Abstract
Simple SummaryThe application of simultaneous and different strategies to treat cancer appears a promising therapeutic approach. Herein we proposed the application of chemotherapy combined with a magnetic nanocarrier delivery system to an in vitro and an in vivo experimental mammary carcinoma model. Drug-loaded biomimetic magnetic nanoparticle can be directed and concentrated on the tumor cells or site by the apposition of a magnet. Moreover, these nanoparticles can respond to an alternating magnetic field by developing hyperthermia around 43 °C, a temperature at which tumor cells, but not healthy cells, are particularly sensitive and thus induced to death. Indeed, when this nanoformulation is injected in vivo in the tumor site, and hyperthermia is generated, the combined chemo-thermal therapy mediated by these drug-loaded magnetic nanoparticles have a stronger therapeutic benefit compared to that carried out by the chemotherapeutic alone. These nanoformulation and strategy are thus promising tools for translational applications in cancer therapy.Biomimetic magnetic nanoparticles mediated by magnetosome proteins (BMNPs) are potential innovative tools for cancer therapy since, besides being multifunctional platforms, they can be manipulated by an external gradient magnetic field (GMF) and/or an alternating magnetic field (AMF), mediating targeting and hyperthermia, respectively. We evaluated the cytocompatibility/cytotoxicity of BMNPs and Doxorubicin (DOXO)-BMNPs in the presence/absence of GMF in 4T1 and MCF-7 cells as well as their cellular uptake. We analyzed the biocompatibility and in vivo distribution of BMNPs as well as the effect of DOXO-BMNPs in BALB/c mice bearing 4T1 induced mammary carcinomas after applying GMF and AMF. Results: GMF enhanced the cell uptake of both BMNPs and DOXO-BMNPs and the cytotoxicity of DOXO-BMNPs. BMNPs were biocompatible when injected intravenously in BALB/c mice. The application of GMF on 4T1 tumors after each of the repeated (6×) iv administrations of DOXO-BMNPs enhanced tumor growth inhibition when compared to any other treatment, including that with soluble DOXO. Moreover, injection of DOXO-BMNPs in the tumor combined with application of an AMF resulted in a significant tumor weight reduction. These promising results show the suitability of BMNPs as magnetic nanocarriers for local targeted chemotherapy and as local agents for hyperthermia.
Highlights
With its high burden on lives and being the second most common cause of morbidity and mortality in western countries, cancer represents a major public health problem
The same results were observed for the expression of mTOR, for which expression and level of phosphorylation are the full cytocompatibility of biomimetic magnetic nanoparticles (BMNPs) the presence ofthe a gradient magnetic field (GMF), we evaluated whether underShowing the control of Akt
Showing the full cytocompatibility of BMNPs in the presence of a GMF, we evaluated whether the apposition of the GMF enhanced the interaction of BMNPs with cells. 4T1 and MCF-7 cells plated on coverslips were incubated for different times with 100 μg/mL BMNPs in the presence or absence of a magnet, were fixed, were washed, and were stained with Prussian blue
Summary
With its high burden on lives and being the second most common cause of morbidity and mortality in western countries, cancer represents a major public health problem. One way to increase DOXO efficiency is to optimize selective drug delivery to the tumor site, which could be done by means of nanocarriers that allow external guidance and control. In this context, magnetic nanoparticles (MNPs) offer a series of advantages that make them attractive candidates for this goal. BMNPs from oxidation and confers new surface properties to the BMNPs due to exposition of the functional groups of the protein These BMNPs have an iep at pH 4.4, which allows electrostatic coupling to positively charged molecules such as DOXO at physiological pH and drug release at acidic pH [14,15]. The in vivo suitability of the use of DOXO-BMNPs for nano-targeted chemotherapy and MH elicitation in a mammary carcinoma experimental model was evaluated
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