Surface modification of magnetic nanoparticles in biomedicine

Progress in surface modification of magnetic nanoparticles(MNPs)is summarized with regard to organic molecules,macromolecules and inorganic materials.Many researchers are now devoted to synthesizing new types of multi-functional MNPs,which show great application potential in both diagnosis and treatment of disease.By employing an ever-greater variety of surface modification techniques,MNPs can satisfy more and more of the demands of medical practice in areas like magnetic resonance imaging(MRI),fluorescent marking,cell targeting,and drug delivery.     

Multifunctional antitumor magnetite/chitosan-<Emphasis Type="SmallCaps">l</Emphasis>-glutamic acid (core/shell) nanocomposites

The development of anticancer drug delivery systems based on biodegradable nanoparticles has been intended to maximize the localization of chemotherapy agents within tumor interstitium, along with negligible drug distribution into healthy tissues. Interestingly, passive and active drug targeting strategies to cancer have led to improved nanomedicines with great tumor specificity and efficient chemotherapy effect. One of the most promising areas in the formulation of such nanoplatforms is the engineering of magnetically responsive nanoparticles. In this way, we have followed a chemical modification method for the synthesis of magnetite/chitosan-l-glutamic acid (core/shell) nanostructures. These magnetic nanocomposites (average size ≈340 nm) exhibited multifunctional properties based on its capability to load the antitumor drug doxorubicin (along with an adequate sustained release) and its potential for hyperthermia applications. Compared to drug surface adsorption, doxorubicin entrapment into the nanocomposites matrix yielded a higher drug loading and a slower drug release profile. Heating characteristics of the magnetic nanocomposites were investigated in a high-frequency alternating magnetic gradient: a stable maximum temperature of 46 °C was successfully achieved within 40 min. To our knowledge, this is the first time that such kind of stimuli-sensitive nanoformulation with very important properties (i.e., magnetic targeting capabilities, hyperthermia, high drug loading, and little burst drug release) has been formulated for combined antitumor therapy against cancer.     

Magnetic nanoparticle-based cancer therapy

Nanoparticles(NPs) with easily modified surfaces have been playing an important role in biomedicine.As cancer is one of the major causes of death,tremendous efforts have been devoted to advance the methods of cancer diagnosis and therapy.Recently,magnetic nanoparticles(MNPs) that are responsive to a magnetic field have shown great promise in cancer therapy.Compared with traditional cancer therapy,magnetic field triggered therapeutic approaches can treat cancer in an unconventional but more effective and safer way.In this review,we will discuss the recent progress in cancer therapies based on MNPs,mainly including magnetic hyperthermia,magnetic specific targeting,magnetically controlled drug delivery,magnetofection,and magnetic switches for controlling cell fate.Some recently developed strategies such as magnetic resonance imaging(MRI) monitoring cancer therapy and magnetic tissue engineering are also addressed.     

Effects of surfactants on properties of polymer-coated magnetic nanoparticles for drug delivery application

The objective of this research was to compare the effects of two different surfactants on the physicochemical properties of thermo-responsive poly(N-isopropylacrylamide-acrylamide-allylamine) (PNIPAAm-AAm-AH)-coated magnetic nanoparticles (MNPs). Sodium dodecyl sulfate (SDS) as a commonly used surfactant in nanoparticle formulation process and Pluronic F127 as an FDA approved material were used as surfactants to synthesize PNIPAAm-AAm-AH-coated MNPs (PMNPs). The properties of PMNPs synthesized using SDS (PMNPs-SDS) and PF127 (PMNPs-PF127) were compared in terms of size, polydispersity, surface charge, drug loading efficiency, drug release profile, biocompatibility, cellular uptake, and ligand conjugation efficiency. These nanoparticles had a stable core–shell structure with about a 100-nm diameter and were superparamagnetic in behavior with no difference in the magnetic properties in both types of nanoparticles. In vitro cell studies showed that PMNPs-PF127 were more cytocompatible and taken up more by prostate cancer cells than that of PMNPs-SDS. Cells internalized with these nanoparticles generated a dark negative contrast in agarose phantoms for magnetic resonance imaging. Furthermore, a higher doxorubicin release at 40 °C was observed from PMNPs-PF127, and the released drugs were pharmacologically active in killing cancer cells. Finally, surfactant type did not affect the conjugation efficiency to the nanoparticles when folic acid was used as a targeting ligand model. These results indicate that PF127 might be a better surfactant to form polymer-coated magnetic nanoparticles for targeted and controlled drug delivery.     

