In vitro and in vivo evaluation of microparticulate drug delivery systems composed of macromolecular prodrugs

Macromolecular prodrugs are very useful systems for achieving controlled drug release and drug targeting. In particular, various macromolecule-antitumor drug conjugates enhance the effectiveness and improve the toxic side effects. Also, polymeric micro- and nanoparticles have been actively examined and their in vivo behaviors elucidated, and it has been realized that their particle characteristics are very useful to control drug behavior. Recently, researches based on the combination of the concepts of macromolecular prodrugs and micro- or nanoparticles have been reported, although they are limited. Macromolecular prodrugs enable drugs to be released at a certain controlled release rate based on the features of the macromolecule-drug linkage. Micro- and nanoparticles can control in vivo behavior based on their size, surface charge and surface structure. These merits are expected for systems produced by the combination of each concept. In this review, several micro- or nanoparticles composed of macromolecule-drug conjugates are described for their preparation, in vitro properties and/or in vivo behavior.     

Mesoporous silica nanoparticles for 19F magnetic resonance imaging,fluorescence imaging,and drug delivery

Multifunctional mesoporous silica nanoparticles (MSNs) are good candidates for multimodal applications in drug delivery, bioimaging, and cell targeting. In particular, controlled release of drugs from MSN pores constitutes one of the superior features of MSNs. In this study, a novel drug delivery carrier based on MSNs, which encapsulated highly sensitive ¹⁹F magnetic resonance imaging (MRI) contrast agents inside MSNs, was developed. The nanoparticles were labeled with fluorescent dyes and functionalized with small molecule-based ligands for active targeting. This drug delivery system facilitated the monitoring of the biodistribution of the drug carrier by dual modal imaging (NIR/¹⁹F MRI). Furthermore, we demonstrated targeted drug delivery and cellular imaging by the conjugation of nanoparticles with folic acid. An anticancer drug (doxorubicin, DOX) was loaded in the pores of folate-functionalized MSNs for intracellular drug delivery. The release rates of DOX from the nanoparticles increased under acidic conditions, and were favorable for controlled drug release to cancer cells. Our results suggested that MSNs may serve as promising ¹⁹F MRI-traceable drug carriers for application in cancer therapy and bio-imaging.     

Fe3O4@mMoO3介孔多功能纳米载体的制备及其微波响应药物传递

以氨基功能化的Fe_3O_4纳米颗粒为磁核,结合直接沉淀法和模板法在其表面包覆上介孔MoO_3层,制备磁性-微波热转换性-介孔结构于一体的多功能核-壳结构复合纳米载体Fe_3O_4@mMoO_3,并对其结构、载药及微波控制靶向给药性进行研究。TEM图表明所得的复合纳米载体具有明显的核壳结构,完美的球形,且壳层中有清晰的孔状结构。磁性和微波热转换特性分析表明,该复合载体兼具良好的磁性和微波热转换特性,可实现药物的靶向可控给药。以布洛芬(IBU)为模型药物,对该复合纳米载体的药物负载能力和微波响应可控释放性进行研究,结果表明,在持续微波辐射90 s时IBU的释放率达到90%,远远高于仅搅拌时的释放率。     

Prussian Blue Derived Nanoporous Iron Oxides as Anticancer Drug Carriers for Magnetic‐Guided Chemotherapy

New nanoporous iron oxide nanoparticles with superparamagnetic behavior were successfully synthesized from Prussian blue (PB) nanocubes through a thermal conversion method and applied to the intracellular drug‐delivery systems (DDS) of bladder cancer cells (i.e., T24) with controlled release and magnetic guiding properties. The results of the MTT assay and confocal laser scanning microscopy indicate that the synthesized iron oxide nanoparticles were successfully uptaken by T24 cells with excellent biocompatibility. An anticancer drug, that is, cisplatin, was used as a model drug, and its loading/release behavior was investigated. The intracellular drug delivery efficiency was greatly enhanced for the cisplatin‐loaded, PB‐derived, magnetic‐guided drug‐delivery system compared with the non‐drug case. The synthesized nanomaterials show great potential as drug vehicles with high biocompatibility, controlled release, and magnetic targeting features for future intracellular DDS.     

