Regulating Aggregation-Induced Emission Luminogen for Multimodal Imaging-Navigated Synergistic Therapy Involving Anti-Angiogenesis

Abstract

As a new avenue for cancer research, phototheranostics has shown inexhaustible and vigorous vitality as it permits real-time diagnosis and concurrent in situ therapy upon non-invasive light-initiation. However, construction of an advanced material, allowing prominent phototheranostic outputs and synchronously surmounting the inherent deficiency of phototheranostics, would be an appealing yet significantly challenging task. Herein, an aggregation-induced emission (AIE)-active luminogen (namely DBD-TM) featured by intensive electron donor-acceptor strength and twisted architecture with finely modulated intramolecular motion, is tactfully designed and prepared. DBD-TM simultaneously possessed fluorescence emission in the second near-infrared (NIR-II) region and high-efficiency photothermal conversion. By integrating DBD-TM with anti-angiogenic agent sorafenib, a versatile nanomaterial is smoothly fabricated and utilized for trimodal imaging-navigated synergistic therapy involving photothermal therapy and anti-angiogenesis toward cancer. This advanced approach is capable of affording accurate tumor diagnosis, complete tumor elimination, and largely restrained tumor recurrence, evidently denoting a prominent theranostic formula beyond phototheranostics. This study will offer a blueprint for exploiting a new generation of cancer theranostics.

Keywords: NIR‐II FLI; aggregation‐induced emission; anti‐angiogenesis; multimodal phototheranostics.

Scheme 1

A) Chemical structures of DBD‐P, DBD‐T, and DBD‐TM. B) Nanofabrication of TS NPs and its application in integrated multimodal phototheranostics and antiangiogenesis.

Figure 1

A) Normalized absorption spectra of DBD‐P, DBD‐T, and DBD‐TM (1.0 × 10⁻⁵ m) in THF. B) Normalized PL spectra in the solid state. C) PL spectra of DBD‐TM (1.0 × 10⁻⁶ m, λ_ex: 592 nm) in THF solution with different water fractions. D) Plots of relative PL intensity (I/I ₀) in water/THF of DBD‐P, DBD‐T, and DBD‐TM. E) Stability analysis for size variation of TS NPs at a concentration of 100 µm measured by DLS at room temperature. F) Photothermal conversion of TS NPs (660 nm, 300 mW cm⁻²) in PBS at different concentrations. G) Photothermal conversion of TS NPs (100 µm, 300 mW cm⁻²) in PBS at different power densities. H) Photothermal stability of TS NPs after five on/off exposures in PBS (200 µm) with a 660 nm laser at a power density of 0.5 W cm⁻².

Figure 2

A) The CLSM images of 4T1 cells after treated with FITC@TS NPs and other dyes. Blue: Hoechst 33 342 (λ_ex: 405 nm, emission filter: 425–465 nm); red: Lyso Tracker Deep Red (λ_ex: 643 nm, emission filter: 660–700 nm); green: FITC@TS NPs (λ_ex: 488 nm, emission filter: 510–600 nm). Live/dead CLSM images of 4T1 cells after treatment with B) 50 µg mL⁻¹ and C) 100 µg mL⁻¹ of DBD‐TM NPs with (up) or without (down) laser irradiation (laser: 660 nm, 0.3 W cm⁻² for 5 min). The green field from Calcein‐AM is identified as live cells and red field from PI identified as dead cells. D) Viabilities of 4T1 cells after incubation with different concentrations of sorafenib NPs. E) Viabilities of 4T1 cells with DBD‐TM NPs with or without laser irradiation. F) Cells incubated with TS NPs with laser irradiation, and viabilities of 4T1 cells at different concentrations of sorafenib. G) Cells incubated with TS NPs with laser irradiation, and the viabilities of 4T1 cells at different concentrations of DBD‐TM.

Figure 3

A) NIR‐II FLI and B) PAI of tumor area at different times after intravenous injection of TS NPs into 4T1‐tumor‐bearing mice. C) The changes of temperature in the tumor area with the extension time of 660 nm NIR laser irradiation and thermal images at different times after TS NPs (up) or PBS (down) were injected into 4T1‐tumor‐bearing mice.

Figure 4

A) The schematic diagram of tumor‐bearing mice and the treatment process. B) Tumor images of mice after 14 days’ treatment. C) Anatomical images of tumors dissected from the sacrificed mice after treatment. Growth curve of tumor volume D) and body weight E) change with time in different treatment groups (n = 5). F) Histopathological view of the tumor tissue dissected from the mice after CD31, Dextran, and DAPI staining. G–J) Blood biochemistry indexes of ALT, AST, ALP, CREA, BUN, and ALB. Data are presented as the mean ± SD (n = 5).