The hyperthermia (HT) of human malignant tumor is used in the combined antitumor therapy and demonstrates significant modifying effect that results in the improvement of patients’ survival [
One of the approaches to resolve this problem is a creation of magnetic fluids (MF) on the basis of ferromagnetic nanoparticles which are able to heat the tumor tissue under external alternating magnetic field (AMF), that was shown in the pioneer work of Jordan et al. [
The studies of MF on the basis of magnetite nanoparticles, that is, Fe3O4, that has the high level of biocompatibility, have received significant distribution since the first publication of Jordan et al. [
At the same time the high Curie point (phase transition point) of magnetite is a cause of overheating of normal tissue surrounding the tumor [
At the same time the analysis of the obtained results has indicated the necessity to optimize the synthesis and to enhance their magnetic properties [
Solid solution of L
Optimal concentration of nanoparticles (50 mg/mL) in organic-matrix solutions at which the fluid remains stable and cannot separate into layers has been determined.
A high frequency generator produced by Institute of Electrodynamics (NASU of Ukraine) was used to induce an alternating current of 70 A at a frequency of 100–440 kHz, maximum magnetic field strength above 7.7 kA/m (Figure
Experimental setup consists of a high frequency generator (a) and coil (b).
The ability of MF to be heated in AMF was evaluated by the following matter: MF was placed into plastic tube at a volume of 1.5 mL that was located then in the coil of AMF generator in such way that the tube was setting up in the center of field configuration.
All studies were conducted with strain IEPOR bread rats (150–250 g of b.w.) with transplanted tumors: Guerin carcinoma, carcinosarcoma Walker-256, and C57Bl/6 mice (20–25 g of b.w.) bearing Lewis lung carcinoma. Tumors were transplanted intramuscularly into the femur. In separate experiments, Guerin carcinoma was transplanted into the femur of both legs of the same rat. The principle and method of transplantation were conventional. Animals were kept in Makrolon cages bedded with dust-free wood granulate and had free access to a standard diet and tap water. All experiments had been approved by the regional animal ethics committee.
It was early determined [
Rat is in the net-hammock and the femur is located in the coil of magnetic field generator.
When tumor volume has reached 1.5–2.0 cm3 (Guerin carcinoma, Walker-256 carcinosarcoma) or 150–200 mm3 (Lewis lung carcinoma), animals were enrolled into the study. Animals were anaesthetized with “Calipsovet plus” i.m. at a dose of 0.1 mL
Tumor temperature during heating was measured by means of cooper-constantan thermocouples (0.1 mm diameter; IF-Kiev). The thermocouples were calibrated against a certified precision mercury-in-glass thermometer (Committee of State Standards, Ukraine) before and after each experiment. The temperature of MF was measured every 5 min during the
Data are presented as the mean ± s.e.m. Differences between the experimental points were evaluated by Student’s
The ability of MF based on the synthesized nanoparticles of perovskite manganite (L
Time-dependent temperature curve of manganite MF heating induced with AMF (300 kHz, 7.7 kA
The ability of MF injected into the muscle or tumor to heat targeted tissue was checked up in experiments
Time-dependent temperature curves of muscle as well as tumor (Guerin carcinoma) heating by MF under the AMF (300 kHz, 7.7 kA
Growth of Guerin carcinoma after combined treatment MF with AMF (twice) versus growth of nontreated tumor. ●—growth of nontreated tumor, ■—growth of treated tumor. Ordinate—tumor volume, cm3; abscise—time of observation from the first treatment, days. Treatments were indicated with arrows. Data are presented as the mean ± s.e.m.
There was also noted the dependence of nanohyperthermia efficacy from the number of heating sessions. Single administration of MF into the tumor followed by AMF during 30 min (in a series of experiments heating was repeated 3-4-times with 2-3 days break) has resulted in more impressive delay of tumor growth: Figure
Rat number 1 (8.02.12). Growth of Guerin carcinoma after combined treatment MF with AMF versus growth of nontreated tumor: tumor was transplanted into both femurs on the same rat. ●—growth of treated tumor (right leg), ■—growth of nontreated tumor (left leg). Ordinate—tumor volume, cm3; abscise—time of observation from the first treatment, days. Treatments were indicated with arrows.
Obtained results are presented in Table
Results of nanohyperthermia influence on rat’s solid tumors.