应用于药物传输系统的聚合物纳米粒

载药聚合物纳米粒具有良好的组织靶向性和缓控释性，本文简要介绍了聚合物纳米粒在药物传输系统中的特点，综合分析并讨论了纳米粒的制备技术及应用，展望了今后的研究方向。     

Effect of the Folate Ligand Density on the Targeting Property of Folated‐Conjugated Polymeric Nanoparticles

Targeted drug delivery systems have attracted increasing attention due to their ability for delivering anticancer drugs selectively to tumor cells. Folic acid (FA)‐conjugated targeted block copolymers, FA‐Pluronic‐polycaprolactone (FA‐Pluronic‐PCL) are synthesized in this study. The anticancer drug paclitaxel (PTX) is loaded in FA‐Pluronic‐PCL nanoparticles by nanoprecipitation method. The in vitro release of PTX from FA‐Pluronic‐PCL nanoparticles shows slow and sustained release behaviors. The effect of FA ligand density of FA‐Pluronic‐PCL nanoparticles on their targeting properties is examined by both cytotoxicity and fluorescence methods. It is shown that FA‐Pluronic‐PCL nanoparticles indicated better targeting ability than non‐targeted PCL‐Pluronic‐PCL nanoparticles. Furthermore, FA‐F127‐PCL nanoparticle with 10% FA molar content has more effective antitumor activity and higher cellular uptake than those with 50% and 91% FA molar content. These results prove that FA‐F127‐PCL nanoparticle with 10% FA molar content can be a better candidate as the drug carrier in targeted drug delivery systems.     

Functionalized mesoporous silica materials for controlled drug delivery

In the past decade, non-invasive and biocompatible mesoporous silica materials as efficient drug delivery systems have attracted special attention. Great progress in structure control and functionalization (magnetism and luminescence) design has been achieved for biotechnological and biomedical applications. This review highlights the most recent research progress on silica-based controlled drug delivery systems, including: (i) pure mesoporous silica sustained-release systems, (ii) magnetism and/or luminescence functionalized mesoporous silica systems which integrate targeting and tracking abilities of drug molecules, and (iii) stimuli-responsive controlled release systems which are able to respond to environmental changes, such as pH, redox potential, temperature, photoirradiation, and biomolecules. Although encouraging and potential developments have been achieved, design and mass production of novel multifunctional carriers, some practical biological application, such as biodistribution, the acute and chronic toxicities, long-term stability, circulation properties and targeting efficacy in vivo are still challenging.     

Nanozyme technology at Moscow State University. Achievements and development perspectives

The work describes novel functional bionanosystems for treatment and diagnostics on the basis of proteins, enzymes, polymeric coatings, and magnetic nanoparticles developed at Lomonosov Moscow State University Laboratory for Chemical Design of Bionanomaterials in collaboration with scientists from UNC Eshelman School of Pharmacy (USA). The properties of enzymes (superoxide dismutase, catalase, organophosphate hydrolase, and lysines of bacteriophages) and other drug molecules immobilized in polymeric complexes, as well as the methods for targeted drug delivery using cell-mediated systems and magnetic nanoparticles in in vitro and in vivo operating conditions, are discussed. Physical and chemical characteristics, including data on the functional properties of the nanoformulations, are obtained. The nanoformulations developed demonstrated high potential therapeutic efficacy for the treatment of central nervous system and brain diseases, inflammations (including inflammatory diseases of the eye), cancer and infectious diseases, neurotoxic injury, and others. The possibilities of remote control biochemical reactions using a nonheating low-frequency alternating magnetic field (AMF) for the controlled release of drugs are analyzed in the review. The experimental results of the AMF effects on bionanosystems containing magnetic nanoparticles, such as changing the catalytic activities of enzymes bound to magnetic nanoparticles and ‘disordering’ of the lipid bilayer in membranes, are considered.     

