Magnetic Microcarriers : A Novel Approach For Targeted Drug Delivery

Swarnlata Saraf

There has been keen interest in the development of a novel drug delivery system. Novel drug delivery system aims to deliver the drug at a rate directed by the needs of the body during the period of treatment, and target the active entity to the site of action.

A number of novel drug delivery systems have emerged encompassing various routes of administration, to achieve controlled and targeted drug delivery, magnetic microcarriers being one of them. These microcarriers include magnetic microspheres, magnetic liposomes, magnetic nanoparticles, magnetic resealed erythrocytes, magnetic emulsion etc. Magnetic micro/nanoparticles & molecular magnetic labels have been used for great number of application in various areas of biosciences, targeted drug delivery, imaging & in bioseparation technology. This review paper will discuss about mechanism of magnetic targeted drug delivery, benefits and drawbacks of magnetic targeting, magnetic carriers, and application of magnetism in targeted drug delivery and some other field.

Introduction:

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. Various nonmagnetic microcarries (nanoparticles, microspheres and microparticles etc.) are successfully utilized for drug targeting but they show poor site specificity and are rapidly cleared off by RES (reticuloendothelial system) under normal circumstances. Magnetism play an important role in these case, magnetic particles composed of magnetite which are well tolerated by the body, magnetic fields are believed to be harmless to biological systems and adaptable to any part of the body¹. Up to 60% of an injected dose can be deposited and released in a controlled manner in selected nonreticuloendothelial organs. So magnetic microcarriers were developed to overcome two major problems encountered in drug targeting namely RES clearance and target site specificity². Magnetism has application in numerous fields like diagnostics, drug targeting, molecular biology, cell isolation, cell purification, hyperthermia, and radioimmunoassay. This article discusses the potential applications of magnet in drug targeting, magnet containing particles & mechanism of targeted drug delivery by magnetism.

Magnetic Drug Targeting: Mechanism

Magnetic drug delivery by particulate carriers is a very efficient method of delivering a drug to localized disease site. 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 takes place within area to which the magnetic field is applied & often augmented by magnetic agglomeration. The accumulation of the carrier at the target site allows 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 helps to extravasate the magnetic carrier into the targeted area. Very high concentration of chemotherapeutic agents can be achieved near the target site without any toxic effect to normal surrounding tissue or to whole body. It is thus possible to replace large amounts of drug targeted magnetically to localized disease site, reaching effective and up to several fold increased drug levels³.

Benefits And Drawbacks:

Magnetic microcarriers are site specific and by localization of these microcarriers in the target area, the problem of their rapid clearance by RES is also surmounted. Linear blood velocity in capillaries is 300 times less i.e.0.05cm/sec as compared to arteries, so much smaller magnetic field, 6-8 Koe, is sufficient to retain them in the capillary network of the target area. Other benefits includes avoidance of acute toxicity directed against endothelium and normal parenchyma cell, controlled release within target tissue for intervals of 30 minutes to  30 hrs. as desired, adaptable to any part of body. This drug delivery system reduces circulating concentration of free drug by a factor of 100 or more. Magnetic carrier technology appears to be a significant alternative for the bimolecular malformation (i.e. composition, inactivation or deformation). In case of tumor targeting, microsphere can internalize by tumor cells due to its much increased phagocytic activity as compared to normal cells. So the problem of drug resistance due to inability of drugs to be transported across the cell membrane can be surmounted.

Apart from these benefits, this novel approach suffers from certain drawbacks i.e. drug can not be targeted to deep seated organs in the body, so this approach is confined to the targeting of drugs in superficial tissue only like skin, superficial tumor or to joints only. Magnetic targeting is an expensive, technical approach and requires specialized manufacturer and quality controlled system. The magnet must have relatively constant gradients in order to avoid local overdosing with toxic drugs. It needs specialized magnet for targeting, advanced technique for monitoring, and trained personnel to perform the procedure. A large fraction (40-60%) of the magnetite, which is entrapped in carriers, is deposited permanently in target tissues. Due to this limitation magnetic drug targeting is likely to be approved only for very severe diseases that are refractory to other approaches².

