引导磁场下磁性药物靶向治疗的理论分析

应用电磁场理论，对引导磁场下铁磁性“药物”颗粒在靶向治疗中的受力和运动轨迹进行了分析和研究.得到了磁场、血流和血管壁对铁磁性“药物”颗粒的作用及运动规律.给出了铁磁性“药物”在靶向治疗中可采用的一种新方法——利用体外磁激励装置产生的变化磁场来实现铁磁性“药物”靶向治疗，还给出了采用这种方法实现靶向治疗的条件. 关键词： 磁性药物 靶向治疗 血流动力学 引导磁场     

Quantitative targeting maps based on experimental investigations for a branched tube model in magnetic drug targeting

Magnetic drug targeting (MDT), because of its high targeting efficiency, is a promising approach for tumour treatment. Unwanted side effects are considerably reduced, since the nanoparticles are concentrated within the target region due to the influence of a magnetic field. Nevertheless, understanding the transport phenomena of nanoparticles in an artery system is still challenging. This work presents experimental results for a branched tube model. Quantitative results describe, for example, the net amount of nanoparticles that are targeted towards the chosen region due to the influence of a magnetic field. As a result of measurements, novel drug targeting maps, combining, e.g. the magnetic volume force, the position of the magnet and the net amount of targeted nanoparticles, are presented. The targeting maps are valuable for evaluation and comparison of setups and are also helpful for the design and the optimisation of a magnet system with an appropriate strength and distribution of the field gradient. The maps indicate the danger of accretion within the tube and also show the promising result of magnetic drug targeting that up to 97% of the nanoparticles were successfully targeted.     

Quantification of drug-loaded magnetic nanoparticles in rabbit liver and tumor after in vivo administration

Magnetic nanoparticles have been investigated for biomedical applications for more than 30 years. The development of biocompatible nanosized drug delivery systems for specific targeting of therapeutics is imminent in medical research, especially for treating cancer and vascular diseases. We used drug-labeled magnetic iron oxide nanoparticles, which were attracted to an experimental tumor in rabbits with an external magnetic field (magnetic drug targeting, MDT). Aim of this study was to detect and quantify the biodistribution of the magnetic nanoparticles by magnetorelaxometry. The study shows higher amount of nanoparticles in the tumor after intraarterial application and MDT compared to intravenous administration.     

Enhancement of the efficiency of magnetic targeting for drug delivery: Development and evaluation of magnet system

Deep magnetic capture and clinical application are the current trends for magnetic targeted drug delivery system. More promising and possible strategies are needed to overcome the current limitations and further improve the magnetic targeting technique. Recent advances in the development of targeting magnet system show promise in progressing this technology from the laboratory to the clinic. Starting from well-known basic concepts, current limitations of magnetic targeted drug delivery system are analyzed. Meanwhile, the design concepts and evaluations of some effective improvements in magnet system are discussed and reviewed with reference to (i) reasonable design of magnet system; (ii) control modes of magnet system used to generate dynamical magnetic fields; and (iii) magnetic field driving types.     

A New Glioblastoma Targeting Therapy Concept by Using Square Shaped Janus Drug Carrier Assisted with 3D Printed External Magnetic Wearables

At present, the clinical treatment of malignant glioma is still unsatisfactory. The existence of the blood–brain barrier hinders most chemical and biological drugs to reach the brain tissue. In this study, a square‐shaped Janus drug carrying system, which incorporated with high infrared responsiveness, large drug loading capacity, and reliable magnetic targeting capabilities is synthesized. Combined with an external 3D printed magnetic wearable equipment, this carrying system can effectively penetrate the blood–brain barrier in both in vitro and in vivo tests, it is thus applied to two different targeting tumor therapies (including glioma). Animal experiments demonstrate the multiple therapeutic effects of the proposed system. The subsequent studies imply that the obtained carrier has no obvious toxic effects on the organs of animals. Different from the classical biochemical targeting method, this study uniquely combines the porous Janus nanocarrier with an external wearable magnetic guidance device (physical targeting), which is a promising target therapeutic concept with impressive flexibility and reliability.     

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.     

