Targeted delivery of polyoxometalate nanocomposites

Polyoxometalate/carboxymethyl chitosan nanocomposites with an average diameter of 130 nm are synthesized and labeled with fluorescein isothiocyanate (FITC) for a combined drug-carrier and cellular-monitoring approach. [Eu(β(2) -SiW(11) O(39) )(2) ](13-) /CMC nanospheres as a representative example do not display cytotoxicity for POM concentrations up to 2 mg mL(-1) . Cellular uptake of fluoresecently labelled {EuSiW(11) O(39) }/FITC-CMC nanoparticles is monitored with confocal laser scanning microscopy. Nanoparticle uptake occurs after incubation times of around 1 h and no cyctotoxic effects are observed upon prolonged treatment. The preferential location of the POM/CMC nanocomposites in the perinuclear region is furthermore verified with transmission electron microscopy investigations on unlabeled nanoparticles. Therefore, this approach is a promising dual strategy for the safe cellular transfer and monitoring of bioactive POMs.     

Boosting Glioblastoma Therapy with Targeted Pyroptosis Induction

Glioblastoma (GBM) is a highly aggressive cancer that currently lacks effective treatments. Pyroptosis has emerged as a promising therapeutic approach for cancer, but there is still a need for new pyroptosis boosters to target cancer cells. In this study, it is reported that Aloe-emodin (AE), a natural compound derived from plants, can inhibit GBM cells by inducing pyroptosis, making it a potential booster for pyroptosis-mediated GBM therapy. However, administering AE is challenging due to the blood-brain barrier (BBB) and its non-selectivity. To overcome this obstacle, AE@ZIF-8 NPs are developed, a biomineralized nanocarrier that releases AE in response to the tumor's acidic microenvironment (TAM). Further modification of the nanocarrier with transferrin (Tf) and polyethylene glycol-poly (lactic-co-glycolic acid) (PEG-PLGA) improves its penetration through the BBB and tumor targeting, respectively. The results show that AE-NPs (Tf-PEG-PLGA modified AE@ZIF-8 NPs) significantly increase the intracranial distribution and tumor tissue accumulation, enhancing GBM pyroptosis. Additionally, AE-NPs activate antitumor immunity and reduce AE-related toxicity. Overall, this study provides a new approach for GBM therapy and offers a nanocarrier that is capable of penetrating the BBB, targeting tumors, and attenuating toxicity.     

Targeted Modification of Ni Nanotubes by Electron Irradiation

Electron beam irradiation of metallic nanostructures is an effective tool for the controlled modification of the structural and conductive properties of materials. Irradiation at electron energies under 500 keV ensures controlled defect annealing in nanotubes, improving their conductive properties due to a decrease in their resistivity. At the same time, irradiation doses above 150 kGy lead to destruction of the samples due to local thermal heating of the nanotubes, which causes breakdown of their crystal lattice and amorphization of the samples.     

生物主动靶向型高分子药物载体的研究现状

许多经普通途径给药的药物由于未修饰,不能够以有效的浓度作用于目的器官,或者由于易被代谢而不能维持有效的给药时间。人们已经尝试许多靶向药物载体与系统来解决这些问题。总结了近几年来生物主动靶向型高分子药物载体的研究进展。针对叶酸介导,生物素介导,以及其他常见官能团介导的药物载体,从载体的合成,细胞检测以及动物实验等进行概述。生物主动靶向型高分子药物载体可以有效提高药物的生物利用度,减少药物的毒副作用。     

Artificial Glycoproteins as a Scaffold for Targeted Drug Therapy

Akin to a cellular “fingerprint,” the glycocalyx is a glycan‐enriched cellular coating that plays a crucial role in mediating cell‐to‐cell interactions. To gain a better understanding of the factors that govern in vivo recognition, artificial glycoproteins were initially created to probe changes made to the accumulation and biodistribution of specific glycan assemblies through biomimicry. As a result, the organ‐specific accumulation for a variety of glycoproteins decorated with simple and/or complex glycans was identified. Additionally, binding trends with regard to cancer cell selectivity were also investigated. To exploit the knowledge gained from these studies, numerous groups thus became engaged in developing targeted drug methodologies based on the use of artificial glycoproteins. This has either been done through adopting the glycoprotein scaffold as a drug carrier, or to directly glycosylate therapeutic proteins/enzymes to localize their biological activity. The principle aim of this Review is to present the foundational research that has driven artificial glycoprotein‐based targeting and subsequent adaptations with potential therapeutic applications.     

