Lipid Cubic Mesophases Combined with Superparamagnetic Iron Oxide Nanoparticles: A Hybrid Multifunctional Platform with Tunable Magnetic Properties for Nanomedical Applications

Hybrid materials composed of superparamagnetic iron oxide nanoparticles (SPIONs) and lipid self-assemblies possess considerable applicative potential in the biomedical field, specifically, for drug/nutrient delivery. Recently, we showed that SPIONs-doped lipid cubic liquid crystals undergo a cubic-to-hexagonal phase transition under the action of temperature or of an alternating magnetic field (AMF). This transition triggers the release of drugs embedded in the lipid scaffold or in the water channels. In this contribution, we address this phenomenon in depth, to fully elucidate the structural details and optimize the design of hybrid multifunctional carriers for drug delivery. Combining small-angle X-ray scattering (SAXS) with a magnetic characterization, we find that, in bulk lipid cubic phases, the cubic-to-hexagonal transition determines the magnetic response of SPIONs. We then extend the investigation from bulk liquid-crystalline phases to colloidal dispersions, i.e., to lipid/SPIONs nanoparticles with cubic internal structure (“magnetocubosomes”). Through Synchrotron SAXS, we monitor the structural response of magnetocubosomes while exposed to an AMF: the magnetic energy, converted into heat by SPIONs, activates the cubic-to-hexagonal transition, and can thus be used as a remote stimulus to spike drug release “on-demand”. In addition, we show that the AMF-induced phase transition in magnetocubosomes steers the realignment of SPIONs into linear string assemblies and connect this effect with the change in their magnetic properties, observed at the bulk level. Finally, we assess the internalization ability and cytotoxicity of magnetocubosomes in vitro on HT29 adenocarcinoma cancer cells, in order to test the applicability of these smart carriers in drug delivery applications.     

An In Vitro Experimental Approach to Study Magnetically Targeted Release of Methotrexate From Superparamagnetic Starch Nanocarriers

In the field of drug delivery, magnetic nanoparticles have great potential to modernize anticancer therapy. In the present study iron oxides containing superparamagnetic starch nanoparticles were prepared by emulsion crosslinking method. The anticancer drug methotrexate was used for loading onto the magnetic starch nanoparticles and released drug was spectrophotometrically monitored at physiological pH (7.4) under application of a modulating magnetic field. The spectroscopic techniques such as FTIR, TEM, X-ray diffraction, and vibrating sample magnetometer (VSEM) studies were used to characterize the magnetic starch nanocarriers. The influence of various experimental parameters such as pH and temperature of the release media, percent drug loading, chemical compositions of nanocarriers, and applied magnetic field were investigated on the drug release profiles of synthesized magnetic starch nanoparticles. The nanoparticles were also evaluated for cytotoxicity and in vitro blood compatibility.     

纳米水基磁性液体在肿瘤治疗领域的研究进展

结合作者在纳米磁性液体方面的研究经历,介绍了生物医学应用领域纳米磁性粒子的组成结构及特点,指出高分子改性纳米磁性粒子具有生物相容性好、稳定性强、载药量高的优点,并对目前高分子改性纳米四氧化三铁颗粒的制备方法及特点进行了对比分析。指出进一步研制磁响应性强、载药量高、粒度分布均匀的纳米磁性粒子,使之对癌细胞具有亲和作用,尽量避免对毛细血管网状内皮系统的清除,是未来肿瘤治疗领域纳米磁性粒子的研发目标,并对目前制备方法中存在的不足提出了改进的建议。     

生物大分子介导仿生矿化制备磁性纳米粒子的研究进展

相比其他纳米材料,磁铁矿（Fe₃O₄）纳米粒子由于具有磁响应性而被广泛应用于酶固定化、定向给药及核酸提取等方面。不同大小和形状的磁铁矿纳米颗粒可用于不同的领域,如晶体尺寸越小的Fe₃O₄对人体副作用越小,有望用于疾病高效、靶向治疗。近年来,控制Fe₃O₄纳米粒子大小和形貌的新方法研究逐步成为热点。因此,本文回顾了传统的共沉淀制备磁性纳米颗粒的方法,这些方法需要使用有机溶剂或高温等条件控制,介绍了这些方法存在的环境污染和安全性问题。在此基础上,本文深入介绍了近年来出现的一种受自然界生物矿化启发的生物大分子介导的仿生矿化制备磁性纳米粒子的新趋势,综述了生物大分子蛋白质（或多肽）介导的仿生矿化的最新研究进展,阐释了该方法在磁铁矿（Fe₃O₄）纳米粒子的大小和形貌控制方面的优缺点,并对其应用前景及面临的挑战进行了展望。     