Application of high gradient magnetic separation principles to magnetic drug targeting

A hypothetical magnetic drug targeting system, utilizing high gradient magnetic separation (HGMS) principles, was studied theoretically using FEMLAB simulations. This new approach uses a ferromagnetic wire placed at a bifurcation point inside a blood vessel and an externally applied magnetic field, to magnetically guide magnetic drug carrier particles (MDCP) through the circulatory system and then to magnetically retain them at a target site. Wire collection (CE) and diversion (DE) efficiencies were defined and used to evaluate the system performance. CE and DE both increase as the strength of the applied magnetic field (0.3–2.0 T), the amount of ferromagnetic material (iron) in the MDCP (20–100%) and the size of the MDCP (1–10 μm radius) increase, and as the average inlet velocity (0.1–0.8 m s⁻¹), the size of the wire (50–250 μm radius) and the ratio (4–10) of the parent vessel radius (0.25–1.25 mm radius) to wire radius decrease. The effect of the applied magnetic field direction (0° and 90°) on CE and DE was minimal. Under these plausible conditions, CEs as high as 70% were obtained, with DEs reaching only 30%; however, when the MDCPs were allowed to agglomerate (4–10 μm radius), CEs and DEs of 100% were indeed achieved. These results reveal that this new magnetic drug targeting approach for magnetically collecting MDCPs at a target site, even in arteries with very high velocities, is feasible and very promising; this new approach for magnetically guiding MDCPs through the circulatory system is also feasible but more limited. Overall, this study shows that magnetic drug targeting, based on HGMS principles, has considerable promise as an effective drug targeting tool with many potential applications.     

Theoretical analysis of a transdermal ferromagnetic implant for retention of magnetic drug carrier particles

The use of a ferromagnetic wire implant placed near an artery to assist the collection of magnetic drug carrier particles (MDCPs) using an external magnet is theoretically studied. Three magnetic drug targeting (MDT) systems are evaluated in terms of their MDCP collection efficiency (CE): a permanent magnet and wire is better than a permanent magnet alone, which is better than a homogeneous magnetic field and wire.     

In vitro study of deep capture of paramagnetic particle for targeting therapeutics

Magnetic targeting, a promising therapeutic strategy for localizing systemically delivered drug to target tissue, is limited by magnetic attenuation. To satisfy the need of deep magnetic targeting, a special apparatus in which the magnetic flux density can be focused at a distance from the pole was designed. To test the aggregation property of this apparatus, we observed the accumulation of 500-nm paramagnetic particles as flowing through a tube served as a model of blood vessels. The relationship of the accumulation of the paramagnetic particles, the magnetic flux density, the magnetic field gradient and the fluid velocity was studied by theoretical considerations.     

Experimental investigations on a branched tube model in magnetic drug targeting

Magnetic drug targeting (MDT) has been established as a promising technique for tumour treatment. Due to its high targeting efficiency unwanted side effects are considerably reduced, since drug-loaded nanoparticles are concentrated within a target region due to the influence of a magnetic field. This work presents experimental results that are based on systematic quantitative measurements on a branched tube model as a model system for a blood vessel supplying a tumour. The systematic measurements are summarized in novel drug targeting maps, combining e.g. the net amount of targeted nanoparticles, the magnetic volume force and also the position of the magnet. The model, the injection procedure and the ferrofluid are chosen close to the parameters of a medical application. This will allow transfer of the results to future medical investigations. This work will present a targeting map, where the concentration of the injected ferrofluid is in the range of experiments with an ex vivo bovine artery model.     

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.     

Numerical modeling of magnetic drug targeting

A special focused magnet, designed for the use in the magnetic targeted drug delivery system, was constructed. The theoretical calculation of the adhesion condition for a magnetic fluid drop in magnetic field with obtained design showed that the constructed focused magnet generates a sufficient magnetic force for the capture of a magnetic drop on the vessel wall and can be used 1.5–2 cm deeper in an organism compared with the prism permanent magnet, which can enable non-invasivity of the magnetic drug targeting procedure. The maximal values for magnetic field and gradient of magnetic field are 0.38 T and 101 T/m, respectively.     

