NIR dye-loaded mesoporous silica nanoparticles for a multifunctional theranostic platform: Visualization of tumor and ischemic lesions, and performance of photothermal therapy

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Abstract

We report the fabrication of multifunctional theranositic biomaterials via non-covalent, rapid, and effective encapsulation of 1,1′dioctadecyl-3,3,3′,3′-tetrametylindotrucarbocyanine iodide (DIR) onto mesoporous silica nanoparticles by coating the surface of polyethylene glycol (PEG-DIR@MSN). PEG-DIR@MSNs exhibited great stability with excellent biocompatibility and photothermal conversion properties. PEG-DIR@MSN allowed for not only the detection of various types of tumor and ischemic lesions but also photothermal therapy against breast cancer in living mice, suggesting that PEG-DIR@MSN is a valuable multifunctional theranostic platform.

Introduction

Mesoporous silica nanoparticles (MSNs) have been extensively investigated as a platform for imaging and therapy owing to their unique properties, including high loading capacity due to large surface area and pore volume, biocompatibility, strong biochemical stability, and easy surface modification [1], [2], [3], [4].

Due to these benefits, extensive studies have been performed focusing on the biosafety evaluation, as well as the therapeutic and diagnostic applications of chemically fabricated MSNs for various diseases [4], [5], [6]. Recent in vivo studies have reported that the safety of MSNs are associated with the fabrication procedures, geometries, particles sizes, dosing parameters, and injection route [1], [4], [7]. Moreover, several reports have identified novel optical imaging agents via encapsulation of semiconductor quantum dots (QDs) [8], [9], carbon dots (CDs) [10], [11], and upconversion nanoparticles (UCNPs) [12], [13] into MSNs. Additional studies have investigated clinically useful imaging agents comparable to nuclear medicine imaging techniques, such as positron emission tomography (PET) [14], [15] single photon emission tomography (SPECT), magnetic resonance imaging (MRI) [16], and computed tomography (CT) [17] imaging, via introduction of their unique imaging tracers. Lastly, reports have also demonstrated the remarkable progress made in the development of MSN-based theranostic nanoparticles via combination of therapeutic agents with imaging probes [4], [18], [19].

Among their various biological applications, MSN functionalized with near infrared (NIR) fluorescence dyes between 700 and 900 nm showed great potential as not only an in vivo optical imaging platform for the visualization of sentinel lymph nodes, cell migration, ischemia and tumor lesion, but also photothermal therapeutic agents with laser irradiation. Due to their unique merits, intensive study has been conducted on biomedical applications of NIR fluorescent functionalized MSNs.

Easy, simple, and efficient fabrication of functionalized MSNs is an important aspect for the accelerated development of attractive biomaterials that would be directly applicable to the clinic [1], [5]. However, time-consuming multistep procedures have still been required to synthesize the functionalized MSNs as a therapeutic platform. Particularly, to encapsulate the NIR fluorescent dyes in MSNs, they should be properly incorporated via either non- or covalent coupling between fluorescent dye and silica. To effectively reduce the production time and complexity, an efficient encapsulation approach of NIR fluorescent dyes onto MSNs is required.

Herein, we report on a ultrafast and efficient coordination bonding method for loading 1,1′dioctadecyl-3,3,3′,3′-tetrametylindotrucarbocyanine iodide (DIR) as a commercial NIR fluorescent dye to MSNs (DIR@MSNs) for the development of novel multifunctional theranostic biomaterials. PEGylated DIR@MSNs (PEG-DIR@MSNs) exhibited superior stability in human serum with good biocompatibility both in vitro and in vivo. Hence, PEG-DIR@MSNs can be used for in vivo detection of various types of tumor and ischemic lesions via eliciting enhanced permeability and retention (EPR) effects. Furthermore, the combination of PEG-DIR@MSNs and NIR 808 nm laser irradiation leads to strong antitumor photothermal therapy (PTT) effects (Fig. 1).

Section snippets

Materials

Hexadecyltrimethylammoniumbromide (CTAB), tetraethylorthosilicate (TEOS) and amino-propyltriethoxysilane (APTES) were purchased from Sigma Aldrich Chemical Co. (St. Louis, MO, USA). Methoxy-PEG24-NHS ester was obtained from NANOCS (NY, USA). Phosphate buffered saline (PBS, pH 7.4) was supplied by Biosesang (Seoungnam, South Korea). 1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DIR) was purchased from Thermo Scientific (Rockford, USA).

Animals and cells

Pathogen-free six-week-old female Balb/c

Synthesis of NIR fluorescent dyes

DIR, loaded mesoporous silica nanoparticles with PEGylation (PEG-DIR@MSNs). In order to produce the PEG-MSNs with 100–150 nm particle size, our previously reported methods were introduced [22]. DIR as NIR fluorescent dyes were selected and applied as in vivo imaging agents owing to the excellent quantum yield and biocompatibility [23], [24], [25]. A reaction between amino functionalized MSN-NH2, 3 mg/mL were and a bulky chain-length N-hydroxyl succinimide (NHS)-PEG (MeO-PEG24-NHS ester, 1 mg/mL)

Conclusion

In this study, we showed the rapid and efficient encapsulation of NIR fluorescent dyes onto mesoporous silica nanoparticles in phosphate buffer conditions via entrapping of coordination bonding inside self-sealed silica nanochannels of mesoporous silica nanoparticles (PEG-DIR@MSNs). PEG-DIR@MSNs have excellent stability, biocompatibility, and photothermal conversion ability in vitro and in vivo. Importantly, we have proved the feasibility of PEG-DIR@MSNs as a multifunctional theranostic

Funding

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korea[A1] government (MSIP; grant numbers 2014R1A1A1003323, 2017R1D1A1B03028340, and 2018R1D1AB07047417); and the Korea [A2] Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI16C1501).

Conflicts of interest

There are no conflicts to declare.

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