LubbeAlexiouBergemann_MagnetDrugTargeting_JSR2001

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Clinical Applications of Magnetic Drug Targeting

Andrea s S. Lu bbe, M.D., P h.D .,* Ch ristoph Alexiou, a nd Ch ristia n B ergeman n

*Cecil ien-Kl in ik , L in denstrasse 26, 33175 Bad L ippsprin ge, Germ any; Kinikum rechts der Isar, Ismaningerstrasse 22,8167 5 M u nch en, G er m an y; an d Ba m ber ger Str ae 51, 10777 B er l i n, G er ma ny

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

Cancer patients often present with localized disease.Yet, surgical eradication or radiation treatment is notalways possible or meaningful. Site-directed drug tar-geting is one way of local or regional antitumor treat-ment. Magnetically controlled drug targeting is one ofthe various possibilities of drug targeting. This tech-

nology is based on binding established anticancerdrugs with ferrofluids that concentratethedrug in thearea of interest (tumor site) by means of magneticfields. Then, the drug desorbs from the ferrofluid andenfolds its mechanism of action. This paper gives thereader an overview of current applications of ferroflu-ds (magnetic liquids) in conjunction with magnetic

fields as they relate to the latest advances in medicalapplications and in particular to anticancer treat-ment. 2000 Academic Press

K ey W o r d s : drug targeting; magnetism; ferrofluids;magnetic fields;epirubicin;cancer treatment;regionalcancer treatment.

INTRODUCTION

C a nce r i s char a ct e r iz ed b y a r ed u ct i on or l os s ofcellular control and normal maturation mechanisms.Its features include excessive cell growth, undifferen-i at e d ce l l s and t i s s u e s , and t he ab i l i t y t o g r o w i nt o

neighboring tissues and to metastasize. The choice ofreatment includes the total excision of tumor t issue

a nd possibly pa rt of t he a djacent t issues, combinat ionche mot he r ap y , i mmu not he r ap y , r ad i at i on t r e at me nt ,a nd a combina tion of these. Since complete eradicat ionof cancer cells is imperative for successful treatment,ota l excision is t he treat ment of choice i f a pplicable.

However, depending on the location and the involve-ment of the tumor with surrounding t issues, surgerymay not always be possible. Under such circumstancesradio- or chemotherapy becomes necessary. However,severe complicat ions with these tr eatm ents ha ve been

reported. Therefore, the development of techntha t could selectively deliver drug molecules tdiseased site, wit hout a concurrent increa se in itsin the healthy tissues of the organism, is currentlof the most active areas of cancer research. This v i e w f o cu s e s o n t he f u nd ame nt al s o f d r u g t ar gwith particular emphasis on magnetically contr

an tica ncer chemothera py.

DRUG TARGETING

Drug targeting is a principle by which the distt ion of drug in the organism is maneuvered in a ner such that i ts major fraction interacts excluswi t h t he t ar g e t t i s s u e at t he ce l l u l ar o r s u b ce llevel. Theoretica lly, selective, or ta rget ed drug d elsystems can improve the outcome of chemotheraone or more of the following processes:

1 . b y a l l o wi ng t he max i mu m f r act i o n o f t he dered drug m olecule to rea ct exclusively w ith th e ccells without adverse effects to the normal cells;

2. by al lowing preferential distribution of drth e can cer cells.

CLASSIFICATION OF DRUG TARGETING

Ta ble 1 [1] present s a list of va rious cla ssifi cat iodrug targeting. First-order drug targeting here rto the localizat ion of th e drug at th e ca pillar y bed target si teorgan or t issue.

Selective passa ge of the drug t o tum or versus nocells within the primary target si te qualifies thenomenon for second-order t a rgeting a nd, in the icellular transport of drugs by cell fusion, endocyor pinocytosis, leads to third-order drug targetingplici t ly , th ird-order drug ta rgeting is most diffi caccomp li sh and al s o r e q u ir es a s ol ut i on t o t he le ng es of fi r s t - a n d s econ d -or d er d r ug t a r g e

J ournal of Surgical Research 95, 200206 (2001)

doi:10.1006/jsre.2000.6030, av aila ble online a t ht tp://w ww .idealib ra ry.com on

2000022-4804/00 $35.00Copyright 2000 by Academic PressAll rights of reproduction in any form reserved.