Tumor | Index of tumor growth inhibition (by |
Tumor growth delay (day) | Number of rats with complete tumor regression (%) | Number of cured rats (%)* |
---|---|---|---|---|
Guerin carcinoma | ||||
Untreated control ( |
0 | 0 | 0 | 0 |
Nanohyperhermia ( |
3.7 | 10.3 ± 1.2 | 35** | 25** |
Walker-256 carcinosarcoma | ||||
Untreated control ( |
0 | 0 | 0 | 0 |
Nanohyperthermia ( |
3.2 | 6.0 ± 1.0 | 15 | 0 |
*Rats with complete tumor regression and without tumor recurrence within 120 days after complete regression of tumor.
**Thermoablation effect was observed that resulted in the complete regression of tumor and absence of tumor recurrence. It has to be noted that this effect (thermoablation) is not observed after application of microwave hyperthermia (43-44°C within 60 min; our data).
Growth of Walker-256 carcinosarcoma after combined treatment MF with AMF (twice) versus growth of nontreated tumor. ●—growth of nontreated tumor, ■—growth of treated tumor. Ordinate—tumor volume, cm3; abscise—time of observation from the first treatment, days. Treatments were indicated with arrows. Data are presented as the mean ± s.e.m.
Temperature in tumor under influence of combined treatment with MF and AMF was reached in the average 46.4–47.0°C at the 30th min of the treatment. Complete regression of tumor was registered in 15% of cases.
Growth of Guerin carcinoma after combined treatment by MF with AMF supplemented with cisplatinum. ■—growth of treated tumor; ●—growth of nontreated tumor. Treatments (nanohyperthermia) were indicated with arrows. Cisplatinum was administered twice (on the 1st and 2nd sessions of nanohyperthermia) at a dose of 1.5 mg
Rat number 2 (07.05.12) with Growth of Guerin carcinoma and non-treated control rat number 1 (07.05.12). Growth of Guerin carcinoma after combined treatment by MF with AMF supplemented with cisplatinum. ■—growth of nontreated tumor; ●—growth of treated tumor. Treatments (nanohyperthermia) were indicated with arrows. Cisplatinum was administered on the 1st and 2nd sessions of nanohyperthermia) at a dose of 1.5 mg
Growth of Walker-256 carcinosarcoma after combined treatment by MF with AMF supplemented with cisplatinum. Treatment was single (it was indicated with arrow) at a dose of 1.5 mg
The equivalency of antitumor effect of cisplatin at a dose of 3.0 mg
Results of nanothermochemotherapy of rat’s solid tumors.
Tumor | Number of rats with complete tumor regression (%) | Number of cured rats (%)* |
---|---|---|
Guerin carcinoma | ||
Untreated control ( |
0 | 0 |
MF + AMF + cisplatin |
75.0 | 75.0 |
cisplatin |
32 | 25 |
cisplatin |
51 | 45 |
Walker-256 carcinosarcoma | ||
Untreated control ( |
0 | 0 |
MF + AMF + cisplatin |
80.0 | 80.0 |
cisplatin |
85 | 80 |
cisplatin |
92.0 | 85.0 |
*Rats with complete tumor regression and without tumor recurrence within 120 days after complete regression of tumor;
Lewis lung carcinoma growth and metastasis value after treatment of primary tumor with MF combined with AMF.
Animal groups | Change in the volume of primary tumor (on the 15th day after the treatment) | Number of metastases in lungs per mice |
---|---|---|
Nontreated tumor-bearing mice, |
Increase by 20-fold | 24 ± 2.3 |
Nanohyperthermia of primary tumor, |
Increase by 5-fold |
8 ± 0.8 |
Lewis lung carcinoma growth after two combined treatments by MF with AMF (indicated with arrows) versus nontreated, treated with MF alone as well as AMF alone (■—non-treated, ●—AMF, ▲—MF, ▼—MF + AMF). Ordinate—tumor volume, cm3, abscise—time of observation from the first treatment, days. Data are presented as the mean ± s.e.m.
Pollert et al. [
L
In model experiments, it was determined that the temperature of MF on the basis of lanthanum-strontium manganite under AMF (300 kHz, 7.7 kA
Experiments
The increase of temperature was shown
The authors report no conflict of interests. The authors alone are responsible for the content and writing of the paper.
This research was supported by the National Academy of Sciences of Ukraine (Program “Basic problems of nanostructure systems, nanomaterials, nanotechnologies,” Grant no. 111