具有双重治疗机制的磁性纳米无定型氧化铁基药物递送系统

合成一种具有pH响应性的聚乙二醇(PEG)修饰无定形介孔氧化铁纳米粒子(AFe-PEG). 这种纳米粒子可以高效负载药物分子如阿霉素(DOX),构成新型多功能AFe-PEG/DOX药物递送体系. DOX的负载率高达948 mg/g-纳米粒子. 在酸性溶液中,AFe-PEG/DOX纳米粒子不仅可以有效释放DOX,同时可以释放Fe离子进行Fenton反应,将H₂O₂转变成·OH自由基. 体外实验结果表明,AFe-PEG/DOX纳米粒子对HeLa细胞同时具有化疗和化学动力学疗法的疗效. 同时,由于AFe-PEG/DOX 纳米粒子本身的磁性,使其在外部磁场中的细胞内化效率也得到了提高.     

A Functionalized Hollow Mesoporous Silica Nanoparticles‐Based Controlled Dual‐Drug Delivery System for Improved Tumor Cell Cytotoxicity

Multifunctional nanoparticles for selectively targeting tumor cells and effectively delivering multiple drugs are urgently needed in cancer therapy. Here, a dual‐drug delivery system is prepared, based on functionalized hollow mesoporous silica nanoparticles (HMSNs). Doxorubicin (DOX) hydrochloride is loaded into the hollow core, and dichloro(1,2‐diaminocyclohexane)platinum (II) (DACHPt) is stored in the pores of the shell by the coordination interaction with the carboxyl groups modified on the pore walls, which also serves as barriers to control the DOX release. Detailed studies in vitro indicate that the DACHPt release is triggered by Cl^? through the cleavage of the coordination interaction, and the DOX release depends on the release rate of DACHPt and the environmental pH value. The surface of the mechanized nanoparticles is also modified by transferrin (Tf) to achieve the tumor specificity. Compared with individual drug delivery systems, the dual‐drug delivery system shows synergistic efficacy on the cell cytotoxicity (combination index = 0.30), resulting in improved tumor cell killing. The present dual‐drug delivery system provides a promising strategy to develop controlled and targeted combination therapies for efficient cancer treatment.     

Magnetic lipid nanoparticles loading doxorubicin for intracellular delivery: Preparation and characteristics

Tumor intracellular delivery is an effective route for targeting chemotherapy to enhance the curative effect and minimize the side effect of a drug. In this study, the magnetic lipid nanoparticles with an uptake ability by tumor cells were prepared dispersing ferroso-ferric oxide nanoparticles in aqueous phase using oleic acid (OA) as a dispersant, and following the solvent dispersion of lipid organic solution. The obtained nanoparticles with 200 nm volume average diameter and −30 mV surface zeta potential could be completely removed by external magnetic field from aqueous solution. Using doxorubicin (DOX) as a model drug, the drug-loaded magnetic lipid nanoparticles were investigated in detail, such as the effects of OA, drug and lipid content on volume average diameter, zeta potential, drug encapsulation efficiency, drug loading, and in vitro drug release. The drug loading capacity and encapsulation efficiency were enhanced with increasing drug or lipid content, reduced with increasing OA content. The in vitro drug release could be controlled by changing drug or lipid content. Cellular uptake by MCF-7 cells experiment presented the excellent internalization ability of the prepared magnetic lipid nanoparticles. These results evidenced that the present magnetic lipid nanoparticles have potential for targeting therapy of antitumor drugs.     

A thermo-fluid analysis in magnetic hyperthermia

In the last years, hyperthermia induced by the heating of magnetic nanoparticles （MNPs） in an alternating magnetic field received considerable attention in cancer therapy. The thermal effects could be automatically controlled by using MNPs with selective magnetic absorption properties. In this paper, we analyze the temperature field determined by the heating of MNPs, injected in a malignant tissue, subjected to an alternating magnetic field. The main parameters which have a strong influence on temperature field are analyzed. The temperature evolution within healthy and tumor tissues are analyzed by finite element method （FEM） simulations in a thermo-fluid model. The cooling effect produced by blood flow in blood vessels from the tumor is considered. A thermal analysis is conducted under different distributions of MNP injection sites. The interdependence between the optimum dose of the nanoparticles and various types of tumors is investigated in order to understand their thermal effect on hyperthermia therapy. The control of the temperature field in the tumor and healthy tissues is an important step in the healing treatment.     