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Whereas first-order targeting is determined mainly byhe sha pes a nd sizes a s w ell as the ma terial properties

of a ca rrier a nd by i ts route of a dministrat ion, second-and third-order targeting are dependent upon a mosts pe ci fi c i nt er act i on amo ng t he car r i e r , t he d r u g , a ndhe t ar get cell.

Classification two, which categorizes drug targeting

as organ, cellular , and subcellular processes, is ana-ogue t o t he fi rst-, second-, a nd th ird-order processes.

According to classification three, passive drug tar-g e t i ng r e f e r s t o t he nat u r al i n v i v o deposition of thedrug carrier in the body. This can be accomplished byco nt r o l l i ng t he s i z e o f t he d r u g , t he car r i e r , and i t sroute of adm inistra tion. Active drug t a rgeting requiresguidan ce of drugs or drug ca rriers t o specifi c cells in ama nner t ha t differs from its normal disposition in theorgan ism. The car rier or technique designed for a ctiveargeting must possess characteristics that minimize

drug removal from t he norma l cells of th e body, pa rtic-

ularly the phagocytes of the reticulo endothelia l sys-e m. A g o o d e x amp l e o f act i v e d r u g t ar g e t i ng i s t he

conjugat ion of drugs to a nt ibodies specifi c to the t a rgetcell an tigen or its delivery by a ma gnetically responsivedrug carr ier .

In classification four, the approaches that involve apassive, active, or physicalchemical basis of drug de-ivery can be grouped under site-directed drug target-ng. However, at t imes the use of a specific approach

may not necessarily favor drug delivery to target cells;nstead, i t may reduce drug delivery to the most vul-

nerable normal cells. This technique is considered site-

avoidance drug targeting. Application of liposomes to

reduce the cardiotoxicity of doxorubicin is a gooample of this type of delivery.

Yet ano t he r w ay t o c las s i fy d r u g t a r g et i ng i s bon t h e t r a n s por t of ca r r i er a c ros s t h e t a r g e t tmicrova sculature. Hence, according to classificfi v e , b ioch em ica l t a r g et i n g r ef er s t o ex t r a v a st r a ns por t b y s pe ci fi c i nt er act i on b et w e en t a r g eligan ds a nd drug carriers. Biomecha nica l ta rgetin

f e r s t o e x t r av as cu l ar d r u g d e l i v e r y b y t he t r anregional opening of endothelial junctions as the rof osmotic imbala nce or a noxia follow ing embolizaBiophysical targeting refers to the magnetic dragresponsive drug carrier through the endotheliuuse of a tempera ture-sensitive drug carrier w ithcommi t t an t r eg ional hy pe r t her mi a. B i oad he s iv egeting combines biochemical and biophysical effea process, for insta nce, in w hich specifi c binding od r u g car r i e r t o t he e nd o t he l i u m i s f o l l o we d b y sient al teration of the microcirculatory barrier ,m a t e l y l e a d i n g t o t h e e x t r a v a s c u l a r t r a n s f e r o

drug carrier . On t he si te of drug delivery in the ttissue, th e process ma y be defi ned a s carr ier-depenor ca rrier-independent . In th e former, t he drug cais taken up by the target cell and drug release ointra cellularly ; in th e latt er , the drug release fromca rrier occurs extra cellula rly . H ence, t he drug ainside the t ar get cells is not influenced by the caO t he r f o r ms o f d r u g t ar g e t i ng r e f e r t o t he nat u rvivodeposition of the drug carrier in the body orgorize drug ta rgeting a t orga n, cellular , a nd sublar processes. Finally , the approaches that invopassive, a ctive, or physicochemical ba sis of drug

ery can be grouped under site-directed dr ug t a rge

TARGETED DRUG DELIVERY SYSTEMS

IN CANCER CHEMOTHERAPY

Multiple systems and strategies have been invga ted t o meet t he goa ls of selective delivery of chthera peutic agents. S ome of them ha ve now beenin humans. Table 2 [2] gives some examples of vatargeted drug delivery systems that are currentling investigated.