Magnetic Carriers:

A) Magnetic microspheres :

Magnetic microspheres are supramolecular particles that are small enough to circulate through capillaries without producing embolic occlusion (<4 μm) but are sufficiently susceptible (ferromagnetic) to be captured in microvessels and dragged in to the adjacent tissues by magnetic fields of 0.5-0.8 tesla (T)². Magnetic microspheres were prepared by mainly two methods namely phase separation emulsion polymerization (PSEP) and continuous solvent evaporation (CSE). The amount and rate of drug delivery via magnetic responsive microspheres can be regulated by varying size of microspheres, drug content , magnetite content , hydration state and drug release characteristic of carrier⁴. the amount of drug and magnetite content of microspheres needs to be delicately balanced in order to design an efficient therapeutic system. magnetic microsphere are characterized for different attributes such as particle size analysis including size distribution ,surface topography, and texture etc. using scanning electron microscopy (SEM), drug entrapment efficiency, percent magnetite content, and in vitro magnetic responsiveness and drug release.

Targeting by magnetic microspheres  i.e. incorporation of magnetic particles in to drug carriers (polymers) and using an externally applied magnetic field is one way to physically direct this magnetic drug carriers to a desired site, Widder et al. first reported on the use of magnetic albumin microspheres.Widder et al. also shows that in the presence of a suitable magnetic field, the microspheres are internalized by the endothelial cells of  target tissues in healthy as well as tumor bearing animals⁵. Gupta and Hung suggests that in presence of  magnetic field, the microspheres demonstrated 16 fold increase in the maximum drug concentration, 6 fold increase in drug exposure and 6 fold increase in the drug targeting efficiency to rat tail target segments⁶. Morimoto and Natsume studied the utilization of magnetic microparticulate system for cancer therapy by formulating a novel cationic delivery system based on magnetic aminodextran microspheres (MADM) and compared with the neutral magnetic dextran microspheres (MDM) ⁷. The magnetic microspheres were effectively used for drug targeting to tumor cells, cell separation, diagnosis of disease and magnetic targeting of radioactivity².

B)Magnetic liposomes:

Liposomes are simple microscopic vesicles in which lipid bilayer structures are present with an aqueous volume entirely enclosed by a membrane, composed of lipid molecule. There are a number of components present in liposomes, with phospholipids and cholesterol being the main ingredients but in case of magneto liposomes magnetite is one of the component of the liposomes⁸. Generally these are magnetic carrier which can be prepared by entrapment of Ferro fluid within core of liposomes ^{9, 10}. 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 phospholipids¹¹. Alternatively magnetoliposomes are prepared using the phospholipid vesicle as a nanoreactor for the in situ precipitation of magnetic nanoparticles¹². Vesicles are also prepared containing didodecyl methyl ammonium bromide; contain an ionic magnetic fluid^13. These magnetoliposomes were effectively used for site specific targeting, cell sorting & as magnetic resonance contrast enhancing agent. Thermo sensitive magnetioliposomes can release the entrapped drug after selective heating caused by the electromagnetic fields^14. Magnetofluorescent liposomes were used for increasing sensitivity of immunofluorescence.

The magneto liposomes are characterized for their physical attributes i.e. size, shape, and size distribution, surface charge, percent capture, percent magnetite content, entrapped volume lamellarity through freeze fracture microscopy and P-NMR, phase behavior drug release, quantitative determination of phospholipids and cholesterol analysis⁸.

Various researches have been carried out on magnetoliposomes. The finding of Margolis et al. demonstrates utilization of magnetoliposomes in cellular sorting¹⁵. The feasibility of magnetic liposomes as a targeting device in tumor cell was explored by Kiwada et al¹⁶. The preparation, physicochemical properties and their possible use as a targeting carrier have been described by Ishii et al¹⁷. The possibility of dextran magnetite incorporated thermosensitive liposomes was studied by Mausko et al¹⁸. Antibody coated magnetoliposomes for hyperthermia treatment of cancer were prepared by coating phospholipid on to magnetic particles were studied by Shinkai et al¹⁹. Chen and Langer prepared magnetically responsive polymerized liposomes as potential oral delivery vehicles for complex molecules such as protein and peptide to protect them from gastrointestinal environment and targeting them to the payer’s patches²⁰.

C) Magnetic nanoparticles:

Magnetic nanoparticles are particles in nano size range containing polymers, drug along with ferromagnetic particles (magnetite). In recent years the separation of cells, viruses, and bio-molecules using magnetic microparticles has gained increasing popularity. Hence, new technologies using magnetic microparticles or nanoparticles are emerging. With magnetic separation, it is possible to achieve very high efficiency of separation in complex media. Other applications of magnetic particles include immunoassays, drug targeting, drug transporting, and biosensing²¹.

