Cisplatin-loaded carbon-encapsulated iron nanoparticles and their in vitro effects in magnetic fluid hyperthermia

Iron nanoparticles encapsulated by carbon are protected from reactions with their environment avoiding oxidation in ambient conditions and thus, preserving their magnetic properties. Such particles are good candidates for magnetic fluid hyperthermia. When graphite shells are present, acidic treatments allow the formation of carboxylic groups on the nanoparticle surface. Those carboxylic groups can be used for further complexation with the drug cisplatin. We show the possibility of loading cisplatin on such nanoparticles and that the loading is dependent on the degree of surface functionalization. The drug release is dependent on time and temperature, making it ideal for applications involving hyperthermia. We show the possibility of applying hyperthermia in vitro using these nanoparticles. When loaded with cisplatin a stronger cytotoxic effect is observed. Such particles could be potentially used as multimodal anti-cancer agents for therapies based on the synergistic effect of chemotherapy and hyperthermia.     

Poly(N-isopropylacrylamide)-coated β-cyclodextrin–capped magnetic mesoporous silica nanoparticles exhibiting thermal and pH dual response for triggered anticancer drug delivery

In this research a novel controlled anticancer drug delivery system with dual pH and thermal responses was designed based on magnetic mesoporous silica nanoparticles that were anchored by β-cyclodextrin and coated by poly(N-isopropylacrylamide) (PNIPAM). Results demonstrated that the behavior of doxorubicin (anticancer drug) release depended on pH and temperature conditions. At endosomal pH (pH 5.5) the amount of drug release enhanced because the cap was removed from the pores. Furthermore, PNIPAM shell collapsed above the lower critical solution temperature and the releasing of drug increased. Thus, this nanocarrier would have the potential to be applied in the tumor therapy.     

Biocompatible tumor micro-environment responsive CS-g-PNIPAAm co-polymeric nanoparticles for targeted Oxaliplatin delivery

The objective of the research study was to develop and characterize a biodegradable, thermo and pH dual responsive Oxaliplatin-loaded chitosan-graft-poly-N-isopropylacrylamide (CS-g-PNIPAAm) co-polymeric nanoparticles as a tumor-targeting drug delivery system. CS-g-PNIPAAm co-polymers were synthesized, characterized and optimized its thermo and pH responsive properties for tumor microenvironment conditions. Optimized co-polymer could be efficiently loaded with Oxaliplatin in nanoparticle form, evaluated for their morphology (TEM), particle size, zeta potential, loading efficiency and drug content. In vitro drug release study at tumor microenvironment and physiological pH and temperature conditions. The in vitro drug release was optimal at above lower critical solution temperature (LCST) and tumor microenvironment pH when compared to physiological pH & temperature. MTT assay and fluorescence microscopic study showed that drug release and cell uptake was significantly enhanced in tumor microenvironment. In conclusion, the obtained nanoparticles appeared to be of great promise in tumor targeted drug delivery of oxaliplatin.     

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.     

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     

基于纤维素模板的聚合物空心微球作为药物载体的性能研究及分析

以羟丙基纤维素为模板材料,分别采用不同的聚合方法制备了2种不同形态和结构的聚合物空心微球--聚N-异丙基丙烯酰胺-co-聚丙烯酸(PNIPAm-co-PAA)微凝胶和聚N-异丙基丙烯酰胺-聚丙烯酸(PNIPAm-PAA)水凝胶微囊。以盐酸阿霉素(Dox)作为模型药物,考察了聚合物空心微球作为药物载体的载药能力和体外释放性能。研究表明,PNIPAm-co-PAA微凝胶、PNIPAm-PAA水凝胶微囊和Dox分子能够通过正负电荷的相互吸引实现有效结合;载药微球具有良好的缓释性能,并对Dox的释放表现出明显的pH值敏感性和温度敏感性。体外细胞毒性实验表明,载药PNIPAm-co-PAA微凝胶、PNIPAm-PAA水凝胶微囊具有很高的抗肿瘤活性,细胞相对存活率均可达20%左右。PNIPAm-co-PAA微凝胶、PNIPAm-PAA水凝胶微囊在作为水溶性药物或蛋白类药物载体方面,具有潜在的应用价值,同时有望应用于木材胶黏剂防腐等。     

Fe_3O_4磁性纳米微粒的制备及药物缓释性能的研究

采用水热法制备了Fe3O4磁性纳米微粒,采用FTIR、XRD和SEM等技术对样品的粒径、晶体结构和形貌进行了表征,选用盐酸多西环素为模型药物,研究了不同药物浓度条件下Fe3O4磁性纳米微粒的吸附性能以及不同pH条件下的药物释放行为。结果表明:Fe3O4磁性纳米微粒在药物浓度0.1 g/L时,对药物吸附率高,达到46.2%,pH=3时药物缓释性能佳。     

Multiresponsive polymeric particles with tunable morphology and properties based on acrylonitrile (AN) and 4-vinylpyridine (4-VP)

We report the synthesis of amphiphilic, pH and magnetic field sensitive polymeric particles obtained from the modification of poly(acrylonitrile-co-4-vinylpyridine) (p(AN-c-4-VP)) core-shell nanoparticles. The magnetic metal nanoparticles were encapsulated in the microemulsion during the polymerization to achieve magnetic-p(AN-c-4-VP)-composites with various morphology. We further chemically modified each component of p(AN-c-4-VP) particles and its composite to tune the hydrophilicity of the particles. Modification of nitrile (hydrophobic) groups to amidoxime (hydrophilic) groups by amidoximation reaction on AN, and quarternization of nitrogen on pyridine ring of 4-VP were carried out to tune the hydrophilicity and the charge of the particles. The modification also performed on magnetic responsive composites after inclusion of separately prepared magnetic Fe₃O₄ nanoparticles. It was further demonstrated that these multiresponsive particles can be used as drug carrier. A nonsteroidal and anti-inflammatory drug Naproxen was used as a model active agent for drug loading and the release studies from (p(AN-c-4-VP) based particles in phosphate buffer solution (pH = 7.4) at ambient temperature.     

Synthesis of amino-cosubstituted polyorganophosphazenes and fabrication of their nanoparticles for anticancer drug delivery

The development of safe drug carriers is cardinal in cancer therapy, which can target the cancer cells and release the loaded drug on-demand without damaging the healthy cells of the body. In our work, we synthesized three different biodegradable polymers, poly[(ethyl aminobezoate) (ethyl glycinato) phosphazenes] (PABGPs), in different mole ratio of side groups. The successful synthesis of these PABGPs was confirmed by ¹H NMR, ³¹P NMR, FT-IR, and gel permeation chromatography. These PABGPs were fabricated into drug (camptothecin, CPT, a hydrophobic anticancer drug) loaded nanoparticles. These drug-loaded nanoparticles showed good drug release behaviors under normal physiological conditions (pH 7.4 and temperature 37°C). These PABGPs-based nanoparticles may find their application as effective drug carriers for cancer therapy.     

Functionalization of magnetic nanoparticles for biomedical applications

Interest in utilizing magnetic nanoparticles for biomedical treatments originates from their external controllability of transportation and movement inside biological objects and magnetic heat generation. Advances in nanoparticle and nanotechnology enable us to produce magnetic nanoparticles of specific morphology and to engineer particle surfaces to manipulate their characteristics for specific applications. Intensive investigations and developments have been carried out in improving the quality of magnetic particles, regarding their size, shape, size distribution, their magnetism and their surface. The magnetic nanoparticles with appropriate surface chemistry can conjugate various biomaterials such as drugs, proteins, enzymes, antibodies, or nucleotides to be used for numerous in vivo applications including MRI contrast enhancement, immunoassay, hyperthermia, drug delivery, and cell separation. Here we review both the key technical principles of magnetic nanoparticle synthesis and the ongoing advancement of biomedical treatments using magnetic nanoparticles, specifically, the advancement in controlled drug delivery and hyperthermia.     

Doxorubicin loading and in vitro release from poly(alkylcyanoacrylate) nanoparticles produced by redox radical emulsion polymerization

The aim of this work was to explore the capacity to load an anticancer agent Doxorubicin (Dox) on new poly(alkylcyanoacrylate) (PACA) nanoparticles prepared by redox radical emulsion polymerization (RREP). These nanoparticles present several advantages compared with the previously described PACA nanoparticles obtained by anionic emulsion polymerization (AEP). Their cytotoxicity was lower and because they do not activate the complement system, they are believed to behave like stealth nanoparticles after intravenous administration. Dox was incorporated during the preparation of the nanoparticles. However, the drug molecules were degraded by cerium IV, which is a strong oxidant agent. To avoid drug degradation, Dox must be loaded by adsorption on preformed nanoparticles. Optimal loading capacity was deduced from a Scatchard's analysis of the Dox adsorption pattern. The loading performance [Loading efficiency (LE) 74%, Loading content (LC) 3.7%], the Dox release and the amount of Dox retained by the new nanoparticles 75% were similar to those of the already well described PACA nanoparticles obtained by AEP (LE 79% and LC 4.2%, drug retention capacity 75%). It can be concluded that the loading and releasing properties make the new nanoparticles an interesting carrier candidate for the in vivo delivery of Dox. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Study on Maximum Specific Loss Power in Fe3O4 Nanoparticles Decorated with Biocompatible Gamma-Cyclodextrins for Cancer Therapy with Superparamagnetic Hyperthermia

Different chemical agents are used for the biocompatibility and/or functionality of the nanoparticles used in magnetic hyperthermia to reduce or even eliminate cellular toxicity and to limit the interaction between them (van der Waals and magnetic dipolar interactions), with highly beneficial effects on the efficiency of magnetic hyperthermia in cancer therapy. In this paper we propose an innovative strategy for the biocompatibility of these nanoparticles using gamma-cyclodextrins (γ-CDs) to decorate the surface of magnetite (Fe₃O₄) nanoparticles. The influence of the biocompatible organic layer of cyclodextrins, from the surface of Fe₃O₄ ferrimagnetic nanoparticles, on the maximum specific loss power in superparamagnetic hyperthermia, is presented and analyzed in detail in this paper. Furthermore, our study shows the optimum conditions in which the magnetic nanoparticles covered with gamma-cyclodextrin (Fe₃O₄–γ-CDs) can be utilized in superparamagnetic hyperthermia for an alternative cancer therapy with higher efficiency in destroying tumoral cells and eliminating cellular toxicity.     

Hollow poly(N‐isopropylacrylamide)‐co‐poly(acrylic acid) microgels with high loading capacity for drugs

A convenient approach has been developed for the preparation of microsize hydrogels composed of crosslinked poly(acrylic acid) (PAA) and poly(N‐isopropylacrylamide) (PNIPAm). First, semi‐interpenetration polymer networks of hydropropylcellulose (HPC) and PNIPAm‐co‐PAA copolymer are formed through the copolymerization and crosslinking of monomer acrylic acid and N‐isopropylacrylamide in HPC aqueous solution. After the selective removal of HPC from networks due to ionization of PAA units and disruption of hydrogen bonding with increasing pH, PNIPAm‐co‐PAA microgels are obtained, whose volume is confirmed to be responsive to both temperature and pH. Doxorubicin hydrochloride (Dox) can be encapsulated in PNIPAm‐co‐PAA microgels with high drug loading driven by the electrostatic interaction, and a sustained‐release characteristic of Dox from the microgels is observed under physiological pH value and temperature. In vitro cell experiments, the drug‐loaded microgels can be taken up by LoVo cells and release their payload in cell cytoplasm without loss of drug efficacy. This indicates that PNIPAm‐co‐PAA microgels might be a potential drug delivery carriers especially for water‐soluble or polypeptide drugs. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

A bio-inspired gelatin-based pH- and thermal-sensitive magnetic hydrogel for in vitro chemo/hyperthermia treatment of breast cancer cells

Gelatin (Gel)-based pH- and thermal-responsive magnetic hydrogels (MH-1 and MH-2) were designed and developed as novel drug delivery systems (DDSs) for cancer chemo/hyperthermia therapy. For this goal, Gel was functionalized with methacrylic anhydride (GelMA), and then copolymerized with (2-dimethylaminoethyl) methacrylate (DMAEMA) monomer in the presence of methacrylate-end capped magnetic nanoparticles (MNPs) as well as triethylene glycol dimethacrylate (TEGDMA; as crosslinker). Afterward, a thiol-end capped poly(N-isopropylacrylamide) (PNIPAAm-SH) was synthesized through an atom transfer radical polymerization technique, and then attached onto the hydrogel through “thiol-ene” click grafting. The preliminary performances of developed MHs for chemo/hyperthermia therapy of human breast cancer was investigated through the loading of doxorubicin hydrochloride (Dox) as an anticancer agent followed by cytotoxicity measurement of drug-loaded DDSs using MTT assay by both chemo- and chemo/hyperthermia-therapies. Owing to porous morphologies of the fabricated magnetic hydrogels according to scanning electron microscopy images and strong physicochemical interactions (e.g., hydrogen bonding) the drug loading capacities of the MH-1 and MH-2 were obtained as 72 ± 1.4 and 77 ± 1.8, respectively. The DDSs exhibited acceptable pH- and thermal-triggered drug release behaviors. The MTT assay results revealed that the combination of hyperthermia therapy and chemotherapy has synergic effect on the anticancer activities of the developed DDSs.     

H2O2-Responsive Organosilica-Doxorubicin Nanoparticles for Targeted Imaging and Killing of Cancer Cells Based on a Synthesized Silane-Borate Precursor

Doxorubicin (Dox) is a widely used fluorescent chemotherapy drug. Its primary delivery systems, based on physical adsorption to silica nanoparticles, can lead to low drug loading. Direct loading of Dox via covalent bonds during the formation of silica nanoparticles has never been reported. In this work, we designed and synthesized a silane-borate precursor, which contains not only an alkoxysilane moiety to form organosilica nanoparticles but also a phenylboronic acid moiety to react with diol-containing compounds. Using this compound, the covalent loading of Dox during the preparation of organosilica nanoparticles was effectively realized with a high drug loading content up to 22.4 %. Further modification by hyaluronic acid (HA) bestowed the Si-Dox@HA nanoparticles with the ability to target CD44-overexpressing cancer cells. The Si-Dox@HA nanoparticles exhibited H₂O₂-responsive release of about 80 % Dox and displayed seven-fold selectivity for killing cancer cells over normal cells, relative to Dox and Si-Dox nanoparticles. Moreover, these Si-Dox@HA nanoparticles are also suitable for targeted fluorescence imaging of CD44-overexpressing cancer cells.     

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.     

Iron Oxide Nanoparticles for Magnetically-Guided and Magnetically-Responsive Drug Delivery

In this review, we discuss the recent advances in and problems with the use of magnetically-guided and magnetically-responsive nanoparticles in drug delivery and magnetofection. In magnetically-guided nanoparticles, a constant external magnetic field is used to transport magnetic nanoparticles loaded with drugs to a specific site within the body or to increase the transfection capacity. Magnetofection is the delivery of nucleic acids under the influence of a magnetic field acting on nucleic acid vectors that are associated with magnetic nanoparticles. In magnetically-responsive nanoparticles, magnetic nanoparticles are encapsulated or embedded in a larger colloidal structure that carries a drug. In this last case, an alternating magnetic field can modify the structure of the colloid, thereby providing spatial and temporal control over drug release.     