New advances in gated materials of mesoporous silica for drug controlled release

Drug delivery systems (DDS) are used to deliver therapeutic drugs to improve selectivity and reduce side effects. With the development of nanotechnology, many nanocarriers have been developed and applied to drug delivery, including mesoporous silica. Mesoporous silica nanoparticles (MSNs) have attracted a lot of attention for simple synthesis, biocompatibility, high surface area and pore volume. Based on the pore system and surface modification, gated mesoporous silica nanoparticles can be designed to realize on-command drug release, which provides a new approach for selective delivery of antitumor drugs. Herein, this review mainly focuses on the “gate keepers” of mesoporous silica for drug controlled release in nearly few years (2017–2020). We summarize the mechanism of drug controlled release in gated MSNs and different gated materials: inorganic gated materials, organic gated materials, self-gated drug molecules, and biological membranes. The facing challenges and future prospects of gated MSNs are discussed rationally in the end.     

Enzyme-inspired controlled release of cucurbit[7]uril nanovalves by using magnetic mesoporous silica

The controlled release of drugs by biostimuli is highly desirable under physiological conditions for their potential use in advanced applications. The enzyme-inspired controlled release of cucurbituril nanovalves by using magnetic mesoporous silica nanoparticles (MSNs) in near-neutral aqueous solutions is reported for the first time. The encirclement of cucurbit[7]uril (CB[7]) onto the protonated 1,4-butanediamine stalks tethered to the external surfaces of superparamagnetic Fe(3) O(4) -embedded mesoporous silica particles leads to tight blocking of the nanopores. The supramolecular nanovalves are activated by the enzymatic decarboxylation products of lysine, cadaverine (in the protonated form), which has a high affinity for CB[7], so that the encapsulated guest molecules, calcein, in the nanopores are released into the bulk solution. The release of calcein can be controlled in small portions on command by alternating changes in enzymatic decarboxylation products and CB[7]. The amino acid derived polyamines have long been associated with cell growth and cancers. The guest molecules released from the delivery system of magnetic MSNs can act not only on sensing probes for levels of decarboxylases and polyamines, but also on efficacious drugs to specific tissues and cells for regulation of polyamine synthesis.     

氧化铁磁性纳米粒子的制备、表面修饰及在分离和分析中的应用

氧化铁磁性纳米粒子通过表面化学修饰得到无机、有机或聚合物壳包覆在其表面。其中的壳结构既具有生物适应性,又具有可键合生物分子如细胞、蛋白质、酶、抗体和核酸的活性基团,而核具有磁性特性。本文总结了氧化铁磁性纳米粒子的制备方法,介绍了其表面化学修饰及在分离和分析应用的最新进展。     

Differential magnetic catch and release: experimental parameters for controlled separation of magnetic nanoparticles

Differential magnetic catch and release (DMCR) has been used as a method for the purification and separation of magnetic nanoparticles. DMCR separates nanoparticles in the mobile phase by magnetic trapping of magnetic nanoparticles against the wall of an open tubular capillary wrapped between two narrowly spaced electromagnetic poles. Using Au and CoFe(2)O(4) nanoparticles as model systems, the loading capacity of the 250 μm diameter capillary is determined to be ～130 μg, and is scalable to higher quantities with larger bore capillary. Peak resolution in DMCR is externally controlled by selection of the release time (R(t)) at which the magnetic flux density is removed, however, longer capture times are shown to reduce the capture yield. In addition, the magnetic nanoparticle capture yields are observed to depend on the nanoparticle diameter, mobile phase viscosity and velocity, and applied magnetic flux. Using these optimized parameters, three samples of CoFe(2)O(4) nanoparticles whose diameters are different by less than 10 nm are separated with excellent resolution and capture yield, demonstrating the capability of DMCR for separation and purification of magnetic nanoparticles.     

