustained drug release from stimuli‐responsive nanodelivery systems is limited by the irreversible and uncontrolled disruption of the currently used nanostructures. Bionic nanocapsules are designed by cross‐linking polythymine and photoisomerized polyazobenzene (PETAzo) with adenine‐modified ZnS (ZnS‐A) nanoparticles (NPs) via nucleobase pairing. The ZnS‐A NPs convert X‐rays into UV radiation that isomerizes the azobenzene groups, which allows controlled diffusion of the active payloads across the bilayer membranes. In addition, the nucleobase pairing interactions between PETAzo and ZnS‐A prevent drug leakage during their in vivo circulation, which not only enhances tumor accumulation but also maintains stability. These nanocapsules with tunable permeability show prolonged retention, remotely controlled drug release, enhanced targeted accumulation, and effective antitumor effects, indicating their potential as an anticancer drug delivery system.     

Identification of Toxin Inhibitors Using a Magnetic Nanosensor‐Based Assay

A magnetic nanosensor‐based method is described to screen a library of drugs for potential binding to toxins. Screening is performed by measuring changes in the magnetic relaxation signal of the nanosensors (bMR nanosensors) in aqueous suspension upon addition of the toxin. The Anthrax lethal factor (ALF) is selected as a model toxin to test the ability of our bMR nanosensor‐based screening method to identify potential inhibitors of the toxin. Out of 30 molecules screened, sulindac, naproxen and fusaric acid are found to bind LF, with dissociation constants in the low micromolar range. Further biological analysis of the free molecules in solution indicate that sulindac and its metabolic products inhibited LF cytotoxicity to macrophages with IC₅₀ values in the micromolar range. Meanwhile, fusaric acid is found to be less effective at inhibiting LF cytotoxicity, while naproxen does not inhibit LF toxicity. Most importantly, when the sulindac and fusaric acid‐bMR nanosensors themselves are tested as LF inhibitors, as opposed to the corresponding free molecules, they are stronger inhibitors of LF with IC₅₀ values in the nanomolar range. Taken together, these studies show that a bMR nanosensors‐based assay can be used to screen known drugs and other small molecules for inhibitor of toxins. The method can be easily modified to screen for inhibitors of other molecular interactions and not only the selected free molecule can be study as potential inhibitors but also the bMR nanosensors themselves achieving greater inhibitory potential.     

壳聚糖/PHB复合缓释微包囊的制备与体外释药评价

用疏水性聚酯PHB外包覆壳聚糖-三聚磷酸钠-阿斯匹林药物缓释体(CPA)制备了壳聚糖/PHB复合缓释微包囊(CPAB),以克服CPA遇酸不稳定的释药特点.用傅立叶红外分光光度计、激光粒度仪、扫描电镜表征了CPAB的组成、粒径及表面形貌.结果显示,CPAB粒径在50～100nm和载药率18.5%时,表面有不均匀的空隙.体外释药评价证实CPAB能有效解决CPA在酸性下的不稳定性,具有长效缓释作用.     

A Very Highly Efficient Magnetic Nanomaterial for the Removal of PAHs from Aqueous Media

Two new hybrid magnetic recyclable nanomaterials are developed. These new materials are based on bisimide perylene dopamine or bisimide perylene 3‐aminopropyltriethoxysilane and iron oxide nanoparticles. One of them, the bisimide perylene dopamine, has proven to be very efficient in the removal, by magneto filtration, of 15 carcinogenic polycyclic aromatic compounds (PAHs), especially naphthalene, acenaphthene, anthracene, phenanthrene, and fluorene. These compounds are known to be common contaminants of drinking and underground water. This nanomaterial presents a high dispersivity and stability in an aqueous media, and it is capable of forming supramolecular fluorescent magnetic nanofibers with benzo‐alpha‐pyrene or benzo[k]fluoranthene, BKF. This strong association is due to hydrophobic forces and the π–π interaction, between the bisimide perylene motif and the polycyclic aromatic compounds. The resilience of this material is tested in different media. No good results are obtained in ethanol, acetone, or acetonitrile, but an 85% recovery is achieved using toluene or hexane. Once washed, nanoparticles are shown to retain their ability to continue capturing PAHs.     