MAGNETICALLY CONTROLLED DRUG TARGETI

AND PARTICLE SORTING

Magnetic drug ta rgeting a l lows the concentra tid r ug s a t a d efi n e d t a r g et s it e g en er a l ly a n d , i mt a n t l y , a w a y f rom t h e r et i cu la r en d ot h el ia l s y(RES) with the aid of a magnetic field. Typicallyintended drug a nd a suitable magnetically activeponent a re formulat ed into a pharma cologica lly sf or mu lat i on. Yet v er y f ew of t ho se hav e b ee n successfully in an imals. Typica lly , this compouinjected through the artery supplying the tumor t

in th e presence of a n external m agn etic fi eld w ith

TABLE 1

Classification of Drug Targeting

Cla s s ifica t ion I

First-order targeting

Second-order t ar geting

Third-order ta rgeting

Cla s s ifica t ion I I

Orga n t a rget ing

Cellula r t a rget ingSubcellula r t a rget ing

Cla s s ifica t ion I I I

P a s s ive t a rget ing

Active targeting

Physiochemical targeting

Cla s s ifica t ion I V

Site-directed targeting

Site-avoidance targeting

Cla s s ifica t ion V

Biochemical targeting

B iomecha nica l t a rget ing

B iophys ica l t a rget ing

B ioa dhes ive t a rget ing

Cla s s ifica t ion V I

Carrier-dependent

Carrier-independent

L U B B E, A L EXI OU , A ND B ER G EM ANN: M AGNE TI C DR U G TAR GE TI NG


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ficient field strength and gradient to retain the carrierat t he t ar g e t s i t e .

The development of ma gnetically responsive m icro-s phe r es has b r ou g ht an ad d i t i onal d r iv ing f or ce i nt opla y. P ar ticles tha t a re bound to ma gnetic fl uids ca n be

used to remove cells a nd molecules by a pplying ma g-ne t ic fi e ld s a nd i n v i v o t o conce nt r at e d r u gs a t an -atomical sites with restricted access. These possibili-i es f or m t he b as i s f or we l l-e st a b li she d b iome di cal

applications in protein and cell separation. Additionalmodificat ions of t he ma gnetic particles w ith monoclo-na l a ntibodies, lectins, peptides, or hormones ma kehese a pplica tions more effi cient a nd a lso highly spe-

cific. A combinat ion of these two a dvant a ges make thema gnetic microspheres a pplication so successful inmolecular and cell biology, advancing both basic sci-ence and clinical practice [24].

The purifi cat ion of bone ma rrow cells from conta mi-na tion with tumor cells, using so-called immunoma g-n et ic bea d s, for exa m ple, h a s becom e a w ell-established routine method in cl inical thera py [25].Newly developed surface modifications of biodegrad-a ble magn etic polymer pa rt icles resulted in longer cir-cu l at i on t i mes and b r ou g ht r e newe d i nt er e st i n P au lEh rlichs ideas in directed i n v i v o drug delivery. Theirsuccess depends to a large extent on the construction ofs t r o ng mag ne t s , ab l e t o p r o d u ce hi g h mag ne t i c fi e l dg r a d ien t s a t t h e t a r g et s it e s. M os t of t h e cu r r en t l ya va ilable inhomogeneous fields a re only str ong enough

for the ma nipulation of part icles a gainst the diffusion

an d blood stream velocities found in l iving syso v e r a d i s t ance o f a f e w ce nt i me t e r s f r o m t he sedge of a magnet pole [26]. In other words, technii t i s d if fi cu lt t o b u il d u p s u f fi cie nt fi e ld s t r e ng t hf ocu s es o n a s mal l a r ea and i s ab l e t o cou nt e r ac

linear blood-flow rates in the t issue (10 cm/s iteries and 0.05 cm/s in capilla ries), so t ha t to tively reta in the ma gnetic drug ca rrier, ma gnetic fmust be high enough to reach that goal .

Even with stronger magnets, one important proremains and must be overcome. How can we demo s t o f t he mag ne t i c car r i e r s t o t he t ar g e t ar eavoid normal t issue clearance? The circulation(V Q: A w i t h V velocity, Q fl o w , A arcond u it ) d ep end s r e ci pr ocal l y on t he p ar t i cl e whereas the magnetic susceptibil i ty of the indivparticle is directly proportiona l to the particle

Magnetic susceptibility expresses the ability of aplied fi eld to ma gnetize specific qua nti ty of ma termay b e d e s cr i b e d q u al i t a t i v e l y , s u ch as d i amagsusceptibili ty , wh ich is very wea k, or ferromagsusceptibility, w hich is very st rong. It ca n a lso besured quantitatively, as molar-magnetic susceptibatomic magnetic susceptibil i ty , and volume magsusceptibili ty , w hich indica tes t he ma gnet a bili tymat e r i al p e r u ni t mo l e cu l ar we i g ht , p e r u ni t a tweight, and per unit volume, respectively.