Protein-Precoated Surface of Metal-Organic Framework Nanoparticles for Targeted Delivery

Metal-organic framework (MOF) nanoparticles have recently emerged as a promising vehicle for drug delivery with high porosity and feasibility. However, employing a MOF-based drug delivery system remains a challenge due to the difficulty in controlling interfaces of particles in a biological environment. In this paper, protein corona-blocked Zr₆-based MOF (PCN-224) nanoparticles are presented for targeted cancer therapy with high efficiency. The unmodified PCN-224 surface is precoated with glutathione transferase (GST)-fused targetable affibody (GST-Afb) proteins via simple mixing conjugations instead of chemical modifications that can induce the impairment of proteins. GST-Afb proteins are shown to stably protect the surface of PCN-224 particles in a specific orientation with GST adsorbed onto the porous surface and the GST-linked Afb posed outward, minimizing the unwanted interfacial interactions of particles with external biological proteins. The Afb-directed cell-specific targeting ability of particles and consequent induction of cell death is demonstrated both in vitro and in vivo by using two kinds of Afb, which targets the surface membrane receptor, human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR). This study provides insight into the way of regulating the protein-adhesive surface of MOF nanoparticles and designing a more effective MOF-hosted targeted delivery system.     

设计扶贫精准识别与推进策略

目的探讨在精准扶贫背景下设计介入扶贫,为贫困地区提供设计解决方案及可持续设计理念,这是近年来设计扶贫亟待解决的问题。设计扶贫要实现精准化效果,必须要进行精准化识别,这对设计介入扶贫有着非常重要的理论价值和实践指导意义。方法结合贫困地区现状分析地域特点和目标群体特征,在阐述设计扶贫识别的概念内涵及价值基础上,针对目前的盲目粗放式设计扶贫,帮扶主体单一、帮扶措施简单、帮扶机制不健全等问题。提出运用AHM分析法、TOPSIS模型分别对设计扶贫目标群体和项目进行精准化识别。结论要实现脱贫目标就必须由粗放式扶贫转为精准化扶贫,对贫困者精准化识别提供具体的推进办法,使资源达到最优匹配让真正的贫困者受益于设计,设计扶贫精准识别对推进设计扶贫工作精细化提供了积极的推动作用。     

Targeted SLNs for management of HIV-1 associated dementia

Context: HIV-1 associated dementia (HAD) is an evolving disease in the category of neurological disorders.

Objective: Nifedipine-loaded solid lipid nanoparticles (SLNs) were developed and coated with Tween 80 to facilitate enhanced brain drug delivery for the treatment of HAD.

Materials and methods: SLNs were prepared using solvent injection method. Lipids consisted of tristearin, hydrogenated soya phosphatidylcholine (HSPC) (1.5:1 w/w). Nifedipine was model drug in this study. Tween 80 (0.5% v/v) was taken as key modulator. SLNs were characterized for particle shape, size, zeta potential, entrapment efficiency, in vitro drug release, DNA fragmentation, cytotoxicity potential and in vivo studies.

Results: The SLNs (plain and coated) were found to be in nanometric in size (～120?nm) with more than 70% entrapment efficiency. In vitro drug release profile reflected sustained release up to 48?h. Tween 80-coated SLNs showed higher percentage of DNA fragmentation in vitro and enhanced cell viability in sulforhodamine assay (rat cortical cells) as compared to plain drug and uncoated SLNs due to facilitated uptake of SLNs and reversal of P-gp efflux by virtue of Tween 80. Biodistribution study performed on vital organs, i.e. brain, heart, liver, spleen, lungs and kidney showed increased accumulation of Tween 80-coated SLNs in the brain.

Discussion and conclusion: Tween 80 enhanced localization of SLNs in the brain as compared to uncoated SLNs. This approach can be employed effectively to transport chemotherapeutics across the BBB for management of HIV-1 associated dementia and other ailments.     

Heteroanionic Materials by Design: Progress Toward Targeted Properties

The burgeoning field of anion engineering in oxide‐based compounds aims to tune physical properties by incorporating additional anions of different size, electronegativity, and charge. For example, oxychalcogenides, oxynitrides, oxypnictides, and oxyhalides may display new or enhanced responses not readily predicted from or even absent in the simpler homoanionic (oxide) compounds because of their proximity to the ionocovalent‐bonding boundary provided by contrasting polarizabilities of the anions. In addition, multiple anions allow heteroanionic materials to span a more complex atomic structure design palette and interaction space than the homoanionic oxide‐only analogs. Here, established atomic and electronic principles for the rational design of properties in heteroanionic materials are contextualized. Also described are synergistic quantum mechanical methods and laboratory experiments guided by these principles to achieve superior properties. Lastly, open challenges in both the synthesis and the understanding and prediction of the electronic, optical, and magnetic properties afforded by anion‐engineering principles in heteroanionic materials are reviewed.     