Magnetic colloidal iron oxide nanoparticles were prepared with the method of coprecipitation²². Ferromagnetic iron-dextran nanoparticles were prepared by reacting a mixture of ferrous chloride and ferric chloride with dextran polymers under alkaline condition. Interfacial polymerization was also applied to synthesize magnetic nanoparticles²³. Pedro Trataj et al. review article described synthetic routes for the preparation of magnetic nonoparticles useful for biomedical applications²⁴.Bacterial magnetite nanoparticles obtained from magneto tactic 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 modified²⁵.Vyas and Malaiya were prepared indomethacin bearing magnetic nanoparticles of polymethylmethacrylate by the emulsion polymerization technique²⁶. Surface modification of super paramagnetic nanoparticles (Ferro fluid) with particle electrophoresis and their application in the specific targeting of cells was studied by sestier et al²⁷.

D)Magnetic Resealed Erythrocytes:

Resealed erythrocytes have various advantages  as drug carriers such as it is biodegradable, biocompatible, large quantity of variety of material can be encapsulated within small volume of cell and can be utilized for organ targeting etc. Due to these advantages of resealed erythrocytes, magnetic resealed erythrocytes came in to existence which contains ferrofluides (magnetite) along with loaded drugs within the cell. Magnetically responsive ibuprofen-loaded erythrocytes were prepared and characterized in vitro by Vyas and Jain²⁸. The erythrocytes loaded with ibuprofen and magnetite (ferrofluids) using the preswell technique. The loaded cell effectively responded to an external magnetic field. Various process variables including drug concentration, magnetite concentration, sonication of ferrofluids that could affect the loading of drugs and magnetite were studied. The loaded erythrocytes were characterized for in vitro drug efflux, hemoglobin release, morphology osmotic fragility, in vitro magnetic responsiveness and percent cell recovery. In the continuous study, diclofenac sodium bearing erythrocytes were prepared by preswell technique and characterized for various in vitro parameters²⁹.Local thrombosis in animal arteries was prevented by means of magnetic targeting of aspirin loaded red cell was studied by Orekhova et al³⁰.

E)Magnetic Emulsion:

Besides magnetic modulated systems, like microcapsules/microspheres 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 external magnetic field to specific target site²⁹.Akimoto and Morimoto prepared magnetic emulsion by utilizing ethyl oleate based magnetic fluid as the dispersed phase, casein solution as the continuous phase and anticancer agent, methyl CCNU trapped in the oily dispersed phase as active chemotherapeutic agent. Magnetic emulsion appears to have potential in conferring site specificity to certain chemotherapeutic agent³¹.

Application:

Magnetic drug delivery system have many application in various fields but out of these drug targeting utilizing magnetic micro carriers is very important. Some of the application of magnetically guided drug targeting especially tumor targeting along with some other application utilizing magnetic micro carriers has been summarized here.

1)Magnetic drug targeting: Tumor targeting:

Magnetic drug targeting allows the concentration of drugs at a defined target site generally and importantly, away from the reticular endothelial system (RES) with the aid of a magnetic field. Site-directed drug targeting is one way of local or regional antitumor treatment. The drug & an appropriate Ferro fluid 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 retentions of the magnetic drug carrier at the target site alleviate or delay the RES clearance & facilitates extra vascular uptake. For effective retaining of magnetic drug carrier, the magnetic forces must be high enough to counteract liner flow rates within the organ or tumor tissue (between 10 & 0.05 cm/s depending on vessel size & branching pattern ^{32, 33, 34}. There is increase in drug concentration in the target tissue after administration of the drug dose has been observed³².The efficiency of chemotherapy treatment may be enhanced to a great extent by magnetically assisted delivery of cytotoxic agent to the specific site. There are a large number of magnetic carrier systems which demonstrates increasing drug concentration efficiency at the tumor site³⁵.

Magnetism can play very important role in cancer treatment. The first clinical cancer therapy trials using magnetic microspheres were performed by Lubbe et al. in Germany for the treatment of advanced solid tumor while current preclinical research is investigating use of magnetic particles loaded with different chemotherapeutic drugs such as mitoxantrone, paclitaxel. Non invasive permanent magnetic field for one hour way found to induces lethal effects on several rodent & human cancers^36. 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.

In case of brain tumors, the therapeutic ineffectiveness of chemotherapy is mainly due to the impervious nature of the blood-brain barrier (BBB), presence of drug resistance and lack of tumor selectivity. Various novel biodegradable magnetic drug carriers are synthesized and their targeting to brain tumor is evaluated in vitro and in animal models. New cationic magnetic aminodextran micro spheres (MADM) have been synthesized. Its potentiality for drug targeting to brain tumor was studied. this particles were retained in brain tissue over a longer period of time³⁵.

