Research Article
Multimodal doxorubicin loaded magnetic nanoparticles for VEGF targeted theranostics of breast cancer

https://doi.org/10.1016/j.nano.2018.04.019Get rights and content

Abstract

In presented paper we have developed new system for cancer theranostics based on vascular endothelial growth factor (VEGF) targeted magnetic nanoparticles. Conjugation of anti-VEGF antibodies with bovine serum albumin coated PEGylated magnetic nanoparticles allows for improved binding with murine breast adenocarcinoma 4T1 cell line and facilitates doxorubicin delivery to tumor cells. It was shown that intravenous injection of doxorubicin loaded VEGF targeted nanoparticles increases median survival rate of mice bearing 4T1 tumors up to 50%. On the other hand magnetic resonance imaging (MRI) of 4T1 tumors 24 h after intravenous injection showed accumulation of nanoparticles in tumors, thus allowing simultaneous cancer therapy and diagnostics.

Graphical Abstract

Targeted therapy is one of the most advanced techniques in treatment of malignant tumors, but still it has some limitations, mostly associated with difficulties in development and clinical approbation of new tumor specific ligands. One of the approaches is to use already existing molecules as targeting moieties. In this study we present use of monoclonal antibodies to VEGF as effective ligand for doxorubicin loaded magnetic nanoparticles delivery for tumor therapy and diagnostics.

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Materials

N-hydroxysuccinimide (NHS), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), bovine serum albumin (BSA), 6-aminofluorescein, Tween-20, Triton X-100, Sepharose CL-4B, 4,6-diamidino-2-phenylindole (DAPI), nonspecific mouse immunoglobulins (IgG), phosphate buffer saline (PBS), dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich, USA. Monoamino terminated poly(ethylene glycol) hydrochloride (NH2-PEG-OH) was from Creative PEGworks, USA. Cyanine5 (Cy5) label was purchased from Lumiprobe

Synthesis and characterization of MNP

Thermal decomposition of iron (III) acetylacetonate has resulted in production of dark brown powder, which nicely dissolves in water at pH 9-11. After adsorption of BSA and stabilization of protein coating by crosslinking and PEGylation the samples were characterized by TEM and AFM (Figure 1) Presented image shows narrow distribution of iron oxide core of obtained MNP with average diameter 8±3 nm. Due to low contrast between elements with low molecular weight e.g. C, O, N on TEM we were not

Discussion

To provide active targeted delivery of anticancer drug and to increase its anti-tumor effectiveness it is needed to obtain nanocarrier with high specificity to cancer cells. As a nanocarrier we chose iron oxide magnetic nanoparticles, which are coated by BSA and PEG and conjugated with mAb VEGF. However during the process of synthesis the conjugation of antibodies by itself might disrupt their three dimensional structure or modify the binding site that will lead to loss of immunochemical

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    This work was supported by Grant of President of Russian Federation (grant number MK-6371.2016.7), RSF grant 17-14-01316 (investigation of Dox loading) and grant of Ministry of Education and Science of the Russian Federation in the framework of Increase Competitiveness Program of NUST «MISiS» №K2-2015-071 (assessment of nanoparticles toxicity) and №K4-2017- 046 (assessment of MRI study).

    Conflicts of interest: There are no conflicts to declare.

    1

    Both authors contributed equally.

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