Multifunctional magnetic Fe3O4 nanoparticles combined with chemotherapy and hyperthermia to overcome multidrug resistance.

BACKGROUND: Multidrug resistance in cancer is a major obstacle for clinical therapeutics, and is the reason for 90% of treatment failures. This study investigated the efficiency of novel multifunctional Fe(3)O(4) magnetic nanoparticles (Fe(3)O(4)-MNP) combined with chemotherapy and hyperthermia for overcoming multidrug resistance in an in vivo model of leukemia. METHODS: Nude mice with tumor xenografts were randomly divided into a control group, and the treatment groups were allocated to receive daunorubicin, 5-bromotetrandrine (5-BrTet) and daunorubicin, Fe(3)O(4)-MNP, and Fe(3)O(4)-MNP coloaded with daunorubicin and 5-bromotetrandrine (Fe(3)O(4)-MNP-DNR-5-BrTet), with hyperthermia in an alternating magnetic field. We investigated tumor volume and pathology, as well as P-glycoprotein, Bcl-2, Bax, and caspase-3 protein expression to elucidate the effect of multimodal treatment on overcoming multidrug resistance. RESULTS: Fe(3)O(4)-MNP played a role in increasing tumor temperature during hyperthermia. Tumors became significantly smaller, and apoptosis of cells was observed in both the Fe(3)O(4)-MNP and Fe(3)O(4)-MNP-DNR-5-BrTet groups, especially in the Fe(3)O(4)-MNP-DNR-5-BrTet group, while tumor volumes in the other groups had increased after treatment for 12 days. Furthermore, Fe(3)O(4)-MNP-DNR-5-BrTet with hyperthermia noticeably decreased P-glycoprotein and Bcl-2 expression, and markedly increased Bax and caspase-3 expression. CONCLUSION: Fe(3)O(4)-MNP-DNR-5-BrTet with hyperthermia may be a potential approach for reversal of multidrug resistance in the treatment of leukemia.

The changes of T lymphocytes and cytokines in ICR mice fed with Fe3O4 magnetic nanoparticles.

The aim of this article is to study the changes inhibited T lymphocytes and cytokines related to the cellular immunity in ICR (imprinting control region) mice fed with Fe(3)O(4) magnetic nanoparticles (Fe(3)O(4)-MNPs). The Fe(3)O(4)-MNPs were synthesized, and their characteristics such as particle size, zeta potential, and X-ray diffraction patterns were measured and determined. All ICR mice were sacrificed after being exposed to 0, 300, 600, and 1200 mg/kg of Fe(3)O(4)-MNPs by single gastric administration for 14 days. Splenocytes proliferation was indicated with stimulate index by MTT assay; release of cytokines in the serum of ICR mice was detected by enzyme-linked immunosorbent assay, and the phenotypic analyses of T-lymphocyte subsets were performed using flow cytometry. Our results indicated that there were no significant differences in splenocyte proliferation and release of cytokines between exposed and control groups. Furthermore, there was no significant difference in the proportions of T-lymphocyte subsets in the low-dose Fe(3)O(4)-MNPs group when compared to the control group, but the proportions of CD3(+)CD4(+) and CD3(+)CD8(+) T-lymphocyte subsets both in the medium- and high-dose Fe(3)O(4)-MNPs groups were higher than those in the control group. It is concluded that a high dose of Fe(3)O(4)-MNPs, to some extent, could influence in vivo immune function of normal ICR mice.

[Influence of magnetic Fe3O4 nanoparticle on functions of lymphocytes and macrophages in mice].

