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, 7 (3), 1901293
eCollection

Engineered Cell-Derived Microparticles Bi 2 Se 3/DOX@MPs for Imaging Guided Synergistic Photothermal/Low-Dose Chemotherapy of Cancer

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Engineered Cell-Derived Microparticles Bi 2 Se 3/DOX@MPs for Imaging Guided Synergistic Photothermal/Low-Dose Chemotherapy of Cancer

Dongdong Wang et al. Adv Sci (Weinh).

Abstract

Cell-derived microparticles, which are recognized as nanosized phospholipid bilayer membrane vesicles, have exhibited great potential to serve as drug delivery systems in cancer therapy. However, for the purpose of comprehensive therapy, microparticles decorated with multiple therapeutic components are needed, but effective engineering strategies are limited and still remain enormous challenges. Herein, Bi2Se3 nanodots and doxorubicin hydrochloride (DOX) co-embedded tumor cell-derived microparticles (Bi2Se3/DOX@MPs) are successfully constructed through ultraviolet light irradiation-induced budding of parent cells which are preloaded with Bi2Se3 nanodots and DOX via electroporation. The multifunctional microparticles are obtained with high controllability and drug-loading capacity without unfavorable membrane surface destruction, maintaining their excellent intrinsic biological behaviors. Through membrane fusion cellular internalization, Bi2Se3/DOX@MPs show enhanced cellular internalization and deepened tumor penetration, resulting in extreme cell damage in vitro without considering endosomal escape. Because of their distinguished photothermal performance and tumor homing target capability, Bi2Se3/DOX@MPs exhibit admirable dual-modal imaging capacity and outstanding tumor suppression effect. Under 808 nm laser irradiation, intravenous injection of Bi2Se3/DOX@MPs into H22 tumor-bearing mice results in remarkably synergistic antitumor efficacy by combining photothermal therapy with low-dose chemotherapy in vivo. Furthermore, the negligible hemolytic activity, considerable metabolizability, and low systemic toxicity of Bi2Se3/DOX@MPs imply their distinguished biocompatibility and great potential for tumor theranostics.

Keywords: cell‐derived microparticles; dual‐modal imaging; electroporation; membrane fusion; synergistic therapy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Schematic illustration for fabrication of multifunctional cell‐derived microparticles (Bi2Se3/DOX@MPs) and their application for CT/PA dual‐modal imaging guided synergistic photothermal/low‐dose chemotherapy.
Figure 1
Figure 1
Characterization of Bi2Se3/DOX@MPs. TEM images of a) Bi2Se3 nanodots, b) MPs, and c) Bi2Se3/DOX@MPs. d) Hydrodynamic size distribution and e) zeta potential of Bi2Se3 nanodots, unloaded MPs and Bi2Se3/DOX@MPs. Stability of Bi2Se3/DOX@MPs during storage in PBS and FBS at 4 °C monitored by f) hydrodynamic size and g) zeta potential. h) Fluorescence images of DiO‐labeled MPs, Bi2Se3/DOX@MPs and DiO‐labeled Bi2Se3/DOX@MPs. i) SDS‐PAGE protein patterns of H22 cells, unloaded MPs, and Bi2Se3/DOX@MPs. j) The intracellular content of DOX and Bi2Se3 (µg 10−6 cells) introduced by electroporation or incubation. k) DOX and Bi2Se3 contents of Bi2Se3/DOX@MPs generated from donor cells by electroporation or incubation. l) The protein amount of Bi2Se3/DOX@MPs generated from donor cells by electroporation or incubation.
Figure 2
Figure 2
Photothermal properties and enhanced cell uptake of Bi2Se3/DOX@MPs. a) UV–vis–NIR absorption spectra and b) temperature elevation curves of Bi2Se3/DOX@MPs at different concentrations. c) Comparison on temperature elevation of Bi2Se3 nanodots, Bi2Se3@MPs and Bi2Se3/DOX@MPs at the same concentration under NIR irradiation. d) Infrared thermal images of Bi2Se3/DOX@MPs at different concentrations under NIR irradiation. e) Photothermal conversion cycling study of Bi2Se3/DOX@MPs under NIR irradiation. f) CLSM images and g) mean fluorescence intensity of H22 cells respectively incubated with free DOX and Bi2Se3/DOX@MPs for 2 and 4 h. h) The containing amount of Bi2Se3 in H22 cells respectively incubated with Bi2Se3 nanodots and Bi2Se3/DOX@MPs for 2 and 4 h.
Figure 3
Figure 3
Cellular internalization pathway of Bi2Se3/DOX@MPs. CLSM images of H22 cells incubated with a) Bi2Se3/DOX@MPs and b) DiO‐labeled Bi2Se3/DOX@MPs for 2 and 4 h. Cell nucleus were labeled with DAPI (blue) in both (a) and (b). Lysosomes were labeled with LysoTracker Deep Red (green) in (a). The concentration of DOX was fixed at 1 µg mL−1. c) Flow cytometric profile and d) relative cellular uptake of Bi2Se3/DOX@MPs in the presence of specific endocytosis inhibitors. e) Flow cytometric profile and f) relative cellular uptake of Bi2Se3/DOX@MPs before or after blocking by VAMP 2 Ab, VAMP 3 Ab, VAMP 7 Ab, VAMP 2/3/7 Ab.
Figure 4
Figure 4
In vitro penetration and cytotoxicity of Bi2Se3/DOX@MPs. a) Z‐stack CLSM images and b) relative fluorescence intensity of DOX into H22 3D tumor spheroids treated with free DOX and Bi2Se3/DOX@MPs for 4 h. c) In vitro cytotoxicity of free DOX, Bi2Se3 nanodots, Bi2Se3/@MPs and Bi2Se3/DOX@MPs with or without NIR irradiation at different concentrations on H22 cells after 24 h incubation. d) Fluorescence images of H22 cells treated with PBS and Bi2Se3/DOX@MPs with or without NIR irradiation. The living cells were stained with calcein‐AM (green) and the dead cells were stained with PI (red).
Figure 5
Figure 5
In vivo biodistribution and photothermal performance of Bi2Se3/DOX@MPs. In vivo biodistribution monitored by Bi element after injecting a) Bi2Se3 nanodots and b) Bi2Se3/DOX@MPs intravenously at 6, 12, 24, and 48 h. c) Infrared thermal images H22 tumor‐bearing BALB/c mice injected with PBS, Bi2Se3 nanodots, Bi2Se3/DOX@MPs for 12 h with NIR irradiation. d) Corresponding temperature increase in tumor site measured from c.
Figure 6
Figure 6
Dual‐modal imaging of Bi2Se3/DOX@MPs. a) Color‐mapped PA images and measured PA intensity of Bi2Se3/DOX@MPs at different Bi2Se3 concentrations. b) In vivo PA imaging of tumor site before and after intravenous injection of Bi2Se3/DOX@MPs (20 mg kg−1) at different time points, corresponded with the average PA intensity. c) CT images and HU value of Bi2Se3/DOX@MPs and iohexol at different concentrations. d) In vivo transverse section and e) reconstructed 3D CT images of tumor‐bearing mice before and after injection of Bi2Se3/DOX@MPs.
Figure 7
Figure 7
In vivo tumor inhibition of Bi2Se3/DOX@MPs. Relative a) tumor volumes and b) body weights of H22 tumor‐bearing BALB/c mice after different treating. c) Representative photos and average tumor weight of excised tumors 15 days after treatments. d) H&E staining (200 ×) of the tumor tissues after the indicated treatments.

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