Monte Carlo Simulation-Guided Design of a Thorium-Based Metal-Organic Framework for Efficient Radiotherapy-Radiodynamic Therapy

Abstract

High-Z metal-based nanoscale metal-organic frameworks (nMOFs) with photosensitizing ligands can enhance radiation damage to tumors via a unique radiotherapy-radiodynamic therapy (RT-RDT) process. Here we report Monte Carlo (MC) simulation-guided design of a Th-based nMOF built from Th₆ -oxo secondary building units and 5,15-di(p-benzoato)porphyrin (DBP) ligands, Th-DBP, for enhanced RT-RDT. MC simulations revealed that the Th-lattice outperformed the Hf-lattice in radiation dose enhancement owing to its higher mass attenuation coefficient. Upon X-ray or γ-ray radiation, Th-DBP enhanced energy deposition, generated more reactive oxygen species, and induced significantly higher cytotoxicity to cancer cells over the previously reported Hf-DBP nMOF. With low-dose X-ray irradiation, Th-DBP suppressed tumor growth by 88 % in a colon cancer and 97 % in a pancreatic cancer mouse model.

Keywords: Metal-Organic Framework; Monte Carlo Simulation; Radiodynamic Therapy; Radiotherapy.

Figure 1.

a) Schematic showing radioenