Journal of Surgical Research 95, 200 –206 (2001)

doi:10.1006/jsre.2000.6030, available online at http://www.idealibrary.com on

Clinical Applications of Magnetic Drug Targeting

Andreas S. Lübbe, M.D., Ph.D.,* Christoph Alexiou,† and Christian Bergemann‡
*Cecilien-Klinik, Lindenstrasse 26, 33175 Bad Lippspringe, Germany; †Kinikum rechts der Isar, Ismaningerstrasse 22,
81675 München, Germany; and ‡Bamberger Straße 51, 10777 Berlin, Germany

Submitted for publication April 27, 2000; published online December 13, 2000

reported. Therefore, the development of techniques

Cancer patients often present with localized disease.
Yet, surgical eradication or radiation treatment is not
always possible or meaningful. Site-directed drug tar-
geting is one way of local or regional antitumor treat-
ment. Magnetically controlled drug targeting is one of
the various possibilities of drug targeting. This tech-
nology is based on binding established anticancer
drugs with ferrofluids that concentrate the drug in the
area of interest (tumor site) by means of magnetic
fields. Then, the drug desorbs from the ferrofluid and
enfolds its mechanism of action. This paper gives the
reader an overview of current applications of ferroflu-
ids (magnetic liquids) in conjunction with magnetic
fields as they relate to the latest advances in medical
applications and in particular to anticancer treat-
ment. © 2000 Academic Press
Key Words: drug targeting; magnetism; ferrofluids;
magnetic fields; epirubicin; cancer treatment; regional
cancer treatment.
INTRODUCTION
Cancer is characterized by a reduction or loss of
cellular control and normal maturation mechanisms.
Its features include excessive cell growth, undifferen-
tiated cells and tissues, and the ability to grow into
neighboring tissues and to metastasize. The choice of
treatment includes the total excision of tumor tissue
and possibly part of the adjacent tissues, combination
chemotherapy, immunotherapy, radiation treatment,
and a combination of these. Since complete eradication
of cancer cells is imperative for successful treatment,
total excision is the treatment of choice if applicable.
However, depending on the location and the involve-
ment of the tumor with surrounding tissues, surgery
may not always be possible. Under such circumstances
radio- or chemotherapy becomes necessary. However,
severe complications with these treatments have been
that could selectively deliver drug molecules to the
diseased site, without a concurrent increase in its level
in the healthy tissues of the organism, is currently one
of the most active areas of cancer research. This over-
view focuses on the fundamentals of drug targeting
with particular emphasis on magnetically controlled
anticancer chemotherapy.
DRUG TARGETING
Drug targeting is a principle by which the distribu-
tion of drug in the organism is maneuvered in a man-
ner such that its major fraction interacts exclusively
with the target tissue at the cellular or subcellular
level. Theoretically, selective, or targeted drug delivery
systems can improve the outcome of chemotherapy by
one or more of the following processes:
1. by allowing the maximum fraction of the deliv-
ered drug molecule to react exclusively with the cancer
cells without adverse effects to the normal cells;
2. by allowing preferential distribution of drug to
the cancer cells.
CLASSIFICATION OF DRUG TARGETING
Table 1 [1] presents a list of various classifications of
drug targeting. First-order drug targeting here refers
to the localization of the drug at the capillary bed of the
target site— organ or tissue.
Selective passage of the drug to tumor versus normal
cells within the primary target site qualifies the phe-
nomenon for second-order targeting and, in the intra-
cellular transport of drugs by cell fusion, endocytosis,
or pinocytosis, leads to third-order drug targeting. Im-
plicitly, third-order drug targeting is most difficult to
accomplish and also requires a solution to the chal-
lenges of first- and second-order drug targeting.

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 LÜBBE, ALEXIOU, AND BERGEMANN: MAGNETIC DRUG TARGETING
TABLE 1
Classification of Drug Targeting
Classification I
First-order targeting
Second-order targeting
Third-order targeting
Classification II
Organ targeting
Cellular targeting
Subcellular targeting
Classification III
Passive targeting
Active targeting
Physiochemical targeting
Classification IV
Site-directed targeting
Site-avoidance targeting
Classification V
Biochemical targeting
Biomechanical targeting
Biophysical targeting
Bioadhesive targeting
Classification VI
Carrier-dependent
Carrier-independent
Whereas first-order targeting is determined mainly by
the shapes and sizes as well as the material properties
of a carrier and by its route of administration, second-
and third-order targeting are dependent upon a most
specific interaction among the carrier, the drug, and
the target cell.
