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Clinical Applications of Magnetic Drug Targeting
Clinical Applications of Magnetic Drug Targeting
Clinical Applications of Magnetic Drug Targeting
Submitted for publication April 27, 2000; published online December 13, 2000
TABLE 2
Representative Examples of Various Targeted Drug Delivery Systems Investigated for Cancer Chemotherapy
Note. i.t., intratumoral; i.v., intravenous; i.a., intraarterial; w/o/w, water-in-oil-in-water; o/w, oil-in-water; s/o, sphere-in-oil.
ficient field strength and gradient to retain the carrier and blood stream velocities found in living systems
at the target site. over a distance of a few centimeters from the sharp
The development of magnetically responsive micro- edge of a magnet pole [26]. In other words, technically,
spheres has brought an additional driving force into it is difficult to build up sufficient field strength that
play. Particles that are bound to magnetic fluids can be focuses on a small area and is able to counteract the
used to remove cells and molecules by applying mag- linear blood-flow rates in the tissue (⬎10 cm/s in ar-
netic fields and—in vivo—to concentrate drugs at an- teries and ⬎0.05 cm/s in capillaries), so that to effec-
atomical sites with restricted access. These possibili- tively retain the magnetic drug carrier, magnetic forces
ties form the basis for well-established biomedical must be high enough to reach that goal.
applications in protein and cell separation. Additional Even with stronger magnets, one important problem
modifications of the magnetic particles with monoclo- remains and must be overcome. How can we deliver
nal antibodies, lectins, peptides, or hormones make most of the magnetic carriers to the target area and
these applications more efficient and also highly spe- avoid normal tissue clearance? The circulation time
cific. A combination of these two advantages make the (V ⫽ Q: A with V ⫽ velocity, Q ⫽ flow, A ⫽ area of
magnetic microspheres’ application so successful in conduit) depends reciprocally on the particle size,
molecular and cell biology, advancing both basic sci- whereas the magnetic susceptibility of the individual
ence and clinical practice [24]. particle is directly proportional to the particle size.
The purification of bone marrow cells from contami- Magnetic susceptibility expresses the ability of an ap-
nation with tumor cells, using so-called immunomag- plied field to magnetize specific quantity of material. It
netic beads, for example, has become a well- may be described qualitatively, such as diamagnetic
established routine method in clinical therapy [25]. susceptibility, which is very weak, or ferromagnetic
Newly developed surface modifications of biodegrad- susceptibility, which is very strong. It can also be mea-
able magnetic polymer particles resulted in longer cir- sured quantitatively, as molar-magnetic susceptibility,
culation times and brought renewed interest in Paul atomic magnetic susceptibility, and volume magnetic
Ehrlich’s ideas in directed in vivo drug delivery. Their susceptibility, which indicates the magnet ability of a
success depends to a large extent on the construction of material per unit molecular weight, per unit atomic
strong magnets, able to produce high magnetic field weight, and per unit volume, respectively.
gradients at the target sites. Most of the currently The presence of matter in the electric and magnetic
available inhomogeneous fields are only strong enough fields modifies the field fluxes at a given field strength.
for the manipulation of particles against the diffusion The electric and magnetic properties of matter are
LÜBBE, ALEXIOU, AND BERGEMANN: MAGNETIC DRUG TARGETING 203
defined by induced polarizations (P and M), respec- Y-90 by a simple mechanical stirring process and im-
tively, which determine how much the electric and mediately were injected into the cavities or the spines
magnetic flux densities change at a given point with of mice and rats [33].
the introduction of matter in the neighborhood of this Goodwin et al. have demonstrated that so-called
point. In isotopic media the polarization vectors (E, H) magnetic targeted carriers (MTC) could be targeted
are parallel to the corresponding field vectors: P ⫽ X e and retained at a region of interest in a swine model
Y OE and M ⫽ X mH, where X e and X m are electric and after intraarterial infusion [34]. MTCs did not redis-
magnetic susceptibilities, respectively, characteristic tribute after removal of the magnetic field. Histopatho-
of the material. Size and magnetic properties must logic results demonstrated a high particle density in
therefore be optimized carefully to decrease the unspe- the area of the magnetic field. Particles were observed
cific RES uptake and to prolong the circulation time in in the interstitium and occasionally intraarterially. Al-
the human organism. This will provide a maximum though MTCs were formed in a high-energy grinding
time span for the extraction and concentration of the process in which activated carbon was incorporated
magnetic particles in the target area. into metallic iron powder to produce microparticle com-
Intense efforts are also ongoing in the development posits with a 75:25 FE:C ratio, the resulting particles
of biocompatible magnetic carriers for the directed ranged from 0.5 to approximately 5 m and therefore
transport and controlled release of drugs or radionu- could only be administered intraarterially [35]. These
clides for use as sources of local temperature increase experiments showed that this technology works and
(hyperthermia) and for local contrast enhancement in demonstrated proof of the principle for currently ongo-
MR imaging [27]. Recently, the principle of magnetic ing clinical trials in patients with hepatocellular car-
manipulation has been applied to concentrating mag- cinoma.
