Hepatic arterial infusion of lipiodol containing ferromagnetic particles can result in excellent targeting of liver tumors with hyperthermia on the subsequent application of an external alternating magnetic field. The promising results of this study warrant further investigation of FEH as a potential treatment for advanced liver cancer.

Localized magnetic heating treatments (hyperthermia, thermal ablation) using superparamagnetic iron oxide nanoparticles continue to be an active area of cancer research. The present study uses magnetic nanoparticles (MNP) as bimodal tools and combines magnetically induced cell labelling and magnetic heating. The main focus was to assess if a selective and higher MNP accumulation within tumour cells due to magnetic labelling (max. 56 and 83 mT) and consequently a larger heating effect occurs after exposure to an alternating magnetic field (magnetic heating: frequency 400 kHz, amplitude 24.6 kA m−1) in order to eliminate labelled tumour cells effectively. The results demonstrate that the magnetically based cellular MNP uptake by human adenocarcinoma cells is due to suitable magnetic field gradients in vitro which intensify the temperature increase generated during magnetic heating. A significantly (P≤0.05) enhanced MNP cell uptake due to 83 mT labelling compared to controls or to 56 mT labelling was observed. Our experiments required the following conditions, namely a cell concentration of 2.5 × 107 cells ml−1, a minimum MNP concentration of 0.32 mg Fe ml−1 culture medium, and an incubation time of 24 h, to reach this effect as well as for the significantly enlarged heating effects to occur.

Experimental rabbit liver tumours were preferentially heated to therapeutic temperatures without compromising the surrounding normal hepatic parenchyma. This was achieved by the use of hepatic arterially infused ferromagnetic microspheres that heat as a result of magnetic hysteresis loss when exposed to an alternating magnetic field. Treatment sessions involving a single 20-min exposure to the alternating field resulted in total suppression of tumour growth at 14 days compared to controls, in which tumour sizes increased dramatically over the same period. Histopathological examination of treated tumour sections showed total tumour destruction in some cases. Separate animal groups used to control for the effects of the embolized microspheres alone and for the effect of the applied magnetic field yielded similar tumour growth responses to a control group with no intervention whatsoever. The achievement of positive temperature differentials between tumour and normal liver and the consequent therapeutic responses encourages further development of this technology for the treatment of liver cancer in humans.

It is known that significant heating can be generated by magnetic hysteresis effects in small ferromagnetic particles exposed to a rapidly alternating magnetic field. If such particles can be made to infiltrate the vascular bed surrounding a tumour by intravascular infusion then it may be possible to generate sufficient heating to destroy the tumour by hyperthermia. One of the constraints on such a technique is the limited amount of magnetic material that can be delivered to a tumour via the intravascular route and the consequent heating that can be induced by this material. Here, we report on a series of experiments in which doses of microspheres containing different amounts of ferromagnetic material were infused into rabbit kidneys via the renal artery with the aim of testing whether adequate tissue heating could be achieved using realistic concentrations of the embolised material. Heating rates were measured for each infused quantity under similar conditions with the animal alive and dead to examine the role of blood flow in the heating process. The results show that tissue temperatures above the therapeutic threshold of 42 degrees C can be readily achieved using this method with clinically relevant concentrations of microspheres in living tissue.

PurposeSelective internal radiation therapy (SIRT) is an effective treatment option for liver tumors, using Y-90-loaded polymer microspheres that are delivered via catheterization of the hepatic artery. Since Y-90 is a beta emitter and not conveniently imaged by standard clinical instrumentation, dosimetry is currently evaluated in each patient using a surrogate particle, 99mTechnetium-labeled macroaggregated albumin (99mTc-MAA). We report a new composite consisting of 99mTc-labeled nanoparticles attached to the same polymer microspheres as used for SIRT, which can be imaged with standard SPECT.MethodsCarbon nanoparticles with an encapsulated core of 99mTc were coated with the polycation protamine sulfate to provide electrostatic attachment to anionic polystyrene sulfonate microspheres of different sizes (30, 12, and 8 µm). The in vivo stability of these composites was determined via intravenous injection and entrapment in the capillary network of normal rabbit lungs for up to 3 hours. Furthermore, we evaluated their biodistribution in normal rabbit livers, and livers implanted with VX2 tumors, following intrahepatic artery instillation.ResultsWe report distribution tests for three different sizes of radiolabeled microspheres and compare the results with those obtained using 99mTc-MAA. Lung retention of the radiolabeled microspheres ranged from 72.8% to 92.9%, with the smaller diameter microspheres showing the lowest retention. Liver retention of the microspheres was higher, with retention in normal livers ranging from 99.2% to 99.8%, and in livers with VX2 tumors from 98.2% to 99.2%. The radiolabeled microspheres clearly demonstrated preferential uptake at tumor sites due to the increased arterial perfusion produced by angiogenesis.ConclusionWe describe a novel use of radiolabeled carbon nanoparticles to generate an imageable microsphere that is stable in vivo under the shear stress conditions of arterial networks. Following intra-arterial instillation in the normal rabbit liver, they distribute in a distinct segmented pattern, with the smaller microspheres extending throughout the organ in finer detail, while still being well retained within the liver. Furthermore, in livers hosting an implanted VX2 tumor, they reveal the increased arterial perfusion of tumor tissue resulting from angiogenesis. These novel composites may have potential as a more representative mimic of the vascular distribution of therapeutic microspheres in patients undergoing SIRT.