Magnetically Targeted Drug Delivery System

Chapter 1: Overview

Introduction

Tissue grafts and transplants tend to get rejected by the body, and are also prone to higher rates of infection than other tissues of the human body. Thus the patient must take immunosuppressant drugs as well as drugs that treat infections, which end up in both the tissues they are targeted for and the rest of the body. Unfortunately, many drugs that treat infections also kill innocent cells of the body, such as antibiotics damage on leukocytes (white blood cells) as well as the harmful effects of immunosuppressant drugs on the immune system. These drugs can leave the patient prone to further infection and disease, thus the drugs can end up causing as much harm as the initial infection. Furthermore, cancer and tumor medications have harmful effects on the rest of the body, and even though many of them may have higher affinity for the targeted tissue they end up in nearly the same dosages in the rest of the body since their specified tissue affinities are usually low. The Purpose of this thesis is to discuss alternative ways of delivering medication directly to the targeted tissue or organ and isolate it there. Thus having only minimal-to-none dosage throughout the rest of the body leading to minimal side effects.

If a magnetic field can be set up internally by the use of external magnets it may maintain high concentrations of magnetically labeled particles (which will carry medication) within the assigned part of the body at high concentrations while the rest of the body should have zero to very low concentrations. The system to be discussed is based on ferromagnetic particles that absorb medication and are attracted to magnetized coils, which will be inserted in the required area prior to treatment. The inserted coils will be magnetized by the use of externally applied magnetic fields, which will allow for magnetically targeted drug delivery. Thereafter, different types of ferromagnetic nano particles will be presented and categorized based on their usefulness. The nano particles usefulness is based on their affinity for drug absorption, toxicity, magnetic capability, and ease with which they can be removed from the body once treatment is complete. Secondly, the types of magnetic coils will be discussed; how the coils can be inserted, how they work, their toxicity, and removal mechanisms will be reviewed. Lastly, the factors of the magnetic field required to make this technique work will be examined; factors such as strength required to keep the particles in the specified tissue, side effects the field may cause, and whether these magnets can be made portable to be used by a patient outside the hospital. Once all the issues have been identified and dealt with a conclusion will be made presenting the best nano-particle, magnetic coil, and magnet-setup to be used, in order to create a delivery system with the least side effects and most therapeutic treatment.

This thesis will concentrate on delivering medication to the heart and the main topic being heart valve replacement. This topic is chosen because the heart will have the most extraneous conditions to theoretically test a drug delivery system due to the high pressure as well as blood velocity the ferromagnetic particles would experience. Thus if the system is modeled to the harsh conditions within the heart it should theoretically work throughout the rest of the body.

Parameters

The ferromagnetic particles must be able to withstand the blood flow within the heart, which means that once they are near the induced magnetic field they do not leave the heart. However, during the procedure ferromagnetic nano-particles must be able to be absorbed by the heart tissue and not buildup on the magnetized material leading to blockages or clots. Thus the average blood pressure and velocity must be thoroughly considered.

Blood Pressure

The heart pressure ranges from 120 systolic and 80 diastolic as measured by a blood pressure cuff and auscultation of the Median Cubital artery. However, blood velocity is a bit tougher to calculate since a lot of factors must be considered. The heart is comprised of four chambers; two atriums receive blood from the body and the lungs, whichthey relay to the right and left ventricles. The right ventricle pumps deoxygenated blood in to the lungs, and the left ventricle, which we will be considering here, pumps oxygenated blood through the aorta to the rest of the body. In order to figure out the blood velocity one must consider the work the heart does using W=ΔPV. It is safe to assume that the average blood pressure is the same within the heart as it pumps blood at 120mmHg. However there is residual pressure left over in the ventricle, due to the ventricle not collapsing, which is 9mmHg. Thus the actual average blood pressure within the left ventricle is 120-9=111mmHg minus diastolic 80mmHg in order to get ΔP= 111-80=31mmHg, which is density x gravity x height= 13570 kg/m3 x 9.8m/s2 x 0.031mHg= 4123pa of pressure.