Novel synthetic route for covalent coupling of biomolecules on super‐paramagnetic hybrid nanoparticles

The immobilization of biomolecules on magnetic nanoparticles is an issue with high potential in different fields. We describe herein a new strategy to immobilize biomolecules on super‐paramagnetic nanoparticles based on the reactivity of vinyl sulfone groups with naturally occurring functional groups present in biomolecules (amine and thiol). A new monomer containing a polymerizable methacryloyl group and a secondary amine group was synthesized and used to prepare super‐paramagnetic hybrid nanoparticles (SP‐HNPs) by two‐step miniemulsion polymerization. The Michael addition reaction of divinyl sulfone (DVS) to the secondary amine groups localized on the nanoparticles surface allows the introduction of the vinyl sulfone function in the SP‐HNPs (SP‐HNPs‐VS). The morphology of the functionalized SP‐HNPs was characterized by transmission electron microscopy (TEM), high‐resolution transmission electron microscopy (HRTEM), dynamic light scattering, and magnetic susceptibility. The capacity of SP‐HNPs‐VS for the immobilization of biomolecules was evaluated with three model proteins: avidin, invertase, and horseradish peroxidase (HRP). The model proteins were successfully immobilized in mild aqueous conditions compatible with the biological nature of the enzymes. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Spatially controlled chemistry using remotely guided nanoliter scale containers

In this communication we describe a new chemical encapsulation and release platform using 3D microfabricated nanoliter scale containers with controlled porosity. The containers can be fabricated of magnetic materials that allow them to be remotely guided using magnetic fields. The favorable attributes of the containers that include a versatile highly parallel fabrication process, precisely engineered porosity, isotropic/anisotropic chemical release profiles, and remote magnetic guiding provide an attractive platform for engineering spatially controlled chemical reactions in microfluidic systems.     

Controlled Release of Curcumin via Folic Acid Conjugated Magnetic Drug Delivery System

In the paper, folic acid(FA)-mediated and β-cyclodextrin(β-CD) derivatives functionalized magnetic Fe₃O₄ nanoparticles(MNPs) were successfully prepared as drug carriers for the targeted delivery and controlled release of water-insoluble anticancer drug. FA-sulfobutyl ether-β-CD-MNPs(FA-SBE-β-CD-MNPs), FA-hydroxypropyl-β-CD-MNPs(FA-HP-β-CD-MNPs) and FA-carboxymethyl-β-CD-MNPs(FA-CM-β-CD-MNPs) were fabricated, and the loading efficiency and relative entrapment rate of curcumin are 12.04 mg/g, 95.56% for FA-SBE-β-CD-MNPs, 9.6 mg/g, 81.63% for FA-HP-β-CD-MNPs and 7.88 mg/g, 85.28% for FA-CM-β-CD-MNPs, respectively. Meanwhile, at pH=5.0, the optimal release rate of curcumin is about 46.07% for FA-SBE-β-CD-MNPs in 5 h. Cellular uptake indicates that curcumin can be selectively transported to targeting site and released from the internalized carriers. The in vitro cytotoxicity reveals that non-toxic FA-SBE-β-CD-MNPs have excellent biocompatibility on HepG2 cells in the tested concentrations. Therefore, FA-SBE-β-CD-MNPs could provide a promising platform for the targeting delivery of water insoluble anti-cancer drugs for different treatment needs of cancer therapy.     