netic drug carriers in definite regions, provided that
FIRST CLINICAL EXPERIMENTS WITH MAGNETICALLY
the carriers can be transported to the target site. In a
CONTROLLED DRUG TARGETING
series of papers, Kato et al. [28] published investiga-
tions into selective cancer chemotherapy, in which fer-
Epirubicin is a well-known antibiotic antracyclin
romagnetic mitomycin microcapsules (about 300 m
that has a wide range of application for the treatment
diameter) were magnetically guided to tumor sites of
of solid tumors [36]. Also, a chemically slightly differ-
experimental animals. The particles could be manipu-
ent substance (doxorubicin) has been used frequently
lated by fields of about 56 kA/m. Yet those experiments
in animal experiments, so that comparative analyses
possessed certain methodological problems (kA/m: were possible. The first clinical experiments in human
magnetic moment (M) in Gauss (CGS) ⫽ cm– gram– patients with magnetic drug targeting worldwide were
second system equals ampere (A)–meter 2 according to reported by Lübbe et al. We used a ferrofluid (particle
the SI (MKS ⫽ System International (meter– size 100 nm) to which the drug epirubicine was chem-
kilogram–second system)). ically bound [36]. In brief, special starch polymers coat
Inada et al. [29] performed in vitro investigations of the magnetic particles together with anionic endstand-
localized fibrinolysis by magnetically concentrating ing phophate groups so that a cationic binding to the
urokinase–magnetide complexes. So-called TMs (ther- positively charged amino sugars of epirubicin was pos-
mosensitive magnetoliposomes) have also been pre- sible. This was a worldwide unique approach and al-
pared and were investigated in an in vitro flow system. lowed for a reversible ionic binding of the drug, such
The TMs with a diameter of about 1 m could be that certain physiological parameters (osmolality, pH,
concentrated in relatively high field strengths. It was temperature) affected desorption (of the drug from the
possible to release a specific part of the content from particle in the tumor tissue) characteristics. The fer-
the particles (calcein) by increasing the temperature rofluid was concentrated in the target regions by
above 40°C [30]. means of properly arranged permanent magnets,
Pulfer and Gallo reported in vitro studies of target- which provided a field strength of 0.8 T in tumors
ing magnetic microspheres to brain tumors by an alloy located near the body surface.
of iron [31]. Carbon was prepared by Allen et al. and Those clinical experiments in 14 patients with ad-
was used as a carrier (0.5–2 m) for the antitumor vanced solid tumors resulted from animal experiences
agent paclitacel for head and neck cancers. The desorp- that, for the first time, documented tolerance and effi-
tion sustained over more than 24 h, and by magnetic cacy by methods that included microcirculatory obser-
fields of several hundred kA/m the carriers could be vations in mice as well as in rats [38].
retained within capillaries [32]. The combination of Two forms of therapy with a magnetic fluid have
magnetic carriers with the radioisotope Y-90 was in- been tested in these preclinical experiments: tumor
vestigated by Häfeli et al., who prepared magnetic treatment by mechanical occlusion with a ferrofluid in
microspheres out of poly-lactic acid with diameters high concentrations and magnetically controlled drug
between 20 and 30 m. The particles were loaded with targeting using small amounts of ferrofluid as a vehicle
204 JOURNAL OF SURGICAL RESEARCH: VOL. 95, NO. 2, FEBRUARY 2001
to concentrate epirubicin locally in tumors. As a result patients. Organ toxicity did not increase with the treat-
of those animal experiments, in which no LD50 could ment but some epirubicin-associated toxicity appeared
be found for the ferrofluid, no clinical intolerances or at doses greater than 50 mg/m 2. Although treatment
major laboratory derangements with the epirubicin- with magnetically controlled drug targeting seemed
bound ferrofluid have been demonstrated. The efficacy safe, it was concluded that improvements are neces-
of the treatment was documented by complete tumor sary to make it more effective by increasing ferrofluid
responses in a xenotransplanted human kidney as well particle size and to make it more independent of pa-
as in a colon carcinoma. Hence, the way for the first tient or disease-related problems [39].