Classification two, which categorizes drug targeting
as organ, cellular, and subcellular processes, is ana-
logue to the first-, second-, and third-order processes.
According to classification three, passive drug tar-
geting refers to the natural in vivo deposition of the
drug carrier in the body. This can be accomplished by
controlling the size of the drug, the carrier, and its
route of administration. Active drug targeting requires
guidance of drugs or drug carriers to specific cells in a
manner that differs from its normal disposition in the
organism. The carrier or technique designed for active
targeting must possess characteristics that minimize
drug removal from the normal cells of the body, partic-
ularly the phagocytes of the reticulo– endothelial sys-
tem. A good example of active drug targeting is the
conjugation of drugs to antibodies specific to the target
cell antigen or its delivery by a magnetically responsive
drug carrier.
In classification four, the approaches that involve a
passive, active, or physical– chemical basis of drug de-
livery can be grouped under site-directed drug target-
ing. However, at times the use of a specific approach
may not necessarily favor drug delivery to target cells;
instead, it may reduce drug delivery to the most vul-
nerable normal cells. This technique is considered site-
avoidance drug targeting. Application of liposomes to
201
reduce the cardiotoxicity of doxorubicin is a good ex-
ample of this type of delivery.
Yet another way to classify drug targeting is based
on the transport of carrier across the target tissue
microvasculature. Hence, according to classification
five, biochemical targeting refers to extravascular
transport by specific interaction between target cell
ligands and drug carriers. Biomechanical targeting re-
fers to extravascular drug delivery by the transient
regional opening of endothelial junctions as the result
of osmotic imbalance or anoxia following embolization.
Biophysical targeting refers to the magnetic drag of a
responsive drug carrier through the endothelium or
use of a temperature-sensitive drug carrier with con-
committant regional hyperthermia. Bioadhesive tar-
geting combines biochemical and biophysical effects in
a process, for instance, in which specific binding of the
drug carrier to the endothelium is followed by tran-
sient alteration of the microcirculatory barrier, ulti-
mately leading to the extravascular transfer of the
drug carrier. On the site of drug delivery in the target
tissue, the process may be defined as carrier-dependent
or carrier-independent. In the former, the drug carrier
is taken up by the target cell and drug release occurs
intracellularly; in the latter, the drug release from the
carrier occurs extracellularly. Hence, the drug action
inside the target cells is not influenced by the carrier.
Other forms of drug targeting refer to the natural in
vivo deposition of the drug carrier in the body or cate-
gorize drug targeting at organ, cellular, and subcellu-
lar processes. Finally, the approaches that involve a
passive, active, or physicochemical basis of drug deliv-
ery can be grouped under site-directed drug targeting.
TARGETED DRUG DELIVERY SYSTEMS
IN CANCER CHEMOTHERAPY
Multiple systems and strategies have been investi-
gated to meet the goals of selective delivery of chemo-
therapeutic agents. Some of them have now been tried
in humans. Table 2 [2] gives some examples of various
targeted drug delivery systems that are currently be-
ing investigated.
MAGNETICALLY CONTROLLED DRUG TARGETING
AND PARTICLE SORTING
Magnetic drug targeting allows the concentration of
drugs at a defined target site generally and, impor-
tantly, away from the reticular endothelial system
(RES) with the aid of a magnetic field. Typically, the
intended drug and a suitable magnetically active com-
ponent are formulated into a pharmacologically stable
formulation. Yet very few of those have been used
successfully in animals. Typically, this compound is
injected through the artery supplying the tumor tissue
in the presence of an external magnetic field with suf-
202 JOURNAL OF SURGICAL RESEARCH: VOL. 95, NO. 2, FEBRUARY 2001

TABLE 2
Representative Examples of Various Targeted Drug Delivery Systems Investigated for Cancer Chemotherapy

Delivery system Drugs tested Route of administration Reference

Aqueous media Bleomycin i.t. 3

Tumor necrosis factor i.t. 4
Vinblastine sulfate i.t. 5
w/o/w Emulsion Bleomycin i.t. 3
o/w Emulsion Mitomycin i.t. 6
s/o Emulsion Bleomycin i.t. 7
Liposomes Bleomycin i.t. 8
Cisplatin analogues i.v. 9
Daunorubicin i.a. 10
Doxorubicin i.v. 11
Starch microspheres Carmustin i.a. 12
Fluorouracil i.a. 13
Mitomycin i.a. 14
Doxorubicin i.a. 15
Ethylcellulose microcapsules Cisplatin i.a. 16
Mitomycin i.a. 17
Albumin microspheres Cisplatin i.a. 18
Doxorubicin i.a. 19
Mitomycin i.a. 20
Poly(lactic acid) microspheres Aclarubicin i.a. 21
Polymethacrylate nanoparticles Doxorubicin i.v. 22
Antibodies Vindesine i.v. 23

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
at the target site.