The presence of matter in the electric and magfi elds modifies the fi eld fl uxes at a given fi eld stre

The e le ct r i c a nd mag ne t i c p r op er t i es of mat t e

TABLE 2

Representative Examples of Various Targeted Drug Delivery Systems Investigated for Cancer Chemothe

D elivery syst em D rugs t est ed Rout e of a dm in ist ra t ion Referen ce

Aq ueous media B leomycin i.t . 3

Tumor necrosis fa ct or i.t . 4

Vinbla st ine sulfa t e i.t . 5

w /o/w E m ulsion B leomycin i.t . 3

o/w E mulsion Mit omy cin i.t . 6s/o E mulsion B leomycin i.t . 7

L iposomes B leomycin i.t . 8

C ispla t in a n a logues i.v. 9

D a un orubicin i.a . 10

D oxorubicin i.v. 11

S t a r ch m icrospheres C a rmust in i.a . 12

F luoroura cil i.a . 13

Mit omy cin i.a . 14

D oxorubicin i.a . 15

E t hylcellulose m icroca psules C ispla t in i.a . 16


Albumin m icrospher es C ispla t in i.a . 18

D oxorubicin i.a . 19


P oly (la ct ic a cid) micr ospheres Acla rubicin i.a . 21

P oly met ha cryla t e na nopa rt icles D oxorubicin i.v. 22

An t ibodies Vindesine i.v. 23

Note. i.t., in tr at umora l; i.v., int ra venous; i.a ., int ra ar teria l; w /o/w , w a ter-in-oil-in-w at er; o/w, oil-in-wa ter; s/o, sphere-in-oil.

202 J OU R NAL OF SU R GI CAL R ESE AR CH: V OL . 95, NO. 2, FEB R U A R Y 2001


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defined by induced polarizations (P a nd M), r espec-i v el y , w hi ch d et e r mine how mu ch t he e le ct r i c a nd

mag ne t i c flu x d e ns i t i e s chang e at a g i v e n p o i nt wi t hhe introduction of matter in the neighborhood of this

point. In isotopic media t he polar izat ion vectors (E, H)are parallel to the corresponding field vectors: P XeYO E a n d M Xm H, whe r e Xe a nd Xm a re electric andma gnetic susceptibilities, respectively, cha ra cteristic

o f t he mat e r i al . S i z e and mag ne t i c p r o p e r t i e s mu s th erefore be optimized carefully to decrease t he un spe-

cifi c RES upt a ke and t o prolong t he circulat ion t ime inhe hu man o r g ani s m. T hi s wi l l p r o v i d e a max i mu mime span for the extraction and concentration of the

mag ne t i c par t i cl es i n t he t ar g e t ar e a .Intense efforts are also ongoing in the development

of b iocomp at i b le mag ne t i c car r i e r s f or t he d i re ct e dransport and controlled release of drugs or radionu-

clides for use as sources of local temperature increase(hyperthermia) a nd for loca l contra st enhan cement inMR imaging [27]. Recently, the principle of magnetic

manipulation has been applied to concentrating mag-netic drug carriers in definite regions, provided thathe carriers can be transported to the target si te. In a

series of papers, Kato et al. [28] published investiga-ions int o selective can cer chemothera py, in w hich fer-

romag netic mit omycin microcapsules (a bout 300 mdiameter) were magnetically guided to tumor si tes ofexperimental animals. The particles could be manipu-a ted by fi elds of about 56 kA/m. Yet th ose experiment s

possessed cert a in methodological problems (kA/m:mag ne t i c mome nt (M) i n G a u s s ( C G S ) cm g r am

second syst em equa ls a mpere (A)meter

2

according tohe S I (MK S S y s t em I n t er n a t i on a l (m et e rkilogramsecond system)).

