2D Nano-Sonosensitizers Facilitate Energy Transfer to Enhance Sonodynamic Therapy

Abstract

Although sonodynamic therapy (SDT) has shown promise for cancer treatment, the lack of efficient sonosensitizers (SSs) has limited the clinical application of SDT. Here, a new strategy is reported for designing efficient nano-sonosensitizers based on 2D nanoscale metal-organic layers (MOLs). Composed of Hf-oxo secondary building units (SBUs) and iridium-based linkers, the MOL is anchored with 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) sensitizers on the SBUs to afford TBP@MOL. TBP@MOL shows 14.1- and 7.4-fold higher singlet oxygen (¹ O₂ ) generation than free TBP ligands and Hf-TBP, a 3D nanoscale metal-organic framework, respectively. The ¹ O₂ generation of TBP@MOL is enhanced by isolating TBP SSs on the SBUs of the MOL, which prevents aggregation-induced quenching of the excited sensitizers, and by triplet-triplet Dexter energy transfer between excited iridium-based linkers and TBP SSs, which more efficiently harnesses broad-spectrum sonoluminescence. Anchoring TBP on the MOL surface also enhances the energy transfer between the excited sensitizer and ground-state triplet oxygen to increase ¹ O₂ generation efficacy. In mouse models of colorectal and breast cancer, TBP@MOL demonstrates significantly higher SDT efficacy than Hf-TBP and TBP. This work uncovers a new strategy to design effective nano-sonosensitizers by facilitating energy transfer to efficiently capture broad-spectrum sonoluminescence and enhance ¹ O₂ generation.

Keywords: energy transfer; metal-organic layers; nanoparticles; sonodynamic therapy; sonosensitizers.

Figure 1.

Synthetic scheme of Hf-TBP (left) and TBP@MOL (right). TBP SSs are rigidly confined in the 3D framework of Hf-TBP but flexibly anchored to the SBUs of the 2D MOL in TBP@MOL (orange: Ir, sky blue: Hf, pale light blue: F, red: O, blue: N, grey: C; H atoms are omitted for clarity).

Figure 2.

(a) TEM image of TBP@MOL. (b) AFM topographic image, height profile (inset, left), and modeled height (inset, right) of TBP@MOL (c) Zeta (ζ) potentials of MOL and TBP@MOL in water. (d) Normalized UV–Vis absorption spectra of TBP, DBB-Ir, MOL, and TBP@MOL in DMSO. (e) Number-averaged diameters of MOL and TBP@MOL in ethanol. (f) PXRD patterns of TBP@MOL (as-synthesized and after soaking in PBS for 24 h), MOL, and the simulated pattern of Hf₁₂-MOL.

Figure 3.

¹O₂ generation of different TBP systems upon US (a) and light (b) irradiation as detected by SOSG assay. Cell viability assays of TBP(+), Hf-TBP(+), and TBP@MOL(+) in (c) CT26 and (d) 4T1 cells upon US irradiation (n = 4). CLSM images showing Calcein-AM/PI staining (e) and DCFDA staining (f) of and flow cytometric analyses showing Annexin V/PI staining (g) of CT26 cells after PBS(+), TBP(+), Hf-TBP(+), or TBP@MOL(+) treatment. Scale bar = 20 μm.

Figure 4.

(a) Proposed mechanism of ¹O₂ generation for TBP@MOL under US irradiation. DBB-Ir and TBP absorb high- and low-energy regions of the broad sonoluminescence spectrum, respectively, and the excited DBB-Ir undergoes TTET with TBP. The excited surface-anchored TBP efficiently transfers energy to ³O₂ for enhanced ¹O₂ generation. (b) Normalized steady-state emission and (c) time-resolved emission decay spectra of the TBP systems. (d) Absorption spectrum of TBP (acceptor), normalized emission spectrum of MOL (DBB-Ir; donor), and spectral overlap integral J(λ). Transient absorption spectra of (e) Hf-TBP and (f) TBP@MOL at various time slices, showing the decays of the excited state absorption features. (g) Normalized steady-state emission and (h) time-resolved emission decay spectra of the DBB-Ir ligands in TBP@MOL and MOL.

Figure 5.

(a) Schematic illustration of tumor inoculation and treatment schedule. SDT anticancer efficacy in subcutaneous (b) CT26 and (c) 4T1 tumor-bearing BALB/c mice (n = 5). Weight (d) and photograph (e) of excised CT26 tumors of BALB/c mice after PBS(+), TBP(+), Hf-TBP(+), or TBP@MOL(+) treatment. Scale bar = 1 cm. (f) H&E and TUNEL staining of sectioned CT26 tumors tissues after various treatments. Scale bars = 100 μm, **, p<0.01; ***, p<0.001.