The development of magnetically responsive micro-
spheres 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 mag-
netic fields and—in vivo—to concentrate drugs at an-
atomical sites with restricted access. These possibili-
ties form the basis for well-established biomedical
applications in protein and cell separation. Additional
modifications of the magnetic particles with monoclo-
nal antibodies, lectins, peptides, or hormones make
these applications more efficient and also highly spe-
cific. A combination of these two advantages make the
magnetic microspheres’ application so successful in
molecular and cell biology, advancing both basic sci-
ence and clinical practice [24].
The purification of bone marrow cells from contami-
nation with tumor cells, using so-called immunomag-
netic beads, for example, has become a well-
established routine method in clinical therapy [25].
Newly developed surface modifications of biodegrad-
able magnetic polymer particles resulted in longer cir-
culation times and brought renewed interest in Paul
Ehrlich’s ideas in directed in vivo drug delivery. Their
success depends to a large extent on the construction of
strong magnets, able to produce high magnetic field
gradients at the target sites. Most of the currently
available inhomogeneous fields are only strong enough
for the manipulation of particles against the diffusion
and blood stream velocities found in living systems
over a distance of a few centimeters from the sharp
edge of a magnet pole [26]. In other words, technically,
it is difficult to build up sufficient field strength that
focuses on a small area and is able to counteract the
linear blood-flow rates in the tissue (⬎10 cm/s in ar-
teries and ⬎0.05 cm/s in capillaries), so that to effec-
tively retain the magnetic drug carrier, magnetic forces
must be high enough to reach that goal.
Even with stronger magnets, one important problem
remains and must be overcome. How can we deliver
most of the magnetic carriers to the target area and
avoid normal tissue clearance? The circulation time
(V ⫽ Q: A with V ⫽ velocity, Q ⫽ flow, A ⫽ area of
conduit) depends reciprocally on the particle size,
whereas the magnetic susceptibility of the individual
particle is directly proportional to the particle size.
Magnetic susceptibility expresses the ability of an ap-
plied field to magnetize specific quantity of material. It
may be described qualitatively, such as diamagnetic
susceptibility, which is very weak, or ferromagnetic
susceptibility, which is very strong. It can also be mea-
sured quantitatively, as molar-magnetic susceptibility,
atomic magnetic susceptibility, and volume magnetic
susceptibility, which indicates the magnet ability of a
material per unit molecular weight, per unit atomic
weight, and per unit volume, respectively.
The presence of matter in the electric and magnetic
fields modifies the field fluxes at a given field strength.
The electric and magnetic properties of matter are
 LÜBBE, ALEXIOU, AND BERGEMANN: MAGNETIC DRUG TARGETING
defined by induced polarizations (P and M), respec-
tively, which determine how much the electric and
magnetic flux densities change at a given point with
the introduction of matter in the neighborhood of this
point. In isotopic media the polarization vectors (E, H)
are parallel to the corresponding field vectors: P ⫽ X e
Y OE and M ⫽ X mH, where X e and X m are electric and
magnetic susceptibilities, respectively, characteristic
of the material. Size and magnetic properties must
therefore be optimized carefully to decrease the unspe-
cific RES uptake and to prolong the circulation time in
the human organism. This will provide a maximum
time span for the extraction and concentration of the
magnetic particles in the target area.
Intense efforts are also ongoing in the development
of biocompatible magnetic carriers for the directed
transport and controlled release of drugs or radionu-
clides for use as sources of local temperature increase
(hyperthermia) and for local contrast enhancement in
MR imaging [27]. Recently, the principle of magnetic
manipulation has been applied to concentrating mag-
netic drug carriers in definite regions, provided that
the carriers can be transported to the target site. In a
series of papers, Kato et al. [28] published investiga-
tions into selective cancer chemotherapy, in which fer-
romagnetic mitomycin microcapsules (about 300 ␮m
diameter) were magnetically guided to tumor sites of
experimental animals. The particles could be manipu-
lated by fields of about 56 kA/m. Yet those experiments
possessed certain methodological problems (kA/m:
magnetic moment (M) in Gauss (CGS) ⫽ cm– gram–
second system equals ampere (A)–meter 2 according to
the SI (MKS ⫽ System International (meter–
kilogram–second system)).
Inada et al. [29] performed in vitro investigations of
localized fibrinolysis by magnetically concentrating
urokinase–magnetide complexes. So-called TMs (ther-
mosensitive magnetoliposomes) have also been pre-
pared and were investigated in an in vitro flow system.
The TMs with a diameter of about 1 ␮m could be
concentrated in relatively high field strengths. It was
possible to release a specific part of the content from
the particles (calcein) by increasing the temperature
above 40°C [30].
Pulfer and Gallo reported in vitro studies of target-
ing magnetic microspheres to brain tumors by an alloy
of iron [31]. Carbon was prepared by Allen et al. and
was used as a carrier (0.5–2 ␮m) for the antitumor
agent paclitacel for head and neck cancers. The desorp-
tion sustained over more than 24 h, and by magnetic
fields of several hundred kA/m the carriers could be
retained within capillaries [32]. The combination of
magnetic carriers with the radioisotope Y-90 was in-
vestigated by Häfeli et al., who prepared magnetic
microspheres out of poly-lactic acid with diameters
between 20 and 30 ␮m. The particles were loaded with
203
Y-90 by a simple mechanical stirring process and im-
mediately were injected into the cavities or the spines
of mice and rats [33].
Goodwin et al. have demonstrated that so-called
magnetic targeted carriers (MTC) could be targeted
and retained at a region of interest in a swine model
after intraarterial infusion [34]. MTCs did not redis-
tribute after removal of the magnetic field. Histopatho-
logic results demonstrated a high particle density in
the area of the magnetic field. Particles were observed
in the interstitium and occasionally intraarterially. Al-
though MTCs were formed in a high-energy grinding
process in which activated carbon was incorporated
into metallic iron powder to produce microparticle com-
posits with a 75:25 FE:C ratio, the resulting particles
ranged from 0.5 to approximately 5 ␮m and therefore
could only be administered intraarterially [35]. These
experiments showed that this technology works and
demonstrated proof of the principle for currently ongo-
ing clinical trials in patients with hepatocellular car-
cinoma.
FIRST CLINICAL EXPERIMENTS WITH MAGNETICALLY
CONTROLLED DRUG TARGETING
Epirubicin is a well-known antibiotic antracyclin
that has a wide range of application for the treatment
of solid tumors [36]. Also, a chemically slightly differ-
ent substance (doxorubicin) has been used frequently
in animal experiments, so that comparative analyses
were possible. The first clinical experiments in human
patients with magnetic drug targeting worldwide were
reported by Lübbe et al. We used a ferrofluid (particle
size 100 nm) to which the drug epirubicine was chem-
ically bound [36]. In brief, special starch polymers coat
the magnetic particles together with anionic endstand-
ing phophate groups so that a cationic binding to the
positively charged amino sugars of epirubicin was pos-
sible. This was a worldwide unique approach and al-
lowed for a reversible ionic binding of the drug, such
that certain physiological parameters (osmolality, pH,
temperature) affected desorption (of the drug from the
particle in the tumor tissue) characteristics. The fer-
rofluid was concentrated in the target regions by
means of properly arranged permanent magnets,
which provided a field strength of 0.8 T in tumors
located near the body surface.
Those clinical experiments in 14 patients with ad-
vanced solid tumors resulted from animal experiences
that, for the first time, documented tolerance and effi-
cacy by methods that included microcirculatory obser-
vations in mice as well as in rats [38].