I n a d a et al. [29] perform ed i n v i t r o investigations ofoca lized fi brinolysis by ma gnetica lly concentra ting

urokinasemagnetide complexes. So-called TMs (ther-mosensitive ma gnetoliposomes) ha ve a lso been pre-pared and w ere investigat ed in a n i n v i t r o flow system.Th e TM s w i t h a d ia m e t er of a b ou t 1 m cou ld b econcentrated in relatively high field strengths. I t waspossible to r elease a specific part of the content fromhe particles (calcein) by increasing the temperature

a bove 40 C [30].Pulfer and Gallo reported i n v i t r o studies of target-

ng magnetic microspheres to brain tumors by an alloyof iron [31]. Carbon was prepared by Allen et al. a ndwa s u s e d a s a car r i e r (0.5 2 m) f o r t he ant i t u mo ra gent paclita cel for h ead a nd n eck can cers. The desorp-i on s u st a i ned o v er mor e t ha n 24 h, a nd b y mag ne t i c

fi elds of several hundred kA/m the carriers could beretained with in ca pil la ries [32]. The combinat ion ofmagnetic carriers with the radioisotope Y-90 was in-vestigat ed by Ha feli et al. , who p r ep ar e d ma g net i cmicrospheres out of poly-lactic a cid with diameters

betw een 20 and 30 m. The par ticles w ere loa ded wit h

Y-90 by a simple mechanical stirring process anmediately were injected into the cavities or the sof mice a nd ra ts [33].

Goodwin et a l . hav e d emons t r at e d t ha t s o-cmagnetic targeted carriers (MTC) could be tarand r e t ai ned a t a r e gi on of i nt e r es t i n a s wi ne mafter intraarterial infusion [34]. MTCs did not rtr ibute af t er removal of the ma gnetic field. Histop

logic results demonstrated a high particle densthe a rea of the m a gnetic field. Pa rticles were obsin th e intersti t ium a nd occa siona lly int ra a rterial lthough MTCs were formed in a high-energy grinp roce ss i n whi ch act i vat e d car b on wa s i ncor p oint o meta llic iron pow der t o produce micropar ticleposits w ith a 75:25 FE:C ra tio, th e resulting pa rra nged from 0.5 to a pproximat ely 5 m and thercould only be administered intraarterially [35]. Te x p e r i me nt s s ho we d t hat t hi s t e chno l o g y wo r kdemonstrated proof of the principle for currently ing cl inical tr ials in patients with hepatocellula

cinoma.

FIRST CLINICAL EXPERIMENTS WITH MAGNETIC

CONTROLLED DRUG TARGETING

E p ir u b ici n i s a we l l-k nown ant i bi ot i c ant r acthat has a wide range of application for the treatof solid tumors [36]. Also, a chemically slightly dent substance (doxorubicin) has been used frequi n a ni mal e xp er i ment s , s o t ha t comp ar at i ve a naw ere possible. The fi rst clinica l experiments in hupatients with ma gnetic drug ta rgeting worldwide

report ed b y Lu bbe et al. We used a ferrofl uid (pasize 100 nm) to which the drug epirubicine was cically bound [36]. In brief, special starch polymersthe ma gnetic part icles together with a nionic endsing phophate groups so that a cationic binding tpositively cha rged a mino suga rs of epirubicin w asible. This was a worldwide unique approach anlowed for a reversible ionic binding of the drug, that certain physiological parameters (osmolalitytempera ture) affected desorption (of th e drug fromparticle in the tumor t issue) chara cteristics. Thr ofl u id w a s con cen t r a t ed in t h e t a r g et r eg ion

m ea n s of p rop er ly a r r a n g e d per m a n e nt m a gwhi ch p rov id ed a fi e ld s t r e ngt h of 0.8 T in t ulocated near the body surface.

Those cl inical experiments in 14 patients witvanced solid tumors resulted from animal experietha t , for t he fi rst t ime, documented tolerance andcacy by methods that included microcirculatory ovat ions in mice a s w ell a s in ra ts [38].

Tw o f or m s of t h er a p y w i t h a m a g n et i c fl u i d been tested in these preclinica l experiments: ttreatment by mechanical occlusion with a ferrofluhigh concentra tions a nd ma gnetically controlled

ta rgeting using sma ll a mounts of ferrofl uid as a ve



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o concentra te epirubicin loca lly in t umors. As a resultof t hose a nimal experiments, in wh ich no LD 50 couldbe found for the ferrofluid, no clinical intolerances ormaj o r l ab o r at o r y d e r ang e me nt s wi t h t he e p i r u b i ci n-bound ferrofluid have been demonstrated. The efficacyof the treatment was documented by complete tumorresponses in a xenotransplanted human kidney as wellas i n a co l o n car ci no ma. H e nce , t he way f o r t he fi r s t

clinica l experiments w a s opened.P h a se I/ I I cl i n i ca l t r i a l . Ma gnetically cont rolled

drug targeting wa s used in patients with a dvanced a ndunsuccessfully pretrea ted ca ncers or sa rcoma s. Nine ofhese patients received two treatment courses, three

pat ients received one course, a nd t w o patient s receivedhree courses of magnetically controlled drug target-ng. The treatment protocol consisted of the intrave-

nous infusion of epirubicin in increasing doses (from 5o 100 m g/m 2) that had been chemically bound to the

ma gnetic fluid a nd one course of convent iona l systemicch em ot h e ra p y w i t h t h e s a m e d os e of e pi ru bi ci n 3weeks la ter . Conventional chemotherapy w as the ra pidnfusion of epirubicin into a periphera l vein. Epirubicin

wa s g i v en t o t he p at i ent i n l i q ui d f or m af t e r t he l y o-phylized powder had been diluted with isotonic salines ol ut i on. N o mag ne t i c flu i d o r ma g net i c fi e ld wa s ap -plied. In the treatment group in which magnetic drugargeting was performed, af ter the preparation of the

magnetic epirubicin (0.5%of the estimated blood vol-ume) th e substa nce wa s infused over 15 min int o a veinocat ed contra lat era lly to th e tumor. During the time ofnfu s ion and at l eas t f or t he ne xt 45 mi n, a mag ne t i c

fi e l d was b u i l t u p as c l o s e as p o s s i b l e t o t he t u mo r .H i g h-e ner g y p er mane nt mag ne t s we r e u s e d i n t hi spatient trial. The magnets consisted of rare earths, thema jority being n eodymium. There w ere lar ge (8 4 2 cm) an d sma ll (3 3 1 cm) blocks, a nd th ese blockscould be arra nged a ccording to the individually sha pedu m or of t h e pa t i en t . M a g n et i c fi el d s t r e n gt h s of a tea st 0.5 T a nd in general 0.8 T could be rea ched a nd

were confirmed at the patients bed. The distance be-ween the tumor surface and the magnets was assuredo be less than 0.5 cm. The intravenous injection dif-

fered from most of th e other w orking groups intra a r-

erial a pplica tion. Obvious a dvant a ges (easy access)had t o b e b al ance d ag ai ns t a p o t e nt i a l l y hi g he r RE Sclearance and the necessity of high-energy magneticfi elds. Furt hermore, the d esorption time of the coupledd ay had t o t ak e i nt o acco u nt t he i nt r av as cu l ar av ai l -a bil ity a nd other physiologic pa ra meters.

The ap p li cat i on of mag ne t i c fi e ld s t o t he t u mor sasted for 60 to 120 min. Magnetic drug ta rgeting wa s

clinica lly w ell tolerat ed a nd w a s verifi ed ba sed on ma g-netic resonance imaging techniques, pharmacokinet-cs, and the histological as well as clinical detection of

mag ne t i t es . I t wa s s ho wn t hat t he f e rr oflu i d cou ld b e

successfully directed to the tumors in about half of the

patients. Organ toxicity did not increase with the ment but some epirubicin-a ssociat ed t oxicity a ppat doses great er t ha n 50 mg/m 2. Although treatwi t h mag ne t i cal l y cont r o ll ed d r u g t a r g et i ng s esafe, i t was concluded that improvements are nsary to make it more effective by increasing ferrparticle size and to make i t more independent otient or disease-related problems [39].

P hysiologica l a s w ell a s pha rma cologica l para min ma gnetica lly controlled drug tar geting wa rra nther investigation. This is because the efficacy vivo drug t a rgeting w ith ferrofluids crit ica l ly depon physiologica l pa ra meters. To understa nd thisf or m of p har macol og ical ap p li cat i on as we l l amechanism of action of the concentrated drug itissue at the microcirculatory level one must connot only the ferrofluids parameters (particle sizeface cha ra cteristics of the par ticle, concentra tion fl uid, volume of t he fl uid, reversibil ity a nd strengthe drug/ferrofluid binding, desorption chara c