clinical experiments was opened. Physiological as well as pharmacological parameters
Phase I/II clinical trial. Magnetically controlled in magnetically controlled drug targeting warrant fur-
drug targeting was used in patients with advanced and ther investigation. This is because the efficacy of in
unsuccessfully pretreated cancers or sarcomas. Nine of vivo drug targeting with ferrofluids critically depends
these patients received two treatment courses, three on physiological parameters. To understand this new
patients received one course, and two patients received form of pharmacological application as well as the
three courses of magnetically controlled drug target- mechanism of action of the concentrated drug in the
ing. The treatment protocol consisted of the intrave- tissue at the microcirculatory level one must consider
nous infusion of epirubicin in increasing doses (from 5 not only the ferrofluids’ parameters (particle size, sur-
to 100 mg/m 2) that had been chemically bound to the face characteristics of the particle, concentration of the
magnetic fluid and one course of conventional systemic fluid, volume of the fluid, reversibility and strength of
chemotherapy with the same dose of epirubicin 3 the drug/ferrofluid binding, desorption characteris-
weeks later. Conventional chemotherapy was the rapid tics), but also access to the organism (infusion route/
infusion of epirubicin into a peripheral vein. Epirubicin duration/rate of the injection/infusion time), geometry
was given to the patient in liquid form after the lyo- and strength of the magnetic field, and duration of the
phylized powder had been diluted with isotonic saline magnetic field application. Physiological parameters of
solution. No magnetic fluid or magnetic field was ap- the patient’s organism comprise size, weight, and body
plied. In the treatment group in which magnetic drug surface, blood volume, cardiac output and systemic
targeting was performed, after the preparation of the vascular resistance, circulation time, tumor volume
magnetic epirubicin (0.5% of the estimated blood vol- and location, and vascular content of the tumor as well
ume) the substance was infused over 15 min into a vein as tumor blood flow. Physiological parameters vary
located contralaterally to the tumor. During the time of with the size and species of the animal. Thus, data
infusion and at least for the next 45 min, a magnetic cannot be easily transferred from animals to humans
field was built up as close as possible to the tumor. and adaptation of ferrofluid/drug and magnetic field
High-energy permanent magnets were used in this characteristics is necessary [40].
patient trial. The magnets consisted of rare earths, the Most critical for the efficacy of magnetically con-
majority being neodymium. There were large (8 ⫻ 4 ⫻ trolled drug targeting are the intravascular bioavail-
2 cm) and small (3 ⫻ 3 ⫻ 1 cm) blocks, and these blocks ability of the ferrofluid, its susceptibility (strength to
could be arranged according to the individually shaped be recruited by the magnetic field and, hence, to be
tumor of the patient. Magnetic field strengths of at concentrated in the tumor), and the in vivo desorption
least 0.5 T and in general 0.8 T could be reached and time of the drug. For this reason, a second clinical trial
were confirmed at the patient’s bed. The distance be- in head and neck cancer patients is underway in which
tween the tumor surface and the magnets was assured the optimal particle size and form of application will be
to be less than 0.5 cm. The intravenous injection dif- identified for further use in humans. Further animal
fered from most of the other working groups’ intraar- experiments have supported the concept recently. VX-2
terial application. Obvious advantages (easy access) squamous cell carcinomas have been successfully
had to be balanced against a potentially higher RES heated in the ear region of rabbits by different locore-
clearance and the necessity of high-energy magnetic gional regiments. If subsequent trials demonstrate ef-
fields. Furthermore, the desorption time of the coupled ficacy of the treatment, only then could new and
day had to take into account the intravascular avail- innovative antitumor strategies such as palliative
ability and other physiologic parameters. treatment regiments and adjuvant scenarios be envi-
The application of magnetic fields to the tumors sioned. Possible alternative treatment modalities could
lasted for 60 to 120 min. Magnetic drug targeting was be the substitution of locoregional radiation treatment
clinically well tolerated and was verified based on mag- after breast-conserving surgery by chemotherapy with
netic resonance imaging techniques, pharmacokinet- magnetically controlled drug targeting. If systemic
ics, and the histological as well as clinical detection of chemotherapy is found necessary, then drug targeting
magnetites. It was shown that the ferrofluid could be can be administered in parallel since no major systemic
successfully directed to the tumors in about half of the adverse effects from the latter should occur. Further-
LÜBBE, ALEXIOU, AND BERGEMANN: MAGNETIC DRUG TARGETING 205
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