Ferromagnetic seeding for the magnetic targeting of drugs and radiation in capillary beds

A new implant assisted-magnetic drug targeting approach is introduced and theoretically analyzed to demonstrate its feasibility. This approach uses ferromagnetic particles as seeds for collecting magnetic drug carrier particles at the desired site in the body, such as in a capillary bed near a tumor. Based on the capture cross section (λ_c) approach, a parametric study was carried out using a 2-D mathematical model to reveal the effects of the magnetic field strength (μ₀H₀=0.01–1.0 T), magnetic drug carrier particle radius (R_p=20–500 nm), magnetic drug carrier particle ferromagnetic material content (x_fm,p=20–80 wt%), average blood velocity (u_B=0.05–1.0 cm/s), seed radius (R_s=100–2000 nm), number of seeds (N_s=1–8), seed separation (h=0–8R_s), and magnetic drug carrier particle and seed ferromagnetic material saturation magnetizations (iron, SS 409, magnetite, and SS 304) on the performance of the system. Increasing the magnetic field strength, magnetic drug carrier particle size, seed size, magnetic drug carrier particle ferromagnetic material content, or magnetic drug carrier particle or seed saturation magnetization, all positively and significantly affected λ_c, while increasing the average blood velocity adversely affected it. Increasing the number of seeds or decreasing the seed separation, with both causing less significant increases in λ_c, verified that cooperative magnetic effects exist between the seeds that enhance the performance. Overall, these theoretical results were encouraging as they showed the viability of this minimally invasive, implant assisted-magnetic drug targeting approach for targeting drugs or radiation in capillary beds.     

Development of magnetically targeted drug delivery system using superconducting magnet

Development of a novel drug delivery system was made to accumulate/navigate magnetic drugs with the help of a superconducting magnet in order to control the drugs in blood vessels located deep inside the body. In the present paper, we tested the feasibility of a novel navigation system, made by applying a strong external (magnetic) field through SmBaCuO and YBaCuO bulk superconductors in order to realize the practice of using externally applied magnetic fields for targeting the magnetic particles to a circumscribed body region.     

A novel magnetic fluid based on starch-coated magnetite nanoparticles functionalized with homing peptide

Preparation and characterization in vitro and in vivo of a novel magnetic fluid based on starch-coated magnetite nanoparticles functionalized with homing peptide is reported in this paper. Precursory magnetic fluids stabilized with starch were prepared, in a polymeric starch matrix, by controlled chemical coprecipitation of magnetite phase from aqueous solutions. The average hydrodynamic diameter of starch-coated iron oxide nanoparticles (SIONs) was 46 nm. As a homing peptide, A54 is the most effective peptide specific to the human hepatocellular carcinoma cell line BEL-7402. Final magnetic fluids were obtained through chemical coupling of homing peptide labeled with 5-carboxyl-fluorescein (FAM-A54) and SIONs. Magnetic measurements showed the saturation magnetization value of SIONs amounted to 45 emu/g and the FAM-A54-coupled SIONs showed a good magnetic response in magnetic field. The results of experiments in vitro and in vivo showed that SIONs were endowed with specific affinity to corresponding tumor cells after coupling with FAM-A54 and the FAM-A54-coupled SIONs could be accumulated in the tumor tissue with more efficiency than individual magnetic targeting or biomolecular targeting. This novel magnetic fluid with dual function has great potential applications in diagnostics and therapeutics of human tumor such as drug targeting, magnetic hyperthermia, and magnetic resonance imaging.     

In vitro study of ferromagnetic stents for implant assisted-magnetic drug targeting

Implant-assisted-magnetic drug targeting (IA-MDT) was studied in vitro using a coiled ferromagnetic wire stent made from stainless steel 430 or 304, and magnetic drug carrier particle (MDCP) surrogates composed of poly(styrene/divinylbenzene) embedded with 20 wt% magnetite. The fluid velocity, particle concentration, magnetic field strength, and stent material all proved to be important for capturing the MDCP surrogates. Overall, this in vitro study further confirmed the important role of the ferromagnetic implant for attracting and retaining MDCPs at the target zone.     