A magnetic fluid has been reported to which the drugs, cytokines & other molecule can be chemically bound to enable that agent to be directed within subject under the influence of high energy magnet. In one of such examples magnetic doxorubicin in liposome, significant anticancer effect in nude mice bearing colon cancer ³⁷.

2) Magnetic bioseparation:

Bioseparation is an important phenomenon for the success of several biological processes. Therefore, prospective bioseparation techniques are increasingly gaining importance. Amongst the different bioseparation techniques, magnetic separation is the most promising. The development of magnetically responsive microspheres has brought an additional driving force into play. Particles that are bound to magnetic fluids can be used to remove cells and molecules by applying magnetic fields and-in vivo-to concentrate drugs at anatomical sites with restricted access. These possibilities form the basis for well-established biomedical applications in protein and cell separation. Additional modifications of the magnetic particles with monoclonal antibodies, lectins, peptides, or hormones make these applications more efficient and also highly specific³.

The isolation of various macro molecules such as enzymes, enzyme inhibitors, DNA, RNA, antibodies and antigens etc. from different sources including nutrient media, fermentation broth, tissues extracts and body fluids, has been done by using magnetic absorbents. In case of enzyme separation, the appropriate affinity ligands are immobilized on polymer coated magnetic carrier or magnetizable particles^{38, 39}. Immobilized protein A or protein G on silanized magnetite and fine magnetotactic bacteria can be used for isolation and purification of IgG⁴⁰.  Monosized super paramagnetic particles, Dynabeads, have been used in isolation of mRNA, genomic DNA and proteins⁴¹.

3)Magnetically induced Hyperthermia for treatment of cancer:

Heat treatment of organs or tissues, such that the temperature is increased to 42–46 C and the viability of cancerous cells reduces, is known as hyperthermia. It is based on the fact that tumor cells are more sensitive to temperature than normal cells. In hyperthermia it is essential to establish a heat delivery system, such that the tumor cells are heated up or inactivated while the surrounding tissues (normal) are unaffected.

a)Intracellular hyperthermia:The alternative approach is to use fine particles as heat mediators instead of needles or rods such that hyperthermia becomes noninvasive. When fluids containing submicron-sized magnetic particles(typically 1–100nm) are injected, These particles are easily incorporated into the cells, since their diameters are in the nanometer range. These magnetic particles selectively heat up tissues by coupling AC magnetic field to targeted magnetic nano particles. As a result, the whole tumor can be heated up uniformly This is called intracellular hyperthermia. It has been shown that malignant cells take up nine times more magnetic nano particles than normal cells. Therefore the heat generated in malignant cells is more than in normal cells. Also, as blood supply in the cancerous tissues is not normal, the heat dissipation is much slower. Hence, the temperature rise in the region of tumor is higher than in the surrounding normal tissues. It is therefore expected that this therapy is much more concentrated and localized⁴².

b) Magnetic fluid hyperthermia (MFH):Magnetic fluids can be defined as fluids, consisting of ultramicroscopic particles. (~100Å) of magnetic oxide. Magnetic fluid hyperthermia is based on the fact that sub domain 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^43,44,45. Cationic magnetoliposomes⁴⁶ and affinity magnetoliposomes⁴⁷ have been used for hyperthermia treatment.

c) Combination therapy: There also exists the combination therapy which would induce hyperthermia treatment followed by chemotherapy or gene therapy. A combination of chemotherapy or radiation therapy with hyperthermia is found much more effective than hyperthermia itself. 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 treatment might be very efficient in treating solid tumor^48,49,50,51. Several reasons are given for the enhanced effect. Tumors are poorly vascularised and it can be hard for therapeutic agents to reach their target. Heat increases the perfusion of a tumor and therefore drugs are transported more effectively into the target tissues. In addition, heat makes blood vessels more permeable to drugs. This occurs preferentially in tumors where blood vessels tend to be structurally incomplete. On the other hand, normal blood vessels are surrounded by a basement membrane and other perivascular cells and not significantly affected by heat. It has recently been reported that hyperthermia increases the rate of liposome leakage into tumors by a factor of 2–5 depending on the type of tumor. In normal tissues however, enhancement of liposome leakage is not reported⁴².

