Magnetic Drug Delivery System

Magnetic micro & nanoparticles & molecular magnetic labels have been used for great number of application in variuos areas of biosciences, targeted drug delivery & in separation technology. This review paper will summarize mechanisim of targeted drug delivery by magnetism, magnetic carriers, application of magnetism in targeted drug delivery, characterization & patents on magnetic drug delivery system.

Introduction

The activity of most drugs against disease suffers from their inability to accumulate selectively at the site of action. Drug targeting is the delivery of drugs to receptors or organ or any other specific part of the body to which one wishes to deliver the drug exclusively. There are many different approaches to targeted drug delivery, which are classified broadly into three categories. 1) Physical or mechanical approach which requires formulation of the drug using a particulate delivery device, (for eg. magnet) which by virtue of its physical localization will allow differential release of the drug. 2) Biological approach which involves delivery of the drug using a carrier system like antibodies, lecithin. 3) Chemical Approach which incorporates chemical delivery systems, allow targeting of active biological molecules to specific target sites or organs, based on predictable enzymatic activation¹ Magnetism play an important role in different applications of health care, magnetic particles composed of magnetite which are well tolerated by the body ² Magnetic nanoparticles usually exist or can be prepared in the form of single domain or superparamagnetic magnetite (Fe3o4), greigite (Fe3s4), magnemite (r-Fe2o3), iron, nickel, etc. synthetic magnetic materials have many applications in optics, electronic & energy storage ³. Magnetism have application in numerous field like diagnostics, drug targeting, molecular biology, cell isolation, cell purification, hyperthermia, radioimmunoassay. This article discuss the potential applications of magnet in drug targeting, formulation of magnet containing particles & characterization of magnetic particles.

Mechanism of Targeting by Magnet.

The aim of the specific targeting is to enhance the efficiency of drug delivery & at the same time to reduce the toxicity & side effects.

Magnetic drug transport technique is based on the fact that the drug can be either encapsulated into a magnetic microsphere (or nanosphere) or conjugated on the surface of the micro/nanosphere. When the magnetic carrier is intravenously administered, the accumulation take place within area to which the magnetic field is applied & often augmented by magnetic agglomeration. The accumulation of the carrier at the target site allow them to deliver the drug locally. Efficiency of accumulation of magnetic carrier on physiological carrier depends on physiological parameters eg. particle size, surface characteristic, field strength, & blood flow rate etc. The magnetic field assists to extravasate the magnetic carrier into the targeted area. Some kind of channel opened by the force of the magnet are thought to be associated with process of extrusion by magnetic targeted carriers. ⁴

This technique which requires only a simple injection, is far less invasive than surgical methods of targeted drug delivery. Another advantage is that particles in the magnetic fluid interact strongly with each other, which facilitates the delivery of high concentrations of drug to targeted areas.

Magnetic Carrier:

A. Magnetoliposomes :

These are magnetic carrier which can be prepared by entrapment of ferrofluid within core of liposomes ^{5, 6} Magnetoliposome can also be produced by covalent attachment of ligands to the surface of the vehicles or by incorporation of target lipids in the matrix of structural phospholipids ⁷ Alternatively magnetoliposomes are prepared using the phospholipid vesicle as a nanoreactor for the in situ precipitation of magnetic nanoparticles ⁸. Vesicles are also prepared containing didodecyl methyl ammonium bromide, contain an ionic magnetic fluid ^9. These magnetoliposomes were effectively used for site specific targeting, cell sorting & as magnetic resonance contrast enhancing agent.

Thermosensitive magnetioliposomes can release the entrappped drug after selective heating caused by the electromagnetic fields. ^10.

B. Magnetic Nanoparticles :

Magnetic colloidal iron oxide nanoparticles were prepared with the method of coprecipitation¹¹. Interfacial polymerization was also applied to synthesize magnetic nanoparticles ¹². Pedro Trataj et al. review article described synthetic routes for the preparation of magnetic nonoparticles useful for biomedical applications ¹³.

Bacterial magnetite nanoparticles obtained from magnetotactic bacteria after disruption of the cell wall & subsequent magnetic separation have been used for a variety of bioapplications. Due to the presence of the lipid layer these particles are biocompatible, their suspensions are very stable & the particles can be easily modified. ¹⁴.