Blood Velocity

The average blood volume pumped out of the left ventricle in to the aorta is 80 cm3 =8x10^-5 m3 in one ventricular pump. This signifies that the heart does W=ΔPV=4123pa x 8x10^-5m3= 0.33jules (Pe) of work. This relays in to an average 72 beats per minute and thus 1.2 beats per second. Taking the beats and multiplying them by the volume pumped gives us the volume velocity of blood: 1.2 beat/s x 8 x 10^-5m = 96cm3/s. Since the average aorta radius is 1.25 cm we can use Bernoulli's equation to get the actual velocity density x V2 / 2 = Pressure, hence 4123pa x 2 / 1060 = roughly 3m/s. This can be checked with an energy calculation 1/2 x m x V2= Jules (potential energy), V= sqrt(Pe x 2/(density x volume) =V=sqrt.((0.33 x 2)/ (1060 x 8x10^-5) = about 3 m/s. The actual measured blood flow varies and averages at 4 m/s. For theoretical purposes we will take the average of the two and use 3.5 m/s as the blood velocity.

Friction

Friction with the aortic and ventricular walls, laminar blood flow, and turbulent blood flow, which all lower the velocity of the expelled blood, however these factors do not need to be considered for the heart since this is where the speed originates and thus the speed is not changed within the heart due to these factors. This velocity may seem small compared to our everyday understanding of speed, however within the heart, acting on particles on the nano (x10^-9) scale it ends up being a large force to overcome. Heart wall friction is negligible for the purposes of the procedure discussed because the particles are small and we can theoretically state that their volume is zero. Furthermore the ratio of particles per blood volume is also extremely small and thus does not change the total blood volume or composition. Thus no meaningful friction should be noted for the ferromagnetic nano-particles.

Treatment Topic

Mitral valve replacements will be the topic of discussion throughout this thesis. There are two main types of valve replacements biological tissue grafts and mechanical. Biological valves are made from pulmonary autographs or Porcine valves which come from a pig and are the choice of valve for elderly people because the are organic and do not require anticoagulants. However, they may require immunosuppressant in order to avoid having the valve attacked, and deterred by CT-Killer cells (a specific type of white blood cell). The porcine valve also has a short life span of about 10-15 years in elder people who are less active; in retrospect the porcine valve’s lifespan for younger, more active individuals is much less then the elderly and thus requires replacements. The mechanical valve is the prominent choice for younger individuals because it is more durable and has a lifespan of a few hundred years. The mechanical valve requires only one surgery, but it also requires anti coagulants such as warfarin for the reason that a mechanical valve is prone to inducing clot formations that can lead to an embolus or thrombus (blood clots) and can lead to a myocardial infarction and subsequently death. Both types of valves are also prone to infection and thus the patients are initially required to take antibiotics for an extended period of time. All these drugs induce side effects in the rest of the body and can lower the entire immune system and consequently lead to further infections. If the medication required in both of the valve types can be delivered only to the heart and maintained there then there would be no side effects, or only minimal for the rest of the body. The drugs can be maintained at high concentrations by absorbing them on to ferromagnetic nanoparticles and inducing the particle-drug combination to remain in the heart by having them be attracted to a magnetized coil (or a specific stationary ferromagnetic substance). The stationary ferromagnetic substance can be magnetized by a magnetic field applied externally to the body.

Chapter 2: Ferromagnetic Particles

Nano-Particle Types

There are a few different kinds of magnetic nano-particles that currently exist. However, only a few of them are useful for this research due to the specific nature of the magnetic interaction that is required. The nano-particle must be ferromagnetic within a magnetic field, this means that it must have a dipole and thus the particle must be influenced by the magnetic or electric field. There are two major groups of magnetic particles: superperamagnetic(magnetite -Fe3O4 core)is a particle with sporadic dipole moment which fluctuates within the particle core, and a ferromagnetic (gamma Fe2O3 core) particle has distinct magnetic dipoles which do not fluctuate. The superperamagnetic particle has a dipole under normal conditions with no fields (fig.1). [1] However it has no macroscopic dipole when within a magnetic field (Fig. 2), the cores alight in such a way that the field cancels out the charges. Thus the superperamagnetic particle is not influenced by external magnetic fields in the way this treatment requires it to; that is the particle is unable to be attracted or deflected by the magnetic or electric fields due to the temporary loss of magnetic properties. However, the ferromagnetic particle maintains its magnetism and dipole charges during both the magnetic and electric fields (fig 2 & 3). Thus the ferromagnetic particle is the particle of choice for this experiment; ferromagnetic particles are able to be attracted by a magnetic or electric fields.