Two forms of therapy with a magnetic fluid have
been tested in these preclinical experiments: tumor
treatment by mechanical occlusion with a ferrofluid in
high concentrations and magnetically controlled drug
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
of those animal experiments, in which no LD50 could
be found for the ferrofluid, no clinical intolerances or
major laboratory derangements with the epirubicin-
bound ferrofluid have been demonstrated. The efficacy
of the treatment was documented by complete tumor
responses in a xenotransplanted human kidney as well
as in a colon carcinoma. Hence, the way for the first
clinical experiments was opened.
Phase I/II clinical trial. Magnetically controlled
drug targeting was used in patients with advanced and
unsuccessfully pretreated cancers or sarcomas. Nine of
these patients received two treatment courses, three
patients received one course, and two patients received
three courses of magnetically controlled drug target-
ing. The treatment protocol consisted of the intrave-
nous infusion of epirubicin in increasing doses (from 5
to 100 mg/m 2) that had been chemically bound to the
magnetic fluid and one course of conventional systemic
chemotherapy with the same dose of epirubicin 3
weeks later. Conventional chemotherapy was the rapid
infusion of epirubicin into a peripheral vein. Epirubicin
was given to the patient in liquid form after the lyo-
phylized powder had been diluted with isotonic saline
solution. No magnetic fluid or magnetic field was ap-
plied. In the treatment group in which magnetic drug
targeting was performed, after the preparation of the
magnetic epirubicin (0.5% of the estimated blood vol-
ume) the substance was infused over 15 min into a vein
located contralaterally to the tumor. During the time of
infusion and at least for the next 45 min, a magnetic
field was built up as close as possible to the tumor.
High-energy permanent magnets were used in this
patient trial. The magnets consisted of rare earths, the
majority being neodymium. There were large (8 ⫻ 4 ⫻
2 cm) and small (3 ⫻ 3 ⫻ 1 cm) blocks, and these blocks
could be arranged according to the individually shaped
tumor of the patient. Magnetic field strengths of at
least 0.5 T and in general 0.8 T could be reached and
were confirmed at the patient’s bed. The distance be-
tween the tumor surface and the magnets was assured
to be less than 0.5 cm. The intravenous injection dif-
fered from most of the other working groups’ intraar-
terial application. Obvious advantages (easy access)
had to be balanced against a potentially higher RES
clearance and the necessity of high-energy magnetic
fields. Furthermore, the desorption time of the coupled
day had to take into account the intravascular avail-
ability and other physiologic parameters.
The application of magnetic fields to the tumors
lasted for 60 to 120 min. Magnetic drug targeting was
clinically well tolerated and was verified based on mag-
netic resonance imaging techniques, pharmacokinet-
ics, and the histological as well as clinical detection of
magnetites. It was shown that the ferrofluid could be
successfully directed to the tumors in about half of the
patients. Organ toxicity did not increase with the treat-
ment but some epirubicin-associated toxicity appeared
at doses greater than 50 mg/m 2. Although treatment
with magnetically controlled drug targeting seemed
safe, it was concluded that improvements are neces-
sary to make it more effective by increasing ferrofluid
particle size and to make it more independent of pa-
tient or disease-related problems [39].
Physiological as well as pharmacological parameters
in magnetically controlled drug targeting warrant fur-
ther investigation. This is because the efficacy of in
vivo drug targeting with ferrofluids critically depends
on physiological parameters. To understand this new
form of pharmacological application as well as the
mechanism of action of the concentrated drug in the
tissue at the microcirculatory level one must consider
not only the ferrofluids’ parameters (particle size, sur-
face characteristics of the particle, concentration of the
fluid, volume of the fluid, reversibility and strength of
the drug/ferrofluid binding, desorption characteris-
tics), but also access to the organism (infusion route/
duration/rate of the injection/infusion time), geometry
and strength of the magnetic field, and duration of the
magnetic field application. Physiological parameters of
the patient’s organism comprise size, weight, and body
surface, blood volume, cardiac output and systemic
vascular resistance, circulation time, tumor volume
and location, and vascular content of the tumor as well
as tumor blood flow. Physiological parameters vary
with the size and species of the animal. Thus, data
cannot be easily transferred from animals to humans
and adaptation of ferrofluid/drug and magnetic field
characteristics is necessary [40].