C. Magnetic Resealed Erythrocytes:

Magnetically responsive ibuprofen-loaded erythrocytes were prepared and characterized in vitro. The erythrocytes loaded with ibuprofen and magnetote (ferrofluids) using the preswell technique.The loaded celleffectively responded to an external magnetic.In the continuous study, diclofenac sodium bearing erythrocytes were prepared by preswell technique and characterized for variuos in vitro parameters¹⁵.

D. Magnetic Emulsion:

Magnetic emulsion was also tried as drug carrier for chemotherapeutic agents. The emulsion is magnetically responsive oil in water type of emulsion bearing a chemotherapeutic agent which could be selectively localized by applying an exteranal magnetic field to spesific target site¹⁵.

Application

Magnetically guided drug targeting has been attempted in order to increase the efficiency & reduce the unpleasant side effects. This method of drug delivery involves immobilization of drug or radionuclide in biocompatible magnetic nano or microspheres or in magnetiliposomes. The drug & an appropriate ferrofluid are formulated into a pharmaceutically stable formulation which is usually injected through the artery that supplies the target organ or tumor in the presence of an external magnetic field. Prolonged retension of the magnetic drug carrier at the target site alleviates or delays the RES clearance & facilitates extravascular uptake. This process is based on competition between forces excerted on the particles by macro & microcirculation, the characteristics of the magnetic particles (size, configuration) & the applied magnet. For effective retaining of magnetic drug carrier, the magnetic forces must be high enough to counteract liner flow rates within the organ or tumour tissue (between 10 & 0.05 cm/s depending on vessel size & branching pattern.) ^16,17,18 Upto eight fold increase in drug concentration in the target tissue after administration of only third of the drug dose has been observed. ^16.

A. Cancer targetting

Magnetism can play very important role in cancer treatment. Non invasive permanent magnetic field for one hour way found to induces lethal effects on several rodent & human cancers ^19. Anticancer drugs reversibly bound to magnetic fluids & could be concentrated in locally advanced tumors by magnetic field that or arranged at tumor surface outside of the subject.

A magnetic fluid has been reported to which the drugs, cytokines & other molecule can be chemically bound to enable those agent to be directed within subject under the influence of high energy magnet. In one of such examples, epidoxorubicin was found to be safe in an experimental human kidney & in xerotransplaned colon carcinona model ^20. Another example include magnetic doxorubicin in liposome, significant articancer effect in nude mice bearing colon cancer ^21.

This method of delivery makes chemotherapy more effective by increasing the drug concentration at the tumor site, while limiting the systemic drug concentration. ^{22, 23, 24, 25, 26.} Anchary et al. had demonstrated capturing & aggregating magnetic microspheres at specific points in the vascular system which enable the access to microvessels which are not accessible by catheter & potentially blocked by magnetic targeting methods. This would be an efficient inexpensive method for creating an embolism to starve tumors, or to seal off arteriovenous malformations ²⁷

B. Magnetic fluid hyperthemia.

Hyperthermia is a promising approach to cancer therapy based on the heating of the target tissue to temperature between 42C & 46°C, thus generally reducing the viability of cancer cells & increasing their sensitivity to chemotherapy & radiation. Magnetic fluid hyperthermia is based on the fact that subdomain magnetic particles produce heat through various kinds of energy losses during application of an external AC magnetic field. If magnetic particles can be accumulated only in the tumor tissue, cancer specific heating is available, various biocompatible magnetic fluids ^28,29,30, cationic magnetoliposomes³¹ and affinity magnetoliposomes ³² have been used for hyperthermia treatment. Local hypothermic system was also found to be useful in tunor-bearing tongue³³.

There also exist the combination therapy which would induce hyperthermia treatment followed by chemotherapy or genetherapy. The approach involves use of magnetic carriers containing a drug to cause hyperthermia using the standard procedure, followed by the release of encapsulated drug that will act on the injured cells. It is anticipated that the combined treatement might be very efficient in treating solid tumor. ^34,35,36,37

C. Improvement of Drug release:

Macromolecules such as peptides have been known to release only at a relatively low rate from a polymer controlled drug delivery system, this low rate of release can be improved by incorporating an electromagnetism triggerring vibration mechanism into the polymeric delivery devices with a hemispheric design, a zero-order drug release profile is achieved. ^38.