Applications of polymeric micelles with tumor targeted in chemotherapy

The chitosan-coated magnetic nanoparticles (CS MNPs) were in situ synthesized by cross-linking method. In this method; during the adsorption of cationic chitosan molecules onto the surface of anionic magnetic nanoparticles (MNPs) with electrostatic interactions, tripolyphosphate (TPP) is added for ionic cross-linking of the chitosan molecules with each other. The characterization of synthesized nanoparticles was performed by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS/ESCA), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), dynamic light scattering (DLS), thermal gravimetric analysis (TGA), and vibrating sample magnetometry (VSM) analyses. The XRD and XPS analyses proved that the synthesized iron oxide was magnetite (Fe₃O₄). The layer of chitosan on the magnetite surface was confirmed by FTIR. TEM results demonstrated a spherical morphology. In the synthesis, at higher NH₄OH concentrations, smaller sized nanoparticles were obtained. The average diameters were generally between 2 and 8?nm for CS MNPs in TEM and between 58 and 103?nm in DLS. The average diameters of bare MNPs were found as around 18?nm both in TEM and DLS. TGA results indicated that the chitosan content of CS MNPs were between 15 and 23?% by weight. Bare and CS MNPs were superparamagnetic. These nanoparticles were found non-cytotoxic on cancer cell lines (SiHa, HeLa). The synthesized MNPs have many potential applications in biomedicine including targeted drug delivery, magnetic resonance imaging?(MRI), and magnetic hyperthermia.     

Temperature and Redox Dual‐Responsive Biodegradable Nanogels for Optimizing Antitumor Drug Delivery

The strategy to efficiently deliver antitumor drugs via nanocarriers to targeted tumor sites and achieve controllable drug release is attracting great research interest in cancer therapy. In this study, a novel type of disulfide‐bonded poly(vinylcaprolactam) (PVCL)‐based nanogels with tunable volume phase transition temperature and excellent redox‐labile property are prepared. The nanogels are hydrophilic and swell at 37 °C, whereas under hyperthermia (e.g., 41 °C), the nanogels undergo sharp hydrophilic/hydrophobic transition and volume collapse, which enhances the cellular uptake and drug release. The incorporation of disulfide bond linkers endows the nanogels with an excellent disassembly property in reducing environments, which greatly facilitates drug release in tumor cells. Nanogels loaded with doxorubicin (DOX) (DOX‐NGs) (DOX‐NGs) are stable in physiological conditions with low drug leakage (15% in 48 h), while burst release of DOX (92% in 12 h) can be achieved in the presence of 10 × 10^?3 m glutathione and under hyperthermia. The DOX‐NGs possess improved cell killing efficiency under hyperthermia (IC₅₀ decreased from 1.58 μg mL^?1 under normothermia to 0.5 μg mL^?1). Further, the DOX‐NGs show a pronounced tumor inhibition rate of 46.6% compared with free DOX, demonstrating that this new dual‐responsive nanogels have great potential as drug delivery carriers for cancer therapy in vivo.     

Smart Therapeutic Strategy of pH-Responsive Gold Nanoparticles for Combating Multidrug Resistance

As several multi-target drug delivery approaches are successfully identified through preclinical screening, their clinical success is often hampered by challenges such as poor circulation stability, dissimilarities in the pharmacokinetics of different drugs, as well as targeting inefficiency. Gold nanoparticles (AuNPs) are adopted as promising nanocarriers in the co-delivery of multiple therapeutic drugs for combination therapy. The pH-responsive AuNPs are synthesized and incorporated with multiple chemotherapeutic drugs, such as doxorubicin and bleomycin. Such structures can work as drug carriers to treat cervical carcinoma by adopting a quality by design approach. The designed nanocarrier is characterized by adopting a range of physicochemical and morphological techniques. In vitro drug release and cytotoxicity of optimized nanocarriers are assessed to cervical tumor epithelial cells. The results highlight the notable advantages of colloidal AuNPs, including sustained drug release, therapeutic agent delivery with high stability, and biocompatibility for more effective treatment of cervical carcinoma. Furthermore, by improving the biodistribution and/or bioavailability profiles, it is believed that the two-in-one approach may therefore give evidence on the fate of co-loaded nanocarrier as a promising trajectory for successful clinical translation against ovarian carcinoma to achieve maximum therapeutic synergy for an individual patient.     