Biological and Medical Applications of Calcium Phosphate Nanoparticles

Calcium phosphate nanoparticles have a high biocompatibility and biodegradability due to their chemical similarity to human hard tissue, for example, bone and teeth. They can be used as efficient carriers for different kinds of biomolecules such as nucleic acids, proteins, peptides, antibodies, or drugs, which alone are not able to enter cells where their biological effect is required. They can be loaded with cargo molecules by incorporating them, unlike solid nanoparticles, and also by surface functionalization. This offers protection, for example, against nucleases, and the possibility for cell targeting. If such nanoparticles are functionalized with fluorescing dyes, they can be applied for imaging in vitro and in vivo. Synthesis, functionalization and cell uptake mechanisms of calcium phosphate nanoparticles are discussed together with applications in transfection, gene silencing, imaging, immunization, and bone substitution. Biodistribution data of calcium phosphate nanoparticles in vivo are reviewed.     

Biomedical application of responsive ‘smart’ electrospun nanofibers in drug delivery system: A minireview

Electrospinning is a versatile method for producing continuous nanofibers. It has since become an easy and cost-effective technique in the manufacturing process and drawn keen interests in most biomedical field applications. Nanofibers have garnered great attention in nanomedicine due to their resemblance with the extracellular matrix (ECM). Like nanoparticles, its unique characteristics of higher surface-to-volume ratio and the tunability of the polymers utilizing nanofiber have increased the efficiency in encapsulation and drug-loading capabilities. Smart or “stimuli-responsive” polymers have shown particular fascination in controlled release, where their ability to react to minor changes in the environment, such as temperature, pH, electric field, light, or magnetic field, distinguishes them as intelligent. Polymers are a popular material for the design of drug delivery carriers; consequently, various types of drugs, including antiviral, proteins, antibiotics, DNA and RNA, are successfully encapsulated in the pH-dependent nanofibers with smart polymers which is a polymer that can respond to change such as pH change, temperature. In this minireview, we discuss applications of smart electrospun pH-responsive nanofibers in the emerging biomedical developments which includes cancer drug targeting, oral controlled release, wound healing and vaginal drug delivery.     

基于细乳液聚合的纳米颗粒制备与应用研究进展-撤稿（Withdrawed）

细乳液聚合能够将多种材料封装在聚合物壳层中形成结构复杂的聚合物纳米颗粒。 与普通乳液聚合技术相比,细乳液聚合具有方便、环保、粒径可控、稳定性高等优点。 通过引入功能单体,可以很容易地实现对纳米颗粒的功能化。 目前,细乳液聚合技术已经应用于很多领域,如纺织颜料的合成、粘接剂、分子印迹、磁性靶向纳米颗粒等。 本文综述了近年关于细乳液聚合法合成纳米颗粒的各种应用。     

Intercalation of PM-19 into and in vitro Release of Anti-tumor Drug from Layered Double Hydroxide

Introduction Recently, controlled release of drugs and gene delivery technology have received considerable attention due to their numerous advantages including prolonged duration of action of an active agent, improved efficacy, reduced toxicity and convenience compared to the conventional dosage forms[1]. In this field typical systems are polymer delivery systems depending on the hydrolysis-induced degradation, swelling and erosion of carriers′ structures[1, 2], mesoporous silica carrier systems relying on capturing and releasing the CdS nanoparticles[3], and layered materials release systems based on ion-exchange principle[4].     

PVP-b-PLA 修饰 Fe3O4 磁性纳米粒子的制备与表征

通过硅烷偶联剂与Fe3O4磁性纳米粒子偶合在其表面引入C C端基,进一步与N-乙烯基吡咯烷酮(NVP)加成聚合制备含端羟基PVP包裹的磁体,再引发丙交酯(LA)开环聚合制得PVP-b-PLA修饰的Fe3O4纳米粒子.通过XRD、GPC、FTIR、SEM、TG、DSC和激光粒度仪等,对产物进行分析和表征,结果表明,纳米Fe3O4与PVP以及PVP与PLA之间均为化学键联,PVP和PLA是以嵌段共聚物的形式存在且两者之间存在明显的微相分离,纳米Fe3O4表面聚合物包覆率为35%,厚度约13 nm.此外,该PVP-b-PLA包覆的磁性纳米粒子比饱和磁化强度为53 emu/g,与未包覆相比下降约25%.