Sharpening the Thermal Release of DNA from Nanoparticles: Towards a Sequential Release Strategy

Unlike the sharp melting behavior of DNA‐linked nanoparticle aggregates, the melting of DNA strands from individual gold nanoparticles is broad despite the high surface density of bound DNA. Here, it is demonstrated how sharpened melting can be achieved in colloidal nanoparticle systems using branched DNA–doubler structures hybridized with complementary DNA‐doublers bound to the gold nanoparticle. Moreover, sharpened transitions are observed when DNA‐doublers are hybridized with linear DNA‐modified gold nanoparticles. This result suggests that the DNA density on nanoparticles is intrinsically great enough to form cooperative structures with the DNA‐doublers. Finally, by introducing abasic destabilizing groups, the melting temperature of these DNA‐doublers decreases without decreasing the sharpness. Consequently, by varying the temperature, two DNA‐doublers with different stabilities dissociate sequentially from the gold nanoparticle surface, without overlapping and within a narrow temperature window. Owing to the excellent thermal selectivities exhibited by this system, the implementation of DNA‐doublers in sequential photothermal therapies and with other nanomedicine delivery agents that rely on DNA dissociation as the mechanism of selective release is anticipated.     

Alignment under Magnetic Field of Mixed Fe2O3/SiO2 Colloidal Mesoporous Particles Induced by Shape Anisotropy

When using the bottom‐up approach with anisotropic building‐blocks, an important goal is to find simple methods to elaborate nanocomposite materials with a truly macroscopic anisotropy. Here, micrometer size colloidal mesoporous particles with a highly anisotropic rod‐like shape (aspect ratio ≈ 10) have been fabricated from silica (SiO₂) and iron oxide (Fe₂O₃). When dispersed in a solvent, these particles can be easily oriented using a magnetic field (≈200 mT). A macroscopic orientation of the particles is achieved, with their long axis parallel to the field, due to the shape anisotropy of the magnetic component of the particles. The iron oxide nanocrystals are confined inside the porosity and they form columns in the nanochannels. Two different polymorphs of Fe₂O₃ iron oxide have been stabilized, the superparamagnetic γ‐phase and the rarest multiferroic ε‐phase. The phase transformation between these two polymorphs occurs around 900 °C. Because growth occurs under confinement, a preferred crystallographic orientation of iron oxide is obtained, and structural relationships between the two polymorphs are revealed. These findings open completely new possibilities for the design of macroscopically oriented mesoporous nanocomposites, using such strongly anisotropic Fe₂O₃/silica particles. Moreover, in the case of the ε‐phase, nanocomposites with original anisotropic magnetic properties are in view.     

利用均匀磁场提高聚乙烯亚胺-Fe3O4纳米颗粒复合物的磁转染效果

首次研究了不同均匀度磁场对磁转染效果的影响。测定了单边Halbach磁体和商品化96孔磁板的磁场均匀度。以化学共沉淀法制备聚乙烯亚胺(Polyethyleneimine,PEI)修饰的四氧化三铁(Fe_3O_4)纳米颗粒(PEI-Fe_3O_4),并用透射电子显微镜(TEM)、振动样品磁强计(VSM)、原子力显微镜、琼脂糖凝胶电泳等对其形貌、组成、DNA结合能力等进行表征。用倒置荧光显微镜、流式细胞术观察不同均匀度磁场下人肾上皮细胞(HEK293)对带有绿色荧光蛋白报告基因(GFP)的质粒pDNA(pAdTrackOK)的表达效果,并采用TEM观察PEI-Fe_3O_4磁性纳米颗粒进入细胞的过程。结果显示,所选取的两种磁场均匀度相差约100倍。制备的PEI-Fe_3O_4纳米复合物具有超顺磁性,对质粒pDNA(pAdTrack-OK)有较好的复合能力,其最佳结合氮磷比为0.5;流式细胞术显示转染效率为PEI-Fe_3O_4-pDNA+均匀磁场组(77.75%±0.07%)PEI-Fe_3O_4-pDNA+不均匀磁场组(30.65%±0.49%)PEI-Fe_3O_4-pDNA不加磁场组(7.90%±0.56%)(p0.05);PEI-Fe_3O_4磁性纳米颗粒能有效被细胞吞噬,且对细胞形态的影响不大。结果表明,当磁场强度一定时,磁场均匀度越高,磁转染效率越高,单边Halbach磁体与磁转染结合可以作为一种提高转染效率的新手段,也可以进一步应用在基因治疗中。     

磁诱导下氧化亚铜晶体的制备及表征

在恒定磁场的诱导下，恒电流电沉积制备了氧化亚铜（Cu2O）晶体。X射线衍射（XRD）和X射线光电子能谱仪（XPS）的测定结果表明，电沉积制备的氧化亚铜（Cu2O）为纯净、立方晶系的Cu2O晶体；扫描电子显微镜（SEM）分析结果表明，有无磁场电沉积时，氧化亚铜均表现为多面体聚集，但电结晶行为表现不同，在磁诱导下Cu2O电结晶径向生长的速率明显优于轴向生长，并出现孔洞现象。     