Activatable Protein Nanoparticles for Targeted Delivery of Therapeutic Peptides

Clinical translation of therapeutic peptides, particularly those that require penetration of the cell membrane or are cytolytic, is a major challenge. A novel approach based on a complementary mechanism, which has been widely used for guided synthesis of DNA or RNA nanoparticles, for de novo design of activatable protein nanoparticles (APNPs) for targeted delivery of therapeutic peptides is described. APNPs are formed through self‐assembly of three independent polypeptides based on pairwise coiled‐coil dimerization. They are capable of long circulation in the blood and can be engineered to target diseases. Peptides to be delivered are incorporated into APNPs and released into the disease microenvironment by locally enriched proteases. It is demonstrated that APNPs mediate efficient delivery of NR2B9c, a neuroprotective peptide that functions after cell penetration, and melittin, a cytolytic peptide that perturbs the lipid bilayer, for effective treatment of stroke and cancer, respectively. Due to their robust properties, simple design, and economic costs, APNPs have great potential to serve as a versatile platform for controlled delivery of therapeutic peptides.     

Targeted cell-cell interactions by DNA nanoscaffold-templated multivalent bispecific aptamers

Cell-cell interactions are essential for multicellular organisms, playing important roles in their development, function, and immunity. Herein a bottom-up strategy to construct self-assembled DNA nanostructures is reported, consisting of multivalent, bispecific, cell-targeting aptamers to specifically induce cell-cell interactions. Various DNA nanoscaffolds are rationally designed to assemble aptamers with different valencies and flexibilities, and their cellular binding capabilities are tested. Multivalent aptamers, assembled on more rigid scaffolds, display higher binding activities. Further, multivalent bispecific aptamer fusion molecules are constructed based on this configuration, and successfully link two types of cells. Using cell-targeting aptamers, the presented strategy eliminates the need to chemically modify cell surfaces and offers excellent cell specificity, binding efficiency, and stability. This proof-of-concept study establishes that multivalent bispecific aptamers linked on DNA-nanoscaffolds can mediate cellular engagement, which could lead to their use in directing or guiding cell-cell interactions in many biological events.     

Multiscale Modeling of Functionalized Nanocarriers in Targeted Drug Delivery

Targeted drug delivery using functionalized nanocarriers (NCs) is a strategy in therapeutic and diagnostic applications. In this paper we review the recent development of models at multiple length and time scales and their applications to targeting of antibody functionalized nanocarriers to antigens (receptors) on the endothelial cell (EC) surface. Our mesoscale (100 nm-1 μm) model is based on phenomenological interaction potentials for receptor-ligand interactions, receptor-flexure and resistance offered by glycocalyx. All free parameters are either directly determined from independent biophysical and cell biology experiments or estimated using molecular dynamics simulations. We employ a Metropolis Monte Carlo (MC) strategy in conjunction with the weighted histogram analysis method (WHAM) to compute the free energy landscape (potential of mean force or PMF) associated with the multivalent antigen-antibody interactions mediating the NC binding to EC. The binding affinities (association constants) are then derived from the PMF by computing absolute binding free energy of binding of NC to EC, taking into account the relevant translational and rotational entropy losses of NC and the receptors. We validate our model predictions by comparing the computed binding affinities and PMF to a wide range of experimental measurements, including in vitro cell culture, in vivo endothelial targeting, atomic force microscopy (AFM), and flow chamber experiments. The model predictions agree closely and quantitatively with all types experimental measurements. On this basis, we conclude that our computational protocol represents a quantitative and predictive approach for model driven design and optimization of functionalized NCs in targeted vascular drug delivery.     