Drug-loaded nano/microbubbles for combining ultrasonography and targeted chemotherapy

A new class of multifunctional nanoparticles that combine properties of polymeric drug carriers, ultrasound imaging contrast agents, and enhancers of ultrasound-mediated drug delivery has been developed. At room temperature, the developed systems comprise perfluorocarbon nanodroplets stabilized by the walls made of biodegradable block copolymers. Upon heating to physiological temperatures, the nanodroplets convert into nano/microbubbles. The phase state of the systems and bubble size may be controlled by the copolymer/perfluorocarbon volume ratio. Upon intravenous injections, a long-lasting, strong and selective ultrasound contrast is observed in the tumor volume indicating nanobubble extravasation through the defective tumor microvasculature, suggesting their coalescence into larger, highly echogenic microbubbles in the tumor tissue. Under the action of tumor-directed ultrasound, microbubbles cavitate and collapse resulting in a release of the encapsulated drug and dramatically enhanced intracellular drug uptake by the tumor cells. This effect is tumor-selective; no accumulation of echogenic microbubbles is observed in other organs. Effective chemotherapy of the MDA MB231 breast cancer tumors has been achieved using this technique.     

Carbon Dots‐Cluster‐DOX Nanocomposites Fabricated by a Co‐Self‐Assembly Strategy for Tumor‐Targeted Bioimaging and Therapy

Carbon‐based nanomaterials could afford versatile potential applications in biomedical optical imaging and as nanoparticle drug carriers, owing to their promising optical and biocompatible capabilities. In this paper, it is first found that amphipathic cetylpyridinium chloride (CPC)‐stabilized oil‐soluble carbon dots (CDs) could self‐assemble into hydrophilic CDs clusters with hydrophobic core under ultrasound, in which CPC acts as carbon source, stabilizer, and phase transfer agent. Next, the size‐control (for size‐dependent passive tumor targeting) and doxorubicin (DOX) uploading of aqueous CDs clusters, and subsequent surface charge modification via overcoating with cRGD‐ and octylamine‐modified polyacrylic acid (cRGD‐PAA‐OA) (reversing their surface charges into negative and introducing active tumor‐targeting ability) are explored systematically. Based on this sequential administration mode, CDs‐cluster‐DOX/cRGD‐PAA‐OA nanocomposites exhibit selective human malignant glioma cell line (U87MG) tumor targeting. In in vitro drug release experiments, the nanocomposites could release DOX timely. Owning to the dual tumor targeting effects and seasonable drug release, CDs‐cluster‐DOX/cRGD‐PAA‐OA show remarkably tumor targetability and enhanced antitumor efficacy (and reduced adverse reaction), comparing to free DOX in animal models. These results indicate that fabricating nanocomposite via co‐self‐assembly strategy is efficient toward drug delivery system for tumor‐targeting theranostic.     

Multifunctional Magnetic Nanomedicine Drug Delivery and Imaging-Based Diagnostic Systems

Magnetically guided drug transportation is a technique in which magnetic pharmaceutical transporters in organisms are controlled by applied magnetic forces to deliver drugs to the desired location. Different magnetic drug delivery systems (MDDSs) are developed to treat a variety of illnesses, particularly cancer and neurological disorders. However, a unique magnetic setup is required in each application for an effective magnetically guided drug aiming to direct the drug-carrying nanocarriers to the intended area. The current and future perspectives of MDDS are investigated in this study by considering their biological functions, deliverable efficiency, complexity, and the nature of the externally applied magnetic field. Despite the fact that MDDSs have low cytotoxicity, regulated magneto reactivity, extended circulation lifespan, and high surface stability, very few clinical studies have been conducted to date in order to achieve optimized therapeutic efficacy before entering the market. In recent studies, the development of novel magnetic medication transporting carriers is preferred over direct magnetic medication administration. Better functional magnetic targeting technologies are required for such breakthroughs to enter clinical trials. Because MDDSs are unlikely to work in all clinical situations, more focused research is needed to replace or improve the strategy for treating multiple illnesses.     

Layer-by-layer assembly of a magnetic nanoparticle shell on a thermoresponsive microgel core

We describe the surface modification of magnetic nanoparticles (MNPs), the coverage of poly(N-isopropylacrylamide) (PNiPAM) microgel with the MNPs and the inductive heating of these carriers. PNiPAM surface itself was modified using the layer-by-layer (LbL) assembly of polyelectrolytes to facilitate the deposition of surface-modified MNPs. One advantage of this concept is it allows the tuning of the magnetic and thermoresponsive properties of individual components (nanoparticles and microgels) separately before assembling them. Characterisations of the hybrid core–shell are discussed. In particular, it is shown that (i) each layer is successfully deposited and, more importantly, (ii) the coated microgel retains its thermoresponsive and magnetic behaviour.     