Effect of Oil Phase Lipophilicity on In Vitro Drug Release from O/W Microemulsions with Low Surfactant Content

ABSTRACT

In this work we investigated the effects of oil phase lipophilicity on in vitro drug release from topical o/w microemulsions (MEs) containing low percentages of emulsifiers. Three different lipids, isopropyl myristate (IPM), isopropyl palmitate (IPP), and isopropyl stearate (IPS), whose lipophilicity increased in the order IPM < IPP <IPS, were used as oil phase to prepare o/w MEs containing low amounts (7.7% w/w) of two surfactant/cosurfactant mixtures, isoceteth-20/glyceryl oleate (5:2) (MEs 1–3) and oleth-20/glyceryl oleate (5:2) (MEs 4–6). All the MEs were prepared using the phase inversion temperature (PIT) method.

Three active compounds (0.5% w/w), Naproxen (NAP), Idebenone (IDE), and Butylmethoxydibenzoylmethane (BMBM), were selected as model drugs and their release rates from PIT MEs were evaluated using Franz-type diffusion cells. All the MEs gave a mean droplet diameter ranging from 28 to 44 nm and showed a single peak in size distribution. The addition of IDE to MEs 1–6 did not significantly change ME droplet size. On the contrary, an increase of the droplet size beyond the ME limit (150 nm) was observed when isoceteth-20 was used as surfactant to prepare MEs containing NAP or MEs containing BMBM and IPS as oil phase. Pseudo-first order release rates were observed only for NAP from MEs 1–3, while MEs containing IDE showed an initial slow release followed by an increased release of the test compound. The release rate constants were found to be dependent on the ME composition and on the active compound incorporated. The highest release rate was observed from ME 1 containing IPM as oil phase and NAP as drug. As regards BMBM, its release rate was not calculated since no release was observed until 6 h from the beginning of the experiment. The cumulative amount of active compound released after 22 h was inversely related to drug lipophilicity (NAP Log P = 2,9; IDE Log P 3,5; BMBM Log P 4,8). These findings could be attributable to a reduced thermodynamic activity of the drugs in the vehicles containing the most lipophilic oil phase due to an increase of drug solubility which could lead to an unfavorable drug partition from the oil phase. The results of this study suggest that the choice of proper combinations of oil phase lipids and emulsifiers may allow achieving drug controlled delivery from topical o/w MEs with low emulsifier content.     

<Emphasis Type="Italic">In vivo</Emphasis> evaluation of riboflavin receptor targeted fluorescent USPIO in mice with prostate cancer xenografts

Riboflavin (Rf) receptors bind and translocate Rf and its phosphorylated forms (e.g. flavin mononucleotide, FMN) into cells where they mediate various cellular metabolic pathways. Previously, we showed that FMN-coated ultrasmall superparamagnetic iron oxide (FLUSPIO) nanoparticles are suitable for labeling metabolically active cancer and endothelial cells in vitro. In this study, we focused on the in vivo application of FLUSPIO using prostate cancer xenografts. Size, charge, and chemical composition of FLUSPIO were evaluated. We explored the in vitro specificity of FLUSPIO for its cellular receptors using magnetic resonance imaging (MRI) and Prussian blue staining. Competitive binding experiments were performed in vivo by injecting free FMN in excess. Bio-distribution of FLUSPIO was determined by estimating iron content in organs and tumors using a colorimetric assay. AFM analysis and zeta potential measurements revealed a particulate morphology approximately 20–40 nm in size and a negative zeta potential (–24.23 ± 0.15 mV) in water. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry data confirmed FMN present on the USPIO nanoparticle surface. FLUSPIO uptake in prostate cancer cells and human umbilical vein endothelial cells was significantly higher than that of control USPIO, while addition of excess of free FMN reduced accumulation. Similarly, in vivo MRI and histology showed specific FLUSPIO uptake by prostate cancer cells, tumor endothelial cells, and tumor-associated macrophages. Besides prominent tumor accumulation, FLUSPIO accumulated in the liver, spleen, lung, and skin. Hence, our data strengthen our hypothesis that targeting riboflavin receptors is an efficient approach to accumulate nanomedicines in tumors opening perspectives for the development of diagnostic and therapeutic systems.