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  • In this work we fabricated a

    2019-10-09

    In this work, we fabricated a kind of multifunctional nanoparticles, based on HAuNS coated by chitosan-stearic Ki8751 and copolymer (CSO-SA), which was employed frequently to form micelles for hydrophobic drug delivery in our previous work [21], [22]. The nanoparticles can encapsulate DiR efficiently, a near-infrared lipophilic fluorescent tracer. Furthermore, we conjugated a peptide on the surface of the nanoparticles (TNYL peptide conjugated CSO-SA micelles, Scheme 1), which displayed high binding affinity to EphB4 overexpressed in numerous tumor types [23], [24], [25], [26], [27]. Herein, we hope that the nanoparticles\' accumulation in tumors can be enhanced via the EphB4 mediation. We hypothesized that, firstly, real-time monitoring of the nanoparticles\' biodistribution in EphB4-positive tumors can be obtained by the optical imaging from DiR in the nanoparticles, and then efficient PTT can be carried out according to the information of the nanoparticles\' accumulation in the tumors.
    Materials and methods
    Results
    Discussion High accumulation ratio of photothermal agents in tumors to the normal tissues around the tumors is the key to obtain the high efficacy of PTT and avoid the damage of normal tissues. By increasing the photoabsorber accumulation in tumors, we can ‘burn’ the tumor efficiently under the laser power as low as possible, and so keep the normal tissues more safe. In this work, we conjugated a peptide TNYL on the surface of the nanoparticles to obtain a higher accumulation of the photothermal agent in tumors via the mediation of EphB4. Our results demonstrated adequately that the significantly increased accumulation of DTCSH in the tumors with EphB4 positive expression using the double tumor models with positive and negative EphB4 expression in the same mice (Fig. 5). For A549 tumors (EphB4 negative), the localization of tumor could be only attributed to the enhanced permeability and retention (EPR) effect of the nanoparticles. However, for SKOV3 tumors (EphB4 positive), besides the EPR effect, specific uptake via EphB4 mediation also contributed to the accumulation of DTCSH in the tumors, which was fully demonstrated by the EphB4-blocking study in vitro (Fig. 2B) and in vivo (Fig. 5A: b). At 48 h after injection, DTCSH accumulated in SKOV3 tumors was 2-fold more than that of A549 tumors (Fig. 5C). As far as we know, our study is the first to verify specific nanoparticles tumor location using a double tumor mode in the same mice in vivo and a double tumor-cell co-culture strategy in the same well in vitro. Our results demonstrated the feasibility of increasing the accumulation of nanoparticles into EphB4-positive tumors by the interaction between TNYL-peptide on the nanoparticles and EpHB4 on tumor cells. DTCSH exhibited significantly stronger photothermal ablation activity against EphB4-positive tumors than EphB4-negative tumors (Fig. 6). Coating HAuNS by COS-SA (CS) polymer is to increase the internalization of the nanoparticles into tumor cells. In our previous study, CS polymer was widely employed to form micelles in aqueous medium and increase the cellular uptake of the payload [21], [22], [28], [29]. It was found that the micelles could present a so-called special spatial structure of multiple “minor-cores” in the aqueous medium, which induces its excellent internalization into cells. The explanation is “minor-cores” can insert into the cellular membrane, exerting hydrophobic interactions with membrane components, resulting in membrane perturbation and fusion, thus facilitating endocytosis of the micelles. In this work, the synthesized HAuNS was highly hydrophilic due to the coating of citrate group. So, OMP was firstly conjugated onto the surface of HAuNS using the reaction between hydrosulfide group in OMP with Au to obtain the hydrophobic HAuNS. The hydrophobic HAuNS was easily coated by TNYL-CSO-SA (TCS) due to the interaction between hydrophobic chain in OMP and SA in TCS. The absorption spectra showed that the plasma resonance peaks for TCSH were in the NIR region (∼800 nm) (Fig. 1C). Thus, TCS coating did not affect the spectrum characteristic of HAuNS. Our data showed the obvious fluorescent signal in SKOV3 and A549 cells after only 1 h incubation, indicating the real cellular uptake of DCSH (Non-targeting) and DTCSH (Targeting) in both cell lines (Fig. 2A and C), and more high fluorescent intensity in SKOV3 cells owing to the mediation of EphB4 receptor (Fig. 2A).