Magnetic lamellar nanohydroxyapatite as a novel nanocarrier for controlled delivery of 5-fluorouracil

Magnetic nanoparticles are attractive carriers for drug delivery and layered materials intercalated by drug molecules exhibit improved safety and effectiveness of drug delivery. In this work, we report the loading of a model anticancer drug, 5-fluorouracil (5FU), into a magnetic layered nanohydroxyapatite (ML-HAP) by intercalation technique. The as-prepared ML-HAP nanoparticles with loaded 5FU were characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and vibrating sample magnetometer. We find that, within a certain drug concentration, the drug molecules can be intercalated into the gallery of ML-HAP without breaking its lamellar structure. The drug loading capacity of ML-HAP is extremely large. The drug release profiles display pH-dependent behavior and the drug release mechanisms are a combination of drug diffusion and HAP dissolution. Furthermore, ML-HAP/5FU shows strong superparamagnetism and good biocompatibility. The ML-HAP can be an efficient platform for targeted anticancer drug delivery.     

Recent advances in nonviral vectors for gene delivery

Gene therapy has long been regarded a promising treatment for many diseases, whether acquired (such as AIDS or cancer) or inherited through a genetic disorder. A drug based on a nucleic acid, however, must be delivered to the interior of the target cell while surviving an array of biological defenses honed by evolution. Successful gene therapy is thus dependent on the development of an efficient delivery vector. Researchers have pursued two major vehicles for gene delivery: viral and nonviral (synthetic) vectors. Although viral vectors currently offer greater efficiency, nonviral vectors, which are typically based on cationic lipids or polymers, are preferred because of safety concerns with viral vectors. So far, nonviral vectors can readily transfect cells in culture, but efficient nanomedicines remain far removed from the clinic. Overcoming the obstacles associated with nonviral vectors to improve the delivery efficiency and therapeutic effect of nucleic acids is thus an active area of current research. The difficulties are manifold, including the strong interaction of cationic delivery vehicles with blood components, uptake by the reticuloendothelial system (RES), toxicity, and managing the targeting ability of the carriers with respect to the cells of interest. Modifying the surface with poly(ethylene glycol), that is, PEGylation, is the predominant method used to reduce the binding of plasma proteins to nonviral vectors and minimize clearance by the RES after intravenous administration. Nanoparticles that are not rapidly cleared from the circulation accumulate in the tumors because of the enhanced permeability and retention effect, and the targeting ligands attached to the distal end of the PEGylated components allow binding to the receptors on the target cell surface. Neutral and anionic liposomes have been also developed for systemic delivery of nucleic acids in experimental animal models. Other approaches include (i) designing and synthesizing novel cationic lipids and polymers, (ii) chemically coupling the nucleic acid to peptides, targeting ligands, polymers, or environmentally sensitive moieties, and (iii) utilizing inorganic nanoparticles in nucleic acid delivery. Recently, the different classes of nonviral vectors appear to be converging, and the ability to combine features of different classes of nonviral vectors in a single strategy has emerged. With the strengths of several approaches working in concert, more hurdles associated with efficient nucleic acid delivery might therefore be overcome. In this Account, we focus on these novel nonviral vectors, which are classified as multifunctional hybrid nucleic acid vectors, novel membrane/core nanoparticles for nucleic acid delivery, and ultrasound-responsive nucleic acid vectors. We highlight systemic delivery studies and consider the future prospects for nucleic acid delivery. A better understanding of the fate of the nanoparticles inside the cell and of the interactions between the parts of hybrid particles should lead to a delivery system suitable for clinical use. We also underscore the value of sustained release of a nucleic acid in this endeavor; making vectors targeted to cells with sustained release in vivo should provide an interesting research challenge.     

Alignment of Magnetite-Loaded High Aspect Ratio Aerosol Drug Particles with Magnetic Fields

The present note demonstrates magnetic field alignment of high aspect ratio pharmaceutical aerosol particles loaded with magnetite nanoparticles. This alignment is used to reduce the penetration of the particles through polycarbonate membrane filters when a magnetic field is generated parallel to the face of the membrane. Possible application of magnetic field alignment to noninvasively target respiratory tract deposition during aerosol drug delivery is discussed.     