D. Other Applications :

Magnetically guided ferrofluid nanoparticles were used in retinal repair. Magnetically guided interstitial diffusion of the nanoparticles upto 20mm of the gel over periods of 72 hours was shown to be possible, thus demonstrating that essentially all points on the retinal surfaces are reachable from elsewere in the ocular interior.³⁹

Magnetic elements have been successfully used in gastrointestinal surgery for tissue fixation. which form hermetic seal after surgery & passibility of the gastrointestinal tract is maintained & the patient can able to eat immediately after operation.⁴⁰

Magnetic force used for gene delivery which results in low vector dose, the reduction in incubation time for transfection/transduction & possibility of gene delivery to otherwise non permissive cells.⁴¹

Apart from their application in drug delivery, magnetism have sound applications in biosciences & biotechnologiges like immobilization, detection of biologically active compound & xenobiotic, detection, isolation & study of cells and cells organelles. These applications are reviewed by Ivo Safarik & Mirka Safarikova ⁴² and Saiyed ZM et al. ^43.

Characterization of Magnetic Particles :

Scanning electron microscopy is used to determine the size & morphology of magnetic nanoparticle whereas Dynamic Light Scattering is used to measure the hydrodynamic diameter⁴⁴ Magnetic mobility(overall responsiveness or amount of velocity for a given magnetic field & field gradient) of different types of magnetic micropheres is characterize so that their behavior in patient circulation can be predicted.For this purpose stationery setup similar to cell tracking velocimetry system which can be used on standard microscope eqiipped with a digital camera& computer system. The main difference to above system is that there is no flow of the suspension containg the magnetic particles. The geometry & size of the set up & magnet used can be reduced considerably. Furtermore the close combination of the microscope set up with computer allows fully automated data acquisition & processing⁴⁵.

Patents

Patent No.6,200,547 assigned to Fex Rx Incorporated (San Diego CA) describes magnetic carrier particles having therapeutic quantities of adsorbed paclitaxel, doxorubicin, Tc⁹⁹, and antisense-C Myc oligonucleotide, an hematoporphyrin derivative, 6-mercaptopurine, Amphotericin B, and Camptothecin have been Magnetic carrier particles having diagnostic quantities of adsorbed Re¹⁸⁶ and Re¹⁸⁸ have also been produced using this invention⁴⁶.

Patent No.6,482,436 assigned to Fex Rx Incorporated (San Diego CA) describes a magnetically controllable, or guided, ferrocarbon particle composition and methods of use and production are disclosed. The composition may optionally carry biologically active substances that have been adsorbed onto the particle. The composition is generally administered in suspension⁴⁷.

Patent No.6,767,635 assigned to Biomedical Apherse system Gabh (Jena : DE) invention relates to magnetic nanoparticles, their production, and their use. The object of the invention is to provide nanoparticles capable of specifically forming bonds to intracellular biomacromolecules even in the intracellular region of cells, so that separation is possible by exposure to an exterior magnetic field. This is accomplished by means of magnetic nanoparticles having biochemical activity, consisting of a magnetic core particle and an envelope layer fixed to the core particle^48.

Conclusion:

Targeted Drug delivery is an effective method to assist the drug molecule to reach preferably to the desired site. The main advantage of this technique is the reduction in the dose & side effects of the drug. The magnetic targeted chemoteraphy has better tumour targeting, therapeutic efficasy & lower toxicity. The use of strong magnetic fields of the ferrfluid may be the factros associated with its limited implementation so by more characterization & long term toxicity study, this will be utilized as an effective targeted drug delivery system.

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Dr. Sawant S. D.^*, Kshirsagar S. J.^*, Paranjpe A.S.

^*STES’sSinhgad Institute of Pharmaceutical Sciences, Kusgaon(BK), Lonavala, Pune, Maharashtra, India.

Corresponding author Kshirsagar S. J. currently working as lecturer in STES’s Sinhgad Institute of Pharmaceutical Sciences, Kusgaon (BK), Lonavala,, Pune, Maharashtra, India. He has two international papers to his credit. Major areas of interest are Formulation Development, which have commercial application, targeted drug delivery system & Buccal drug delivery system. He can be contacted at sanjayjk@rediffmail.com .

Dr. Sawant S. D, Principal of STES Sinhgad Institute of Pharmaceutical
sciences, Phd In Pharmaceutical Sciences, twelve years of academic experince,worked
as Manager in Sanjivani Research centre.He is member of several National &
International Pharmaceuutical Associations.Area of interest is Formulation development,
Herbal Formulations

Paranjpe A. S, Student of Pharmacy at MAEERS Maharashtra Institute
of Pharmacy,Pune.Strong interest of working in Research & Development.