Most critical for the efficacy of magnetically con-
trolled drug targeting are the intravascular bioavail-
ability of the ferrofluid, its susceptibility (strength to
be recruited by the magnetic field and, hence, to be
concentrated in the tumor), and the in vivo desorption
time of the drug. For this reason, a second clinical trial
in head and neck cancer patients is underway in which
the optimal particle size and form of application will be
identified for further use in humans. Further animal
experiments have supported the concept recently. VX-2
squamous cell carcinomas have been successfully
heated in the ear region of rabbits by different locore-
gional regiments. If subsequent trials demonstrate ef-
ficacy of the treatment, only then could new and
innovative antitumor strategies such as palliative
treatment regiments and adjuvant scenarios be envi-
sioned. Possible alternative treatment modalities could
be the substitution of locoregional radiation treatment
after breast-conserving surgery by chemotherapy with
magnetically controlled drug targeting. If systemic
chemotherapy is found necessary, then drug targeting
can be administered in parallel since no major systemic
adverse effects from the latter should occur. Further-
 LÜBBE, ALEXIOU, AND BERGEMANN: MAGNETIC DRUG TARGETING
more, successful drug targeting with ferrofluids could
utilize expensive drugs, those with a short half-life or a
high toxicity. Thus, new innovative or otherwise inad-
equate therapeutic substances might find a new area of
applicability.
OTHER CLINICAL APPLICATIONS OF MAGNETIC
DRUG TARGETING
Are there applications other than tumor therapy for
magnetically controlled drug targeting? It has been
shown that cytokines could be concentrated in tumors
and also that cytokine-induced killer cells were direct-
able within mice and rats using a different ferrofluid
family [41]. This and the fact that other drugs such as
antibiotics, thrombolytic agents, and others can be
bound reversibly to the ferrofluid particles suggest that
such fields of therapy are in the room of possibility.
Specifically, as long as unwanted side effects and in-
sufficient local concentrations are limiting factors in
the administration of biologically active substances
such as cytokines, growth factors, DNA sequences, ge-
netically manipulated cells, or cell substances, the
therapeutic efficacy of magnetically targeted cytokine-
induced natural killer cells needs further investiga-
tion.
Recently, by using increasing concentrations of
DEAE nanoparticles, magnetically generated gene
transfer, i.e., the transfection of cells or bacteria to
produce pharmacological biological products, has
gained much interest. Gene therapeutic measures for
the treatment of noncurable diseases will play a major
role in the future. The feasibility of using magnetic
transfections of cytokine-induced killer cells with plas-
mid DNA was found to be possible and opens up inter-
esting perspectives with regard to an industrial exploi-
tation of genetically modified bacteria.
REFERENCES
1. Hofmann, M. A., Pursa, J. J., and Swash, D. F. Annual varia-
tions in the vasopressin neuron population of the human supra-
chiasmatic nucleus. Neuroscience 53: 1003, 1993.
2. Schilsky, R. L., Milano, G. A., and Ratain, M. J. Principles of
Antineoplastic Drug Development and Pharmacology. New
York: Dekker, 1996.
3. Wielgus-Serafinska, E., Plwka, A., and Ksminski, M. Circadian
variation of mitrochondrial succinic dehydrogenase and micro-
somal cytochrome P-450 dependent monooxygenase activity in
the liver of sexually immature and mature rats. J. Physiol.
Pharmacol. 44: 55, 1993.
4. Badwe, R. A., Gregory, W. M., and Chaudary, M. A., et al.
Timing of surgery during menstrual cycle and survival of pre-
menopausal women with operable breast cancer. Lancet 25:
1261, 1991.
5. Senie, R., Rosen, P., and Rhodes, P., et al. Timing of breast
cancer excision during the menstrual cycle influences duration
of disease-free survival. Ann. Intern. Med. 115: 337, 1991.
205
6. Bruguerolle, B. Circadian phase dependent pharmacokinetics
of disopyramide. Chronobiol. Int. 1: 267, 1984.
7. Ratajczak, H. V., Sothern, R. B., and Hrushesky, W. J. M.
Estrous influence on surgical cure of a mouse breast cancer. J.
Exp. Med. 168: 88, 1988.
8. Meyer, K. Season and cycle: Variation in presentation and
response to therapy in premenopausal breast cancer. In 77th
Annual Clinical Congress, Oct. 21–24, Chicago, IL, 1991.