Targeting and deep-penetrating delivery strategy for stented coronary artery by magnetic guidance and ultrasound stimulation

Stent placement is an effective treatment for atherosclerosis, but is suffered from in-stent restenosis (ISR) caused by stent mechanical damage. Conventional ISR treatment such as drug-eluting stents (DES) is challenged by the low therapeutic efficacy and severe complications, unchangeable drug dosage for individuals, and limited drug penetration in the vascular tissue. We hypothesize that magnetic targeting and deep-penetrating delivery strategy by magnetic guidance and ultrasound stimulation might be an effective approach for ISR treatment. In the present study, antiproliferative drug (paclitaxel, PTX) loaded poly (lactide-co-glycolide) (PLGA) nanoparticles (PLGA-PTX) were embedded within the shells of the magnetic nanoparticle coated microbubbles (MMB-PLGA-PTX). Once being targeted to the stent under a magnetic field, a low intensity focused ultrasound (LIFU) is applied to activate stable microbubble oscillations, thereby triggering the release of PLGA-PTX. The generated mechanical force and microstreaming facilitate the penetration of released PLGA-PTX into the thickened vascular tissue and enhance their internalization by smooth muscle cells (SMCs), thereby reducing the clearance by blood flow. In an ex vivo experiment, magnetic targeting improved the accumulation amount of MMB-PLGA-PTX by 10 folds, while the LIFU facilitated the penetration of released PLGA-PTX into the tunica media region of the porcine coronary artery, resulting in prolonged retention time at the stented vascular tissue. With the combination effects, this strategy holds great promise in the precision delivery of antiproliferative drugs to the stented vascular tissue for ISR treatment.     

Analysis of magnetic drug carrier particle capture by a magnetizable intravascular stent—2: Parametric study with multi-wire two-dimensional model

A 2-D mathematical model was developed and used to examine the capture of magnetic drug carrier particles (MDCPs) by a magnetizable intravascular stent (MIS). The roles of both non-stent system parameters, i.e., the blood flow rate, magnetic field strength and direction and MDCP properties, and stent design parameters, i.e., the MIS radius, its wire radius, number of MIS loops, interwire loop spacing and MIS ferromagnetic material were evaluated over a wide range of plausible conditions. The results showed that the MIS could be a very effective magnetic drug targeting tool with many possible applications.     

Synthesis and characterization of tat-mediated O-CMC magnetic nanoparticles having anticancer function

This paper describes a new formulation of magnetic nanoparticles coated by a novel polymer matrix—O-carboxylmethylated chitosan (O-CMC) as drug/gene carrier. The O-CMC magnetic nanoparticles were derivatized with a peptide sequence from the HIV-tat protein to improve the translocational property and cellar uptake of the nanoparticles. To evaluate the O-MNPs-tat as drug carriers, MTX was incorporated as a model drug and MTX-loaded O-MNPs-tat with an average diameter of 45–60 nm were prepared and characterized by TEM, AFM and VSM. The cytotoxicity of MTX-loaded O-MNPs-tat was investigated with U-937 tumor cells. The results showed that the MTX-loaded O-MNPs-tat retained significant antitumor toxicity; additionally, sustained release of MTX from O-CMC nanoparticles was observed in vitro, suggesting that the tat-O-MNPs could be a novel magnetic targeting carrier.     

Synthesis and characterization of polymeric nanospheres loaded with the anticancer drug paclitaxel and magnetic particles

We describe the preparation (by nanoprecipitation) and characterization of nanospheres (NPs) for magnetic drug targeting made of a magnetic fluid with poly(ethylene glycol), poly(d,l-lactic-co-glycolic acid) (PLGA), and the anticancer drug paclitaxel (Taxol^®). Infrared spectroscopy confirmed the incorporation of the drug in the PLGA NPs, which were also characterized in terms of morphology, size (typical diameter 200-250 nm) and colloidal stability in aqueous solutions of NaCl. Drug release and in vivo toxicity experiments of the prepared samples were performed. Their stability, magnetic properties (superparamagnetism), and lethal dose were found to be acceptable for the proposed application in cancer therapy.