4) Magnetic control of pharmacokinetic parameter rand Improvement of Drug release:

Langer et al.embedded magnetite or iron beads in to a drug filled polymer matrix and then showed that they could activate or increase the release of drug from the polymer by moving a magnet over it or by applying an oscillating magnetic field (Langer et al.,1980; Edelman and Langer,1993 ).The microenvironment with in the polymer seemed to have shaken the matrix or produced ‘micro cracks’ and thus made the influx of liquid, dissolution and efflux of drug possible  thereby achieving magnetically controlled 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 triggering vibration mechanism into the polymeric delivery devices with a hemispheric design; a zero-order drug release profile is achieved⁵².

5)Magnetic targeting of radioactivity:

Magnetic targeting can also be used to deliver the therapeutic radioisotopes (Hafely, 2001).the advantage of these method over external beam therapy is that the dose can be increased, resulting in improved tumor cell eradication, without harm to adjacent normal tissues. Magnetic targeted carriers, which are more magnetically responsive iron carbon particles, have been radiolabelled in last couple of years with isotopes such as ¹⁸⁸Re (Hafely et al., 2001), ⁹⁰Y, ¹¹¹In, and ¹²⁵I (Johnson et al. 2002) and are currently undergoing animal trials.

6) Miscellaneous Applications:

The most important application of magnetic particles is as contrast agent for magnetic resonance imaging in diagnosis of diseases. The most commonly used super paramagnetic material is Fe₃O₄ with different coatings such as dextrans, polymers, and silicone. Supramagnetic iron oxide (SPIO) it has been mainly used as a liver-specific contrast agent for intravenous application. It may also be used for detection of metastases in non-enlarged lymph nodes⁴².

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 operation⁵³. Magnetically guided ferrofluid nanoparticles were used in retinal repair. Magnetically guided interstitial diffusion of the nanoparticles up to 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 elsewhere in the ocular interior⁵⁴.

Apart from their application in drug delivery, magnetism have sound applications in biosciences & biotechnologies like immobilization, detection of biologically active compound & xenobiotic, detection, isolation & study of cells and cells organelles. These applications are reviewed by Ivo Safarik & Mirka Safarikova⁵⁵ and Saiyed ZM et al⁵⁶.

Conclusion: 

Magnetic Vesicular systems have been realized as extremely useful carrier systems in various scientific domains. Over the years, magnetic microcarriers have been investigated for targeted drug delivery especially magnetic targeted chemotherapy due to their better tumor targeting, therapeutic efficacy, lower toxicity and flexibility to be tailored for varied desirable purposes. In spite of certain drawbacks, such as strong magnetic field requires for the ferrofluid and deposition of magnetite the magnetic microcarriers still play an important role in the selective targeting, and the controlled delivery of various drugs. It is a challenging area for future research in the drug targeting so more researches, long term toxicity study, and characterization will ensure the improvement of magnetic drug delivery system. The future holds lot of promises in magnetic microcarriers and by further study this will be developed as novel and efficient approach for  targeted drug delivery system.

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About Authors:

Dr.(Mrs.)Swarnlata Saraf has nearly 14 years of research and teaching experience. She is a leading scientist and well-known in the field of herbal cosmetics. Mrs. Saraf did her doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. She has over 40 publications to her credit published in international and national journals. She is an active member of IPA, APTI and ISTE. Her research interest extends from Herbal Cosmetics to transdermal drug delivery (especially Iontophoresis), New Drug Delivery Systems for biological and therapeutic agents. She has Co-authored 1 book on cosmeceuticals. Presently, She is working as a Reader at Institute of Pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.) INDIA.

* For correspondence

Dr. (Mrs.) Swarnlata Saraf , Reader, Institute of Pharmacy , Pt. Ravishankar Shukla University, Raipur (C. G.) - 492010

e-mail- swarnlata_saraf@rediffmail. com

Prof.S.Saraf has nearly 17 years of research and teaching experience at both U.G. and P.G. levels. He is a leading scientist and well-known academician . Prof. Saraf did his doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. under the supervision of Prof. V. K. Dixit, a renowned Pharmacognosist. He has over 50 research publications to his credit published in international and national journals. He has delivered invited lectures and chaired many sessions in several National Conferences and Symposia in India. His research interest extends from Herbal Cosmetics to Herbal drug standardization Modern analytical techniques, New Drug Delivery Systems with biotechnology bias. He has authored 1 books. Presently, he is Professor and Director Institute of pharmacy and Dean, Faculty of Technology, Pt. Ravishankar Shukla University, Raipur , (C.G.).

Gyanil Kumar Sahu

M. Pharm 2 sem (pharmaceutics), Institute of pharmacy, pt. Ravishankar shukla University, Raipur, Chhattisgarh.