Although iron oxide magnetic nanoparticles (MNP) have been proposed for numerous biomedical applications, little is known about their biotransformation and long-term toxicity in the body. Dimercaptosuccinic acid (DMSA)-coated magnetic nanoparticles have been proven efficient for in vivo drug delivery, but these results must nonetheless be sustained by comprehensive studies of long-term distribution, degradation and toxicity. We studied DMSA-coated magnetic nanoparticles effects in vitro on NCTC 1469 nonparenchymal hepatocytes, and analyzed their biodistribution and biotransformation in vivo in C57BL/6 mice. Our results indicate that DMSA-coated magnetic nanoparticles have little effect on cell viability, oxidative stress, cell cycle or apoptosis on NCTC 1469 cells in vitro. In vivo distribution and transformation was studied by alternating current magnetic susceptibility measurements, a technique that permits distinction of MNP from other iron species. Our results show that DMSA-coated MNP accumulate in spleen, liver and lung tissues for extended periods of time, in which nanoparticles undergo a process of conversion from superparamagnetic iron oxide nanoparticles to other nonsuperparamagnetic iron forms, with no significant signs of toxicity.
In vitro and in vivo behavior showed that these nanoparticles are efficient carriers for drug delivery to the liver and brain that can be combined with MRI detection.
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
We analysed magnetic nanoparticle biodistribution, before and after cytokine conjugation, in a mouse model by AC susceptibility measurements of the corresponding resected tissues. Mice received repeated intravenous injections of nanoparticle suspension for two weeks and they were euthanized one hour after the last injection. In general, only 10% of the total injected nanoparticles after multiple exposures were found in tissues. The rest of the particles may probably be metabolised or excreted by the organism. Our findings indicate that the adsorption of interferon to DMSA-coated magnetic nanoparticles changes their biodistribution, reducing the presence of nanoparticles in lungs and therefore their possible toxicity. The specific targeting of the particles to tumour tissues by the use of an external magnetic field has also been studied. Magnetic nanoparticles were observed by transmission electron microscopy (TEM) in the targeted tissue and quantified by AC magnetic susceptibility.
Translationally controlled tumor protein (TCTP) has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. Therefore, TCTP is now recognized as a potential therapeutic target in several cancers including prostate, breast and lung cancers. We previously showed that TCTP is overexpressed in castration-resistant prostate cancer (CRPC), and it has been implicated resistance to treatment. Recently, we developed TCTP antisense oligonucleotides (ASOs) to inhibit TCTP expression. However, the intracellular delivery and silencing activity of these oligonucleotides remains a challenge, and depend on the use of transfection agents and delivery systems. Here we show that lipid-modified ASO (LASOs) has improved penetration and efficiency in inhibiting TCTP expression in the absence of additional transfection agents, both in vitro and in vivo. Transfection with TCTP-LASO led to rapid and prolonged internalization via macropinocytosis, TCTP downregulation and significant decreased cell viability. We also show that lipid-modification led to delayed tumor progression in CRPC xenografts models, with no significant toxic effects observed.
Magnetic hyperthermia has a significant potential to be a new breakthrough for cancer treatment. The simple concept of nanoparticle-induced heating by the application of an alternating magnetic field has attracted much attention, as it allows the local heating of cancer cells, which are considered more susceptible to hyperthermia than healthy cells, while avoiding the side effects of traditional hyperthermia. Despite the potential of this therapeutic approach, the idea that local heating effects due to the application of alternating magnetic fields on magnetic nanoparticle-loaded cancer cells can be used as a treatment is controversial. Several studies indicate that the heating capacity of magnetic nanoparticles is largely reduced in the cellular environment due to increased viscosity, aggregation and dipolar interactions. However, an increasing number of studies, both in vitro and in vivo, show evidence of successful magnetic hyperthermia treatment on several different types of cancer cells. This apparent contradiction might be due to the use of different experimental conditions. Here we analyze the effects of several parameters on the cytotoxic efficiency of magnetic nanoparticles as heat inductors under an alternating magnetic field. Our results indicate that cell-nanoparticle interaction reduces the cytotoxic effects of magnetic hyperthermia, independently of nanoparticle coating and core size, the cell line used and the subcellular localization of nanoparticles. However, there seems to occur a synergistic effect between the application of an external source of heat and the presence of magnetic nanoparticles, leading to higher toxicities than those induced by heat alone, or the accumulation of nanoparticles within cells.
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