9. Waterhouse, J. M., and Minors, D. S. Temporal aspects of renal
drug elimination. In B. Lemmer, (Ed.), Chronopharmacology:
Cellular and Biochemical Interactions. New York: Dekker,
1989. Pp. 35–50.
10. Smaaland, R., Svardal, A. M., and Lote, K., et al. Glutathione
content in human bone marrow and circadian stage relation to
DNA synthesis. J. Natl. Cancer Inst. 83: 1092, 1991.
11. Reinberg, A., and Smolensky, M. H. Circadian changes of drug
disposition in man. Clin. Pharmacokinet. 7: 401, 1982.
12. Conroy, R. T. W. L., and Mills, J. N. Human Circadian
Rhythms. London: Churchill, 1970.
13. Portaluppi, F., and Vergnani, L. Atrial natriuretic peptide and
circadian blood pressure regulation: Clues from a chronobio-
logic approach. Chronobiology 10: 176, 1993.
14. Hrushesky, W. J. M., Levi, F., and Halberg, F., et al. Circadian
stage dependence of cis-diammine-dichloroplatinum lethal tox-
icity in rats. Cancer Res. 42: 945, 1982.
15. Scheving, L. E., Tsai, T. S., and Feuers, R. J., et al. Cellular
mechanisms involved in the action of anticancer drugs. In B.
Lemmer (Ed.), Chronopharmacology: Cellular and Biochemical
Interactions. New York: Dekker, 1989. Pp. 317–369.
16. Killmann, S. A., Cronkite, E. P., and Fliedner, T. M., et al.
Mitotic indices of human bone marrow cells. I. Number and
cytologic distribution of mitosis. Blood 19: 743, 1962.
17. Laerum, O. D., Sletvold, O., and Riise, T. Circadian and circan-
nual variation of the cell cycle distribution in the mouse bone
marrow. Chronobiol. Int. 5: 19, 1988.
18. Smaaland, R., Lote, K., and Sothern, R., et al. DNA synthesis
and ploidy in non-Hodkin’s lymphomas demonstrate variation
depending on the circadian stage of cell sampling. Cancer Res.
53: 3129, 1993.
19. Parker, W. B., and Cheng, Y. C. Metabolism and mechanism of
action of 5-fluorouracil. Pharmacol. Ther. 48: 381, 1990.
20. Moore, R. Y., and Speh, J. C. GABA is the principal neuro-
transmitter of the circadian system. Neurosci. Lett. 150: 112,
1992.
21. Daher, G. C., Harris, B. E., and Diasio, R. B. Metabolism of
pyrimidine analogues and their nucleosides. Pharmacol. Ther.
48: 129, 1990.
22. el Kouni, M. H., Naguib, F. N. M., and Park, K. S., et al.
Circadian rythm of hepatic uridine phosphorylase activity and
plasma concentration of uridine in mice. Biochem. Pharmacol.
40: 2479, 1990.
23. von Roemeling, R., Mormont, M. C., and Walker, K., et al.
Cancer control depends upon the circadian shape of continuous
FUDR infusion. Proc. Am. Assoc. Cancer Res. 28: A1293, 1987.
24. Sieben, S., Bergemann, C., Lübbe, A., Brockmann, B., and
Reischeleit, D. Comparison of different particles and methods
for magnetic isolation of circulating tumor cells. J. Magn.
Magn. Mater. (in press).
25. Singh, M., Ferdous, A. J., and Branham, M. Trends in drug
targeting for cancer treatment. Drug Delivery 3: 289, 1996.
26. Seyei, A., Widder, K., and Czerlinski, G. Magnetic guidance of
drug carrying microspheres. J. Appl. Phys. 49: 3578, 1978.
27. Jordan, A., Wust, P., Scholz, R., Tesche, B., Fähling, H., Mitro-
vics, T., Vogl, T., Cervós-Navarro, J., and Felix, R. Cellular
206 JOURNAL OF SURGICAL RESEARCH: VOL. 95, NO. 2, FEBRUARY 2001
uptake of magnetic fluid particles and their effects on human
adenocarcinoma cells exposed to AC magnetic fields in vitro.
Int. Hypertherm. 12: 705, 1996.
28. Kato, T., Nemoto, R., Mori, H., Unno, K., Goto, A., and Homma,
M. An approach to magnetically controlled cancer chemother-
apy. J. Jpn. Soc. Cancer Ther. 15: 876, 1980.