Liposomal Form of Tetra(Aryl)Tetracyanoporphyrazine: Physical Properties and Photodynamic Activity In Vitro

Tetra(aryl)tetracyanoporphyrazines are the promising group of dyes for photodynamic therapy of tumors with unique combination of photosensitizer properties and sensitivity of fluorescence parameters to the environment viscosity. However, in vivo application of such hydrophobic photosensitizers requires using of drug carriers ensuring efficient delivery to the tumor site. The present study is focused on obtaining liposomes loaded with tetrakis(4-benzyloxyphenyl)tetracyanoporphyrazine and examining their properties depending on lipid composition. An efficient loading of the dye and a high long-term stability were proved for the liposomes composed of phosphatidylcholine with cholesterol and phosphatidylglycerol. This can be explained by the presence of negatively charged lipids in the bilayer and, as a consequence, a high value of the surface potential. A high rate of cellular uptake and a strong photoinduced toxicity give the prerequisites for the further use of the liposomal form of the photosensitizer for photodynamic therapy of tumors.     

GLUT1-Targeting and GSH-Responsive DOX/L61 Nanodrug Particles for Enhancing MDR Breast Cancer Therapy

Efficient targeting to tumor tissues and subsequent rapid drug release in cancer cells remains a major challenge for nanodrug delivery systems. Herein, smart nanodrug particles with reduction-sensitive and active tumor-targeting ability are constructed based on the nanoprecipitation of glucosamine-grafted pluronic L61 (GA-L61) and disulphide-linked doxorubicin dimer (DOX SS DOX) to overcome tumor multidrug resistance (MDR). These nanoparticles show proper size and excellent stability under neutral conditions, while quickly release DOX due to the breakage of disulfide bonds under reductive medium. In vitro cellular uptake and drug efflux demonstrate that L61 can efficiently increase DOX concentration in MCF/ADR resistant cells by inhibiting the function of drug resistance proteins. In vivo biodistribution reveals that glucose transporter 1 (GLUT1)-mediated tumor-targeting significantly improves tumor accumulation of the glucosamine-contained nanoparticles. Finally, the combination of GLUT1-targeting, glutathione (GSH)-responsive, and MDR-reversal effects in nanoparticles achieve superior antitumor effects, which can provide an efficient, safe, and economic approach for drug delivery and cancer chemotherapy.     

Towards dynamic control of magnetic fields to focus magnetic carriers to targets deep inside the body

Magnetic drug delivery has the potential to target therapy to specific regions in the body, improving efficacy and reducing side effects for treatment of cancer, stroke, infection, and other diseases. Using stationary external magnets, which attract the magnetic drug carriers, this treatment is limited to shallow targets (<5 cm below skin depth using the strongest possible, still safe, practical magnetic fields). We consider dynamic magnetic actuation and present initial results that show it is possible to vary magnets one against the other to focus carriers between them on average. The many remaining tasks for deep targeting in-vivo are then briefly noted.     

纳米生物技术及其应用

纳米技术的发展使人们可以观测到纳米量级的介观世界，可以直观地了解生物分子的形态和分子间的相互作用，甚至可以操纵生物大分子，得到不同结构的新的生物分子．运用纳米技术制作的纳米器件可以用作疾病诊断与治疗．由纳米量级的超微粒构成的纳米生物材料具有良好生物相容性和一些独特的纳米效应，主要表现为小尺寸效应和表面或界面效应．纳米生物材料与相同组成的微米材料存在非常显著的差异，体现出许多优异的性能和全新的功能．纳米微粒在癌症的监测、治疗，细胞和蛋白质的分离，基因治疗，靶向和缓释控药物等中都有着广泛的应用．     

Imaging the Magnetic Reversal of Isolated and Organized Molecular‐Based Nanoparticles using Magnetic Force Microscopy

In the race towards miniaturization in nanoelectronics, magnetic nanoparticles (MNPs) have emerged as potential candidates for their integration in ultrahigh‐density recording media. Molecular‐based materials open the possibility to design new tailor‐made MNPs with variable composition and sizes, which benefit from the intrinsic properties of these materials. Before their implementation in real devices is reached, a precise organization on surfaces and a reliable characterization and manipulation of their individual magnetic behavior are required. In this paper, it is demonstrated how molecular‐based MNPs are accurately organized on surfaces and how the magnetic properties of the individual MNPs are detected and tuned by means of low‐temperature magnetic force microscopy (LT‐MFM) with variable magnetic field. The magnetization reversal on isolated and organized MNPs is investigated; in addition, the temperature dependence of their magnetic response is evaluated.