A novel method to prepare magnetic polymer‐based anion exchangers and their application

Magnetic microspheres with ion‐exchange features were prepared by applying a swelling and penetration process using polystyrene–divinylbenzene‐based anion‐exchange resins as starting materials. The polymeric anion‐exchange particles were swollen with an aqueous solution of N‐methyl‐2‐pyrrolidone, followed by incubation with superparamagnetic iron oxide nanoparticles to allow them to penetrate into the swollen particles. The pH value in the solution of magnetic nanoparticles could significantly influence the uptake of magnetic nanoparticles by the swollen anion‐exchange particles. Higher amounts of magnetic nanoparticles entrapped within anion exchangers could be achieved at pH 10–12. An increase in the concentration of magnetic nanoparticles led to a higher density of magnetic nanoparticles entrapped within the interior of anion exchangers and, thus, higher magnetization of the magnetic anion exchangers. Loading of the magnetic nanoparticles onto the exchanger had no effect on anion‐exchange functionality. The utility of the resulting magnetic anion‐exchange resins was demonstrated for the isolation of plasmid pEGFP‐C1 from Escherichia coli cell lysates. The magnetic anion‐exchange microspheres could be easily collected within a few seconds in a magnetic field. Thus, automation of the protocol for DNA isolation using these magnetic anion‐exchange resins has a high potential. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40725.     

Superparamagnetic Hyperthermia Study with Cobalt Ferrite Nanoparticles Covered with γ-Cyclodextrins by Computer Simulation for Application in Alternative Cancer Therapy

In this paper, we present a study by computer simulation on superparamagnetic hyperthermia with CoFe₂O₄ ferrimagnetic nanoparticles coated with biocompatible gamma-cyclodextrins (γ-CDs) to be used in alternative cancer therapy with increased efficacy and non-toxicity. The specific loss power that leads to the heating of nanoparticles in superparamagnetic hyperthermia using CoFe₂O₄–γ-CDs was analyzed in detail depending on the size of the nanoparticles, the thickness of the γ-CDs layer on the nanoparticle surface, the amplitude and frequency of the alternating magnetic field, and the packing fraction of nanoparticles, in order to find the proper conditions in which the specific loss power is maximal. We found that the maximum specific loss power was determined by the Brown magnetic relaxation processes, and the maximum power obtained was significantly higher than that which would be obtained by the Néel relaxation processes under the same conditions. Moreover, increasing the amplitude of the magnetic field led to a significant decrease in the optimal diameter at which the maximum specific loss power is obtained (e.g., for 500 kHz frequency the optimal diameter decreased from 13.6 nm to 9.8 nm when the field increased from 10 kA/m to 50 kA/m), constituting a major advantage in magnetic hyperthermia for its optimization, in contrast to the known results in the absence of cyclodextrins from the surface of immobilized nanoparticles of CoFe₂O₄, where the optimal diameter remained practically unchanged at ~6.2 nm.     

Switchable Fluorescence of Doxorubicin for Label-Free Imaging of Bioorthogonal Drug Release

Monitoring the release and activation of prodrug formulations provides essential information about the outcome of a therapy. While the prodrug delivery can be confirmed by using different imaging techniques, confirming the release of active payload by using imaging is a challenge. Here, we have discovered that the switchable fluorescence of doxorubicin can validate drug release upon its uncaging reaction with a highly specific chemical partner. We have observed that the conjugation of doxorubicin with a trans-cyclooctene (TCO) diminishes its fluorescence at 595 nm. This quenched fluorescence of the doxorubicin prodrug is recovered upon its bond-cleaving reaction with tetrazine. Clinically assessed iron oxide nanoparticles were used to formulate a doxorubicin nanodrug. The release of doxorubicin from the nanodrug was studied under various experimental conditions. A fivefold increase in doxorubicin fluorescence is observed after complete release. The studies were carried out in vitro in MDA-MB-231 breast cancer cells. An increase in Dox signal was observed upon tetrazine administration. This switchable fluorescence mechanism of Dox could be employed for fundamental studies, that is, the reactivity of various tetrazine and TCO linker types under different experimental conditions. In addition, the system could be instrumental for translational research where the release and activation of doxorubicin prodrug payloads can be monitored by using optical imaging systems.