29. Inada, Y., Ohwada, K., Yoshimoto, T., Kojima, T., Takahashi,
K., Kodera, Y., Matsushima, A., and Saito, Y. Fibrinolysis by
urokinase endowed with magnetic property. Biochem. Biophys.
Res. Commun. 148: 392, 1987.
30. Viroonchaptan, E., Ueno, M., Sato, H., Adachi, I., Nagae, H.,
Tazawa, K., and Horikoshi, I. Preparation and characterization
of dextran magnetite-incorporated thermosensitive liposomes:
An on-line flow system for quantifying magnetic responsive-
ness. Pharmaceut. Res. 12: 1176, 1995.
31. Pulfer, S. K., and Gallo, J. M. Targeting magnetic microsheres
to brain tumors. In U. Häfeli, W. Schütt, J. Teller, and M.
Zborowski (Eds.), Scientific and Clinical Applications of Mag-
netic Carriers, New York: Plenum Press, 1997. Pp. 445– 455.
32. Allen, L. M., Kent, J. W., Wolfe, C., Ficco, C., and Johnson, J.
MTC MT: A magnetically targetable drug carrier for paclitaxel.
In U. Häfeli, W. Schütt, J. Teller, and M. Zborowski (Eds.),
Scientific and Clinical Applications of Magnetic Carriers, New
York: Plenum Press, 1997. Pp. 481– 494.
33. Häfeli, U. O., Pauer, G. J., Roberts, W. K., Humm, J. L., and
Macklis, R. M. Magnetically targeted microspheres for intra-
cavitary and intraspinal 90Y radiotherapy. In U. Häfeli, W.
Schütt, J. Teller, and M. Zborowski (Eds.), Scientific and Clin-
ical Applications of Magnetic Carriers, New York: Plenum
Press, 1997. Pp. 501–516.
34. Goodwin, S., Peterson, C., Hoh, C., and Bittner, C. Targeting
and retention of magnetic targeted carriers (MTCs) enhancing
intra-arterial chemotherapy. J. Magn. Magn. Mater. 194: 132,
1999.
35. Fabry, B., Maksym, G. N., Hubmayr, R. D., Butler, J. P., and
Fredberg, J. J. Implications of heterogeneous bead behavior on
cell mechanical properties measured with magnetic twisting
cytometry. J. Magn. Magn. Mater. 194: 120, 1999.
36. Bonadonna, G., Gianni, L., Santoro, A., Bonfante, V., Bidoli, P.,
Casali, P., Demichelis, R., and Valagussa, P. Drugs ten years
later: Epirubicin. Ann. Oncol. 4: 359, 1993.
37. Lübbe, A. S., Bergemann, C., Riess, H., Schriever, F.,
Reichardt, P., Possinger, K., Matthias, M., Dörken, B., Herr-
mann, F., Gürtler, R., Hohenberger, P., Haas, N., Sohr, R.,
Sander, B., Lemke, A.-J., Ohlendorf, D., Huhnt, W., and Huhn,
D. Clinical experiences with magnetic drug targeting: A phase
I study with 4⬘-epidoxorubicin in 14 patients with advanced
solid tumors. Cancer Res. 56: 4686, 1996.
38. Lübbe, A. S., Bergemann, C., Huhnt, W., Fricke, T., Riess, H.,
Brock, J. W., and Huhn, D. Preclinical experiences with mag-
netic drug targeting: Tolerance and efficacy. Cancer Res. 56:
4694, 1996.
39. Lübbe, A. S., and Bergemann, C. Magnetically-controlled drug
targeting. Cancer J. 11(3), 1998.
40. Lübbe, A. S., Bergemann, C., Brock, J., and McClure, D. G.
Physiological aspects in magnetic drug-targeting. J. Magn.
Magn. Mater. 194: 149, 1999.
41. Alexiou, C., Arnold, W., Klein, R., Parak, F. G., Hulin, P.,
Bergemann, C., Erhardt, W., Wagenpfeil, S., and Lübbe, A. S.
Locoregional cancer treatment with “Magnetic Drug Target-
ing.” Cancer Res., (in press).
42. Bergemann, C., Müller-Schulte, D., Oster, J., à Brassard, and
Lübbe, A. S. Magnetic ion-exchange nano- and microparticles
for medical, biochemical and molecular biological applications.
J. Magn. Magn. Mater. 194: 45, 1999.