Targeted multidimensional gas chromatography using microswitching and cryogenic modulation

A new method is described that allows fast target analysis in multidimensional gas chromatography by using a microswitching valve between two GC columns, with cryogenic trapping and rapid re-injection of trapped solutes in the second dimension. The essence of the procedure is that heart-cut fractions from the first column (1D) can be selectively transferred to column 2 (2D), where a moveable cryogenic trap first focuses the transferred solute(s) at the head of the second column and then permits their facile rapid analysis on 2D. Since 2D is a short narrow-bore column, which exhibits very fast analysis (on the order of a few seconds elution), peak responses (heights) are significantly enhanced (by up to 40-fold). Additionally, by using a 2D phase of a selectivity different from that used for 1D, it is possible to also separate components that are not resolved on the first column and to increase the resolution for other compounds. The heart-cut valve isolates the section(s) of solutes of interest from the first column separation, and this provides a considerable simplification to the chromatogram-in addition to the separation and sensitivity advantages. By using this method, multidimensional gas chromatography with multiple heart-cuts can be completed within the same time as the primary column separation. Since the described method permits non-heart-cut fractions to be transferred to a monitor detector, normal detection of these fractions is still permitted. By modulation of the cryotrap, it is also possible to achieve comprehensive two-dimensional gas chromatography for the heart-cut fractions; however, only those compounds passed to the second, separation column, which passes through the cryotrap, will be subjected to GC x GC analysis. The technique and the various modes of operation are described in this paper.     

Targeted delivery of magnetic aerosol droplets to the lung

The inhalation of medical aerosols is widely used for the treatment of lung disorders such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory infection and, more recently, lung cancer. Targeted aerosol delivery to the affected lung tissue may improve therapeutic efficiency and minimize unwanted side effects. Despite enormous progress in optimizing aerosol delivery to the lung, targeted aerosol delivery to specific lung regions other than the airways or the lung periphery has not been adequately achieved to date. Here, we show theoretically by computer-aided simulation, and for the first time experimentally in mice, that targeted aerosol delivery to the lung can be achieved with aerosol droplets comprising superparamagnetic iron oxide nanoparticles--so-called nanomagnetosols--in combination with a target-directed magnetic gradient field. We suggest that nanomagnetosols may be useful for treating localized lung disease, by targeting foci of bacterial infection or tumour nodules.     

Targeted anticancer prodrug with mesoporous silica nanoparticles as vehicles

A targeted anticancer prodrug system was fabricated with 180?nm mesoporous silica nanoparticles (MSNs) as carriers. The anticancer drug doxorubicin (DOX) was conjugated to the particles through an acid-sensitive carboxylic hydrazone linker which is cleavable under acidic conditions. Moreover, folic acid (FA) was covalently conjugated to the particle surface as the targeting ligand for folate receptors (FRs) overexpressed in some cancer cells. The in vitro release profiles of DOX from the MSN-based prodrug systems showed a strong dependence on the environmental pH values. The fluorescent dye FITC was incorporated in the MSNs so as to trace the cellular uptake on a fluorescence microscope. Cellular uptakes by HeLa, A549 and L929 cell lines were tested for FA-conjugated MSNs and plain MSNs respectively, and a much more efficient uptake by FR-positive cancer cells (HeLa) can be achieved by conjugation of folic acid onto the particles because of the folate-receptor-mediated endocytosis. The cytotoxicities for the FA-conjugated MSN prodrug, the plain MSN prodrug and free DOX against three cell lines were determined, and the result indicates that the FA-conjugated MSN prodrug exhibits higher cytotoxicity to FR-positive cells, and reduced cytotoxicity to FR-negative cells. Thus, with 180?nm MSNs as the carriers for the prodrug system, good drug loading, selective targeting and sustained release of drug molecules within targeted cancer cells can be realized. This study may provide useful insights for designing and improving the applicability of MSNs in targeted anticancer prodrug systems.     

基于叶酸靶向的银纳米生物材料研究

采用氧化还原法制备出球状银(Ag)纳米颗粒,通过巯基化反应制备出巯基化叶酸,在水性分散剂中通过分子自组装进行银纳米颗粒的叶酸修饰;采用傅里叶变换红外光谱仪对巯基化叶酸及其中间产物进行测试表征,结果表明叶酸已成功被巯基化;通过透射电镜(TEM)、紫外-可见分光光度计(UV-Vis)、荧光分光光度计进行表征,证明巯基叶酸能够成功修饰到银纳米颗粒表面,银颗粒尺寸约50nm,修饰后复合颗粒尺寸约53nm,复合物不但能够发出紫外吸收信号且金属荧光性能增强;基于叶酸本身的荧光性能及叶酸受体的靶向功能,该复合物有望应用于肿瘤细胞检测、纳米生物探针等医用诊断领域。