Polymers with platinum drugs and other macromolecular metal complexes for cancer treatment

Metal-based anticancer drugs, in particular platinum-drugs, have been investigated for the treatment of cancer for the last 40 years. A small set of platinum-based drugs have meanwhile received FDA approval for the treatment of various cancer. Cisplatin and its relatives are currently one of the most widely used anticancer drugs. The use is however associated with significant side effects and rising drug resistance. To combat these problems, drug delivery carriers have been developed to increase the protection of the drug and increase efficacy. Metal-based drugs represent a rather unique drug delivery challenge. Most anticancer drugs are either physically encapsulated into a polymer matrix or they can be conjugated to the polymer via a degradable linker. While both pathways are possible for metal-based drugs, the conjugation to the polymer can be carried via labile or permanent ligands. In addition, the prodrug strategy using the drug in the higher oxidation state is a common approach that has been widely tested for platinum drug. The delivery of platinum drugs is now a mature field and the various conjugation techniques have been combined with a range of drug carriers including dendrimers, micelles and solid polymer nanoparticles. Hybrids of macromolecular metal complexes with inorganic nanoparticles have been tested in recent years to combine the ability to deliver the drug with imaging properties. An emerging trend is the surface decoration of the polymeric nanoparticles with targeting ligands such as folates. The advanced state of this field is evident by the fact that some macromolecular platinum drugs even advanced to the clinic. While the delivery of platinum drugs has been well explored, the delivery of other metal-based drugs based on gold, ruthenium or cobalt is still in their infancy.     

Enhanced deposition of high aspect ratio aerosols in small airway bifurcations using magnetic field alignment

The present work describes a new approach for non-invasively targeting respiratory tract deposition of high aspect ratio aerosols loaded with magnetic nanoparticles by controlling particle orientations through magnetic field alignment. Enhanced deposition of aligned particles is measured in vitro in a physical model of the small, bifurcating airways found in the lung. Unlike previous approaches to magnetic drug targeting, the approach presented herein requires no gradient in the magnetic field strength, and can be accomplished with small amounts of magnetic material compared to active drug. This approach shows promise for targeting aerosol drug delivery to specific locations within the lung.     

Recent research progress on the preparation and application of magnetic nanospheres

Magnetic nanospheres have numerous applications in biomedicine, biotechnology and wastewater treatment, due to their high surface area, tunable sphere size and superparamagnetic properties. Magnetic nanoparticles can be designed and endowed with optical, electronic and fluorescent properties, allowing a wide range of functionality. Multifunctional magnetic particles with heterodimer structures allow various kinds of target molecules to be attached onto their specific parts via affinity or coordinate bonding, etc. The abilities of these nanodevices, including the encapsulation of target molecules in magnetic hybrid nanostructures and easy magnetic separation in the presence of external magnetic fields, show much promise for magnetic imaging, magnetic separation and drug delivery. Consequently, magnetic particles offer excellent potential future uses in disease diagnosis, hyperthermia, immunoassays, electrochemical biosensors, contaminated water treatment and optical detection. In this article, we review the preparation and application of inorganic and organic magnetic composite spheres in the fields of magnetic separation, drug delivery, hyperthermia, magnetic resonance imaging, and others. The size, specific surface area, structure, magnetic properties and surface functional groups of nanospheres have a great influence on their effectiveness in these applications. The encapsulation of target molecules in magnetic hybrid nanostructures and their easy separation using an external magnetic field show promise for the fabrication of novel nanodevices for many applications. Copyright © 2011 Society of Chemical Industry     

磁性纳米粒子在生物学及医学领域的应用

磁性纳米粒子由于其生物相客性和低毒性而广泛应用于生物医学领域.阐述了近年来磁性纳米粒子在生物分离、生物检测、靶向药物输送、磁共振成像、肿瘤磁感应热疗等生物学和医学领域中的应用进展,并指出其主要发展方向和亟待解决的问题.     

Composites of polymeric gels and magnetic nanoparticles: Preparation and drug release behavior

The article is concerned with the preparation of polymer–iron oxide nanocomposites and the study as drug‐delivery matrices under the influence of applied magnetic field. Biocompatible materials were prepared by incorporating an aqueous ferrofluid in poly(vinyl alcohol) and scleroglucan (SCL) hydrogels, loaded with theophylline as model drug for release studies. The in vitro release profile was obtained using a flat Franz cell and the kinetic parameters were derived applying a semiempirical power law. A magnetic characterization of nanoparticles contained in the ferrofluid was performed by obtaining the magnetization curve. For both systems, the observed drug release profiles decreased when a uniform external magnetic field is applied suggesting they can be used as environmental responsive matrices for biomedical applications. Dynamic rheological measurements show that a higher storage modulus and a more compact structure are obtained by incorporating the ferrofluid into the hydrogels. These rheological results and environmental electron scanning microscopy micrographs point to an understanding of release behavior once the magnetic field is applied. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

New Trends in Nanoparticles: Syntheses and Their Applications to Fuel Cells,Health Care,and Magnetic Storage

