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jurnal hypotermia fisika dasar

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jurnal fisika untuk mata kuliah fisika dasar. mempelajari tentang penyakit hypotermia dan penyembuhannya menggunakan teknologi fisika.
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  * Corresponding author. Tel.: # 49-30-45057073; fax: # 49-30-45078979.  E-mail address:  andreas.jordan @ charite.de (A. Jordan)Journal of Magnetism and Magnetic Materials 201 (1999) 413 } 419 Invited Paper Magnetic  # uid hyperthermia (MFH): Cancer treatment withAC magnetic   eld induced excitation of biocompatiblesuperparamagnetic nanoparticles Andreas Jordan * , Regina Scholz, Peter Wust, Horst Fa   K hling, Roland Felix  Department of Radiation Oncology (WE 07), Uni v ersity Clinic Charite &      , Medical Faculty of the Humboldt Uni v ersita (      t zu Berlin, CampusVirchow-Klinikum, SFB 273, Augustenburger Platz 1, 13353 Berlin, Germany Received 18 May 1998 Abstract The story of hyperthermia with small particles in AC magnetic   elds started in the late 1950s, but most of the studieswere unfortunately conducted with inadequate animal systems, inexact thermometry and poor AC magnetic   eldparameters, so that any clinical implication was far behind the horizon.More than three decades later, it was found, that colloidal dispersions of superparamagnetic (subdomain) iron oxidenanoparticles exhibit an extraordinary speci c absorption rate (SAR [ = /  g ]), which is much higher at clinically tolerable H   f   combinations in comparison to hysteresis heating of larger multidomain particles. This was the renaissance of a cancer treatment method, which has gained more and more attention in the last few years. Due to the increasingnumberof randomized clinicaltrials preferentiallyin Europe withconventional E - eld hyperthermiasystems,the generalmedical and physical experience in hyperthermia application is also rapidly growing. Taking this increasing clinicalexperience carefully into account together with the huge amount of new biological data on heat response of cells andtissues, the approach of magnetic  # uid hyperthermia (MFH) is nowadays more promising than ever before. The presentcontribution reviews the current state of the art and some of the future perspectives supported by advanced methods of the so-called nanotechnology.    1999 Elsevier Science B.V. All rights reserved.  Keywords:  Magnetic  # uids; Hyperthermia; SAR; Nanoparticles; Cancer; Biomedical applications 1. Basic principles of hyperthermia Heating of certain organs or tissues to temper-atures between 41 3 C and 46 3 C preferentially forcancer therapy is called  & Hyperthermia ' . Highertemperatures up to 56 3 C, which yield widespreadnecrosis, coagulation or carbonization (dependingon temperature) is called  & thermo-ablation ' . Bothmechanisms act completely di !  erent concerningbiological response and application technique. The & classical '  hyperthermia induces almost reversibledamage to cells and tissues, but as an adjunct it 0304-8853/99/$  }  see front matter    1999 Elsevier Science B.V. All rights reserved.PII: S0 3 0 4 -8 85 3 (9 9 ) 00 0 8 8- 8  enhances radiation injury of tumor cells andchemotherapeutic e $ cacy. Modern clinical hyper-thermia trials focus mainly on the optimization of thermal homogeneity at moderate temperatures(42 } 43 3 C) in the target volume, a problem whichrequires extensive technical e !  orts and advancedtherapy and thermometry systems.Heating to the target temperatures causes mod-erate cellular inactivation in a dose-dependentmanner. Although thermal dose } response curveslook quite similar to radiation or drug dose re-sponse curves, the critical target of thermal inac-tivation in the cell is not known yet. The mostprobable reason for this situation is that there is noindividual cellular target of hyperthermia, in con-trast to the well known DNA damage after irradia-tion [1,2]. Most of the biomolecules, especiallyregulatory proteins involved in cell growthand di !  erentiation and the expression of certainreceptor molecules (involved in signal transductionpathways) are therefore largely in # uenced byhyperthermia.Today, many cellular e !  ects are known to beimportant for thermal inactivation. New insightsfrom molecular biology have shown that a fewminutes after hyperthermia, a special class of pro-teins is expressed in the cell, the so-called heatshock proteins (hsp). They protect the cell fromfurther heating or subsequent thermal treatmentsand lead to an increase of cell survival after pre-heating, an e !  