This study was purposed to investigate the effects of magnetic nanoparticle of Fe3O4 (Fe3O4-MNPs) on murine immune system. ICR mice were assigned randomly into four groups which were treated with normal saline, low, middle and high dose of MNP-Fe3O4 respectively. The mice were killed after being exposed by intragastric administration for 2 weeks. The ratios of spleen weight to body weight, lymphocyte transformation rate in spleen suspension and phagocytic index of macrophage in abdominal cavity were detected. The results showed that the ratios of spleen weight to body weight in Fe3O4-MNP groups were not significantly different in comparison with the control (p > 0.05). The lymphocyte transformation rate in spleen suspension in Fe3O4-MNP groups were all higher than that in control group (-0.1775 +/- 0.0246), especially in the middle dose group (0.1833 +/- 0.0593) (p < 0.05), and the phagocytic index of macrophages in abdominal cavity of middle dose group (0.2051 +/- 0.0213) was higher than that of control group and other two Fe3O4-MNP group (low dose 0.1538 +/- 0.0100, high dose 0.1511 +/- 0.0184) (p < 0.05). It is concluded that suitable dose of Fe3O4-MNP can enhance the cellular immune activity and phagocytic function of macrophages of mice.

Synergistic effect of magnetic nanoparticles of Fe(3)O(4) with gambogic acid on apoptosis of K562 leukemia cells.

Gambogic acid (GA) has a significant anticancer effect on a wide variety of solid tumors. Recently, many nanoparticles have been introduced as drug-delivery systems to enhance the efficiency of anticancer drug delivery. The aim of this study was to investigate the potential benefit of combination therapy with GA and magnetic nanoparticles of Fe(3)O(4) (MNPs-Fe(3)O(4)). The proliferation of K562 cells and their cytotoxicity were evaluated by MTT assay. Cell apoptosis was observed and analyzed by microscope and flow cytometry, respectively. Furthermore, real-time polymerase chain reaction and Western blotting analyses were performed to examine gene transcription and protein expression, respectively. The results showed that MNPs-Fe(3)O(4) dramatically enhanced GA-induced cytotoxicity and apoptosis in K562 cells. The typical morphological features of apoptosis treated with GA and MNPs-Fe(3)O(4) were observed under an optical microscope and a fluorescence microscope, respectively. The transcription of caspase-3 and bax gene in the group treated with GA and MNPs-Fe(3)O(4) was higher than that in the GA-alone group or MNPs-Fe(3)O(4)-alone group, but the transcription of bcl-2, nuclear factor-kappaB, and survivin degraded as did the expression of corresponding proteins in K562 cells. Our data suggests a potential clinical application of a combination of GA and MNPs-Fe(3)O(4) in leukemia therapy.

Reversal in multidrug resistance by magnetic nanoparticle of Fe3O4 loaded with adriamycin and tetrandrine in K562/A02 leukemic cells.

Drug resistance is a primary hindrance for efficiency of chemotherapy. To investigate whether Fe3O4-magnetic nanoparticles (Fe3O4-MNPs) loaded with adriamycin (ADM) and tetrandrine (Tet) would play a synergetic reverse role in multidrug resistant cell, we prepared the drug-loaded nanoparticles by mechanical absorption polymerization to act with K562 and one of its resistant cell line K562/A02. The survival of cells which were cultured with these conjugates for 48 h was observed by MTT assay. Using cells under the same condition described before, we took use of fluorescence microscope to measure fluorescence intensity of intracellular ADM at an excitation wavelength of488 nm. P-glycoprotein (P-gp) was analyzed with flow cytometer. The expression ofmdrl mRNA was measured by RT-PCR. The results showed that the growth inhibition efficacy of both the two cells increased with augmenting concentrations of Fe3O4-MNPs which were loaded with drugs. No linear correlation was found between fluorescence intensity of intracellular adriamycin and augmenting concentration of Fe3O4-MNPs. Tet could downregulate the level of mdr-1 gene and decrease the expression of P-gp. Furthermore, Tet polymerized with Fe3O4-MNPs reinforced this downregulation, causing a 100-fold more decrease in mdrl mRNA level, but did not reduce total P-gp content. Our results suggest that Fe3O4-MNPs loaded with ADM or Tet can enhance the effective accumulation of the drugs in K562/A02. We propose that Fe3O4-MNPs loaded with ADM and Tet probably have synergetic effect on reversal in multidrug resistance.