tics), but a lso access t o t he orga nism (infusion rdura tion/ra te of th e in jection/infusion tim e), g eoman d strength of the magnetic field, a nd dura tion omagnetic field application. Physiological parameteth e patient s organ ism comprise size, weight, a nds u r face, b lood v ol ume , car d i ac ou t p ut and s y svascula r resista nce, circulation t ime, t umor voan d location, and va scular content of the t umor a sas t u mor b lood flo w. P hy s iol og ical p ar ame t e r swi t h t he s i z e and s p e ci e s o f t he ani mal . T hu s ,canno t b e e as il y t r a ns f er r ed f r om ani ma l s t o hu

and ad a p t at i on of f er r oflu i d /d r u g and mag ne t i cchar a cteristics is n ecessar y [40].Mos t cr i t ical f or t he e ffi cacy of mag ne t i cal l y

t r ol le d d r u g t a r g et i ng ar e t he i nt r av as cu lar b ioaabil i ty of the ferrofluid, i ts susceptibil i ty (strengb e r e cr u i t e d b y t he mag ne t i c fi e l d and , he nce , concentra ted in t he tumor), a nd t he i n v i v o desortime of the drug. For th is reason, a second clinicain head a nd neck ca ncer pat ients is underwa y in wth e optima l part icle size an d form of a pplica tion wi d e nt i fi e d f o r f u r t he r u s e i n hu mans . Fu r t he r anexperimen ts ha ve support ed th e concept r ecent ly.

s q u amo us ce ll car cinomas ha v e b ee n s u cce sheated in the ear region of rabbits by different logiona l regiments. I f subsequent tr ia ls demonstrafi c a cy of t h e t r ea t m en t , on ly t h en cou ld n ewin n ov a t i ve a n t i t u m or s t r a t e gi es s uch a s pa l litreatment regiments and adjuvant scenarios be sioned. Possible a lterna tive trea tm ent moda lities be the substitution of locoregional radiation treatafter breast-conserving surgery by chemotherapymag ne t i cal l y cont r o ll ed d r u g t a r g et i ng . I f s y schemothera py is found n ecessary, t hen drug ta rgcan be a dministered in pa ra llel since no major sys

adverse effects from the lat ter should occur. Fur



6/7

more, successful drug targeting with ferrofluids couldutilize expensive drugs, those with a short half-life or ahigh toxicity. Thus, new innovative or otherwise inad-equat e therapeutic substances might fi nd a new a rea ofapplicability.

OTHER CLINICAL APPLICATIONS OF MAGNETIC

DRUG TARGETING

Are there a pplications other t ha n t umor thera py formag ne t i cal l y cont r o ll ed d r u g t a r g et i ng ? I t has b ee nshown that cytokines could be concentrated in tumorsa nd a lso tha t cytokine-induced killer cells w ere direct-ab l e wi t hi n mi ce a nd r at s u s i ng a d if fe re nt f er r ofl u idfamily [41]. This and the fact that other drugs such asant i bi ot i cs , t hr o mbol y t ic ag e nt s , and ot he r s can b ebound reversibly to th e ferrofl uid part icles suggest t ha tsuch fields of therapy are in the room of possibil i ty .S p eci fi cal ly , a s l ong as u nwa nt e d s i d e e ff ect s and i n-sufficient local concentrations are l imiting factors in

he ad mi ni st r a t i on of b iol og ical l y act i ve s u bs t an ce ssuch as cytokines, growth factors, DNA sequences, ge-ne t ical l y mani p u lat e d ce ll s , or ce ll s u bs t ances , t hehera peutic efficacy of ma gnetica lly ta rgeted cytokine-nduced na tura l kil ler cells needs further investiga-ion.

Re ce nt ly , b y u s ing i ncr e as ing conce nt r at i ons ofD E A E na nop ar t i cl es , mag ne t i cal l y g ene r at e d g ener a ns f er , i .e ., t he t r a ns f ect i on of ce ll s or b act er i a t o

p r od u ce p har macol og i cal b iol og ical p r od u ct s , hasgained much interest . Gene therapeutic measures forhe t reatm ent of noncura ble diseases w ill play a ma jor

role in the future. The feasibil i ty of using magneticransfections of cytokine-induced killer cells with plas-

mid D NA w a s found to be possible a nd opens up int er-esting perspectives wit h rega rd to a n indust ria l exploi-a tion of genetically modified bacteria.

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