ect called thermotolerance [3]. Addi-tionally, the activity of certain regulatory proteins,kinases or cyclins is in # uenced by hyperthermia,causes alterations in the cell cycle and can eveninduce apoptosis, the cell death driven by the cellregulatory system itself [4 } 7]. Current research isalso trying to characterize the interactions of ther-mal tolerance and multidrug resistance [8]. Thecombined e !  ect of radiation and hyperthermiatakes place at the cellular level and is mainly due tothe heat-induced malfunction of repair processesafter radiation-induced DNA damage. They areless e !  ective when heat is given either before orafter irradiation, and a well-de ned time intervalhas been described for the two modalities [9]. Fur-ther e !  ects were observed on the tissue level such aschanges of microvasculature, blood  # ow, energyand oxygen status [10]. Interestingly, heat treatedcancer cells may be better recognized by the hostimmune system due to alterations of some cellsurface receptor molecules which are then recog-nized by natural killer (NK) cells and inactivate thecancer cells, as has been recently demonstrated invitro [11]. The joint action of all the molecularmechanisms involved in hyperthermia is still underinvestigation. 2. Clinical hyperthermia State-of-the-art radiofrequency (RF-) hyperther-mia systems, e.g. annular phased array systems(APAS) for regional hyperthermia of deep seatedtumors, are still limitedby the knownheterogeneityof tissue electrical conductivities or high perfusedtissues, which makes selective heating of those re-gions with such  E - eld dominantsystems very di $ -cult. Further application techniques are wholebody hyperthermia (WBH, with water- ltered in-fra-red irradiation), local hyperthermia (e.g. withcurrent sheet applicators) and interstitial hyper-thermia (requires implantation of microwave- orRF-antennas or self-regulating thermoseeds).A nearly unsolved problem are the bone of thepelvis or the scull, which  & shield '  deep tissues in thecavity of bones, which often result in  & hot spot ' phenomena, which are di $ cult to predict in certaindi !  erent locations of the body. The overall e !  ect isthermal underdosage in the target region, whichoften yields recurrent tumor growth. Despite theseuncertainities, several (preferentially European)randomizedtrials demonstratedtherapeuticbene tof   & state-of-the-art '  (RF-) hyperthermia, so far: Vander Zee and his co-worker [12] reported higherlocal control after three years follow-up with thecombination of hyperthermia and radiation (RHT)withadvanced rectalcarcinoma,bladderand cervixcarcinoma. With the ladder tumor entity evena survival bene t was observed. Our group in Be-rlin (Rau et al., [13]) has found higher responserates with RHT of advanced rectal carcinoma ina pre-operative approach. Valdagni and his co-worker in Italy [14] found higher local control of advanced lymph node metastases after RHT. TheDanish group of Jens Overgaard [15] had successwith malignant melanoma, i.e. increase of local 414  A. Jordan et al.  /   Journal of Magnetism and Magnetic Materials 201 (1999) 413 } 419  control (2 years follow-up). Claire Vernon with hergroup in London [16] obtained higher responserates of recurrent mammary carcinoma when ir-rradiation was combined with local hyperthermia.PennySneed and her group (USA)had success withglioblastoma multiformae in a randomized trial of brachytherapy boost plus interstitial hyperthermiawhich yielded an overall survival bene t in thehyperthermia arm [17].Summarizing all these clinical studies, it is main-ly accepted that preferentially the problems of physical power deposition still limit the clinicaloutcome. This includes not only thermal underdos-age of critical regions, there are also large limita-tions on the body target sites, which are toodi $ cult to treat, like brain tumors. Conclusivelythere is a large demand on alternative physicalconcepts, which may o !  er deep seated power de-position in almost every region of the body. 3. Much more than simple particle heating : the biological concept of magnetic  6 uidhyperthermia  ( MFH )In the early 1960s, a few US groups were the   rst,who tried to perform hyperthermia with magnetiz-able microparticles, which were heated by anexternally applied AC magnetic   eld. The use of  H - eld dominant systems together with powerabsorbing material instead of power steering of  E - eld dominant systems is therefore an oldidea. However, before the early nineties, the statusof this research was di !  