This paper reviews important research on chemical and electrochemical synthesis and application of nanoparticles, especially our recent results in this field: (i) catalytic metal nanoparticles for micro-fuel cells, (ii) magnetic oxide nanoparticles for drug delivery systems, and (iii) magnetic metal nanoparticles for magnetic recording media. To fulfill the requirements of each application, we chose and modified those synthetic methods for obtaining suitable properties, e.g., morphology, catalytic activity, and magnetic properties. (i) For micro-fuel cells, electrodeposition is attractive because of its selective deposition onto current collectors and possible elimination of an annealing process. As a result, we have successfully synthesized Pt, PtRu alloy, and PdCo alloy, which consisted of dendritic structures macroscopically and of interconnected nanoparticles microscopically. (ii) For drug delivery systems, since magnetic nanoparticles should possess ferromagnetism, be dispersible in water, and be nontoxic, Fe₃O₄ nanoparticles synthesized by hydrolysis in aqueous media are suitable. As a result, we have successfully controlled the size (10–40 nm in diameter) and the magnetic properties of Fe₃O₄ nanoparticles by means of adjusting the molar ratio of ferrous to ferric ions in the precursor solution. (iii) For magnetic recording materials, since magnetic nanoparticles should possess high coercivity, a controlled shape, and a uniform small size, we have modified a chemical method for synthesizing FePt by adjusting the growth temperature. As a result, we have succeeded in synthesizing FePt nanoparticles with a controlled shape (cubic) and a uniform size (ca. 5.6 nm).     

Layer-by-Layer Engineered Superparamagnetic Polyelectrolyte Hybrid Hollow Microspheres With High Magnetic Content as Drug Delivery System

Polyelectrolyte hybrid hollow microspheres with sandwich structure of about 450 nm have been accomplished by layer-by-layer self-assembling of two modified ferroferric oxide nanoparticles, lysine modified ferroferric oxide nanoparticles (Fe₃O₄-LYs) and citrate modified ferroferric oxide nanoparticles (Fe₃O₄-CA), as the main assembling materials via electrostatic interaction for the first time. They are superparamagnetic with saturation magnetization of 45.69 emu/g, revealing their high magnetic content of 70%. As drug delivery system, they also exhibited pH-stimuli responsive controlled release of an anticancer drug doxorubicin, following the Fickian diffusion model. Their unique structure and high magnetic content make them good candidate for targeted delivery.     

Lipid-Based Nanoparticulate Systems for the Ocular Delivery of Bioactives with Anti-Inflammatory Properties

The complexity of the eye structure and its physiology turned ocular drug administration into one of the most challenging topics in the pharmaceutical field. Ocular inflammation is one of the most common ophthalmic disorders. Topical administration of anti-inflammatory drugs is also commonly used as a side treatment in tissue repair and regeneration. The difficulty in overcoming the eye barriers, which are both physical and chemical, reduces drug bioavailability, and the frequency of administration must be increased to reach the therapeutic effect. However, this can cause serious side effects. Lipid nanoparticles seem to be a great alternative to ocular drug delivery as they are composed from natural excipients and can encapsulate both hydrophilic and lipophilic drugs of different sources, and their unique properties, as their excellent biocompatibility, safety and adhesion allow to increase the bioavailability, compliance and achieve a sustained drug release. They are also very stable, easy to produce and scale up, and can be lyophilized or sterilized with no significant alterations to the release profile and stability. Because of this, lipid nanoparticles show a great potential to be an essential part of the new therapeutic technologies in ophthalmology to deliver synthetic and natural anti-inflammatory drugs. In fact, there is an increasing interest in natural bioactives with anti-inflammatory activities, and the use of nanoparticles for their site-specific delivery. It is therefore expected that, in the near future, many more studies will promote the development of new nanomedicines resulting in clinical studies of new drugs formulations.     

微/纳米药物给药系统的研究进展

在过去的几十年中,探索高效的微/纳米给药系统一直是药剂学领域的研究热点。不同的微/纳米颗粒已被用于药物输送的研究,以期实现有效靶向给药,最大限度地减少副作用,从而提高治疗效果。本文主要综述了微/纳米药物输送给药系统及在药物制剂领域应用。     

Magnetic Nanoparticles as Intraocular Drug Delivery System to Target Retinal Pigmented Epithelium (RPE)

One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterior eye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterior eye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs) as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE) layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species.     

Preparation of Magnetic pH-Sensitive Film With Alginate Base for Colon Specific Drug Delivery

The aim of this work was to prepare alginate base film and its properties and application in drug delivery field. In order to achieve this, naproxen as a drug and magnetic nanoparticles were placed into the films. Sodium alginate could be crosslinked and form a gel under extremely mild and environmentally friendly conditions without using toxic solvents and reactants. The polymeric films were analyzed by DSC, SEM, and FT-IR spectroscopy. The in vitro release profiles were established separately in both enzyme-free simulated gastric (pH 1) and intestinal fluids (pH 7.4).