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Fig. 3 Ferromagnetic particles under the influence of an external magnetic field. [2] Chemicell.

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Fig. 4 Ferromagnetic particles in absence of an external magnetic field, lattice form. [2] Chemicell.

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Fig. 1Superparamagnetic particles under the influence of an external magnetic field. [2] Chemicell.

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Fig. 2Superparamagnetic particles in absence of an external magnetic field, monodisperse particle distribution. [2] Chemicell.

Ferromagnetic particles can be made with gamma Fe2O3 core, cobalt ferrite CoFe2O4or manganese ferrite MnFe2O4 . The nano-particle consists of two main parts: a solid core such as cobalt ferrite and a hydrodynamic outer surface to which the medication gets absorbed on. The nano-particles can also be encapsulated in a biodegradable/digestive capsule for time-released purposes or magnetic activation. Encapsulated nano-particle (fig. 7) is roughly the same diameter as the free-hydrodynamic shell but is solid and thus more durable as well as can be made to withstand harsher environments than the blood stream such as the digestive tract, liver, kidney, etc. [2] Free-hydrodynamic nano-particles are directly absorbed in to the tissue, however the solid-hydrodynamic nano-particles must first be digested or broken-down in order to be absorbed, thus they are able to last longer in the body as compared to the latter.

illustration not visible in this excerpt[2] Chemicell.

The hydrodynamic outer surface varies and is selected according to the medication type that the particle is set to deliver. The surface types have a wide range, however, the main idea behind the bonding remains within a small scope; most of the hydrodynamic endings are either oxygen an-ions or a nitrogen cat-ions, with the only variables being side groups or holding chains in order to facilitate better medicinal molecule binding. The oxygen an-ion is usually seen as part of a carboxylic acid (fig. 5.1) or a phosphoric acid functional group (fig. 5.2). On the other hand the nitrogen cat-ion is either neutral (since nitrogen is able to bind with an electro-negative functional group) or with a positive charge as part of a carbon chain (fig. 6). [3]

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Fig. 6 Hydrodynamic shell with an amine functional group. [2] Chemicell.

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Fig. 5.1 Hydrodynamic shell with a carboxylic acid – oxygen an-ion functional group. [2] Chemicell.

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Fig. 5.2 hydrodynamic shell with a phosphoric acid – oxygen an-ion functional group. [2] Chemicell.

Making Nano-Particles

The focus will be on cobalt ferrite CoFe2O4 . Ferric chloride of at least 98% purity must be used along with sodium hydroxide as the main reagents. Surfactant must also be used to reduce the surface tension as well as improve the over all dispersion of reacting particles because the original reagents have a tendency to clump together. Mix-in two parts Iron chloride and one part cobalt chloride with double distilled, de-ionized water. Use double distilled, de-ionized water in order to avoid impurities. The mixing of the reagents should be produced by a magnetic stirrer whereby a magnet is moved around in the proximity of the contents mixing the iron chloride with the rest of the reagents. The mixing should commence until a pH level of 11-12 is reached at this point the surfactant consisting of oleic acid should be added. Once the surfactant is added the temperature of the reaction should be raised to 80oC for an hour while continuing to stir. A precipitate will form, at this time the mixture must be washed twice with distilled water and then with ethanol. The washing steps will remove impurities as well as access oleic acid from the solution. Then, the solution should be centrifuged at 3000 rpm for fifteen minutes, the access liquid should be removed and the thick black precipitate leftover. The precipitate should be left to dry for 12 hours at 100oC then grinded in order to produce a fine powder consisting of CoFe2O4 . At this point the CoFe2O4 is still impure because it contains up to 10% water by weight and should be further dried at 600oC for 10 hours. The final product will be pure CoFe2O4 with an inverse spinel structure. [4]