use and clinical applicationwas unthinkable. Poor de ned animal systems [18]or ex vivo tissue samples were used to test an intra-tissue heating up to the present [19]. In contrast,solid and comparable in vivo tumor growth dataare needed including all the important controls,precise on-line temperature monitoring and patho-logical tissue inspection. Those studies have beenrarely performed, so far.For the   rst time, our group could demonstratein 1993 [20], which  H - eld amplitudes and fre-quencies (i.e. speci c absorption rate, SAR) are tol-erable in humans. Based on the Brown and Nee  H lrelaxivity, it was shown, that subdomain particles(nanometer in size) absorb much more power attolerable AC magnetic   elds than is obtained bywell known hysteresis heating of multidomain (mi-crons in size) particles. The SAR of magnetic  # uidsis   H   f  , where    is a material constant for a given H   f   combination.This was the renaissance of a cancer treatmentmethod,whichhas gained more and moreattentionin the last ten years.Systematic in vitro studies were presented byChan and co-worker (1993) [21] and in a moreextended study by our group in 1996 [22], whichboth show consistently, that inactivation of cancercellswithAC magnetic eld excitednanoparticlesisequal to the best homogeneous heating, i.e. waterbath heating, for a given time temperature sched-ule. This result was not self-evident, because a largenumber of single particles, but each acting in prin-ciple as a hot source surprisingly yield a temper-ature homogeneity, which was comparable towater, containing much more excited moleculesthan particles existing in a magnetic  # uid. Accord-ing to these encouraging in vitro results, a homo-geneous cell or tissue inactivation was expected invivo, too, if the  # uid could be administered almosthomogeneously throughout the target region.On the basis of this extended physical and biolo-gical knowledge, advanced AC magnetic   eld ap-plicators were constructed for animal experiments.New studies were started with the isogenic C3Hmammary carcinoma of the mouse [23], which wastransplanted into the right hind leg. The animalswere treated for 30 min at 47 3 C (intratumoralsteady state temperature) includingseveral controls(untreated, coating substance and magnetic  # uidalone). In this approach, the temperature was in-credibly high in order to test unconventionally (fora hyperthermia study) the potential of MFH asa mono-therapy in order to reach local tumor con-trol. Surprisingly, this was obtained in 44% of theanimals (Fig. 1). The magnetic  # uid was given in-tralesionally without anaesthesia. Before AC mag-netic   eld treatment, magnetic  # uid depots in thetarget region were observed as expected, but afterthe   rst MFH session, this distribution had beenhomogenized, which has been termed now as  & ther-mal bystander e !  ect ' . This e !  ect o !  ers broad per-spectives not only in hyperthermia, but also in drugtargeting,gene and immunetherapy. Moreover, the  A. Jordan et al.  /   Journal of Magnetism and Magnetic Materials 201 (1999) 413 } 419  415  Fig.1. C3H mouse mammary carcinomagrowthcurves of untreated (control), dextran,dextran-ferrite andMFH treated animals.Note,that tumor growth remains nearly una !  ecteduntil AC magnetic   eld-inducedheating yields 44% tumor control 30 days after treatment. results suggest, that MFH might become a newminimal invasive modality for regional selectiveheat treatment on the microscopic level, which isnot possible by any other method, so far. 4. Recent results In order to proceed from the encouraging resultswith the mammary carcinoma of the mouse, moreanimal experiments are required to   x the currentstate of MFH as an almost site-speci c modality,which allows regional heating in di !  erent locationsof the body. As a precondition, the technology of AC magnetic   eld application is currently underdevelopment [24]. If an almost regional AC mag-netic   eld application could be realized, migrationof any ferro # uid to distant locations could be ne-glected. Many aspects have to be considered, like E - eld shielding of the  & patient ' , heat loss of the 416  A. Jordan et al.  /   Journal of Magnetism and Magnetic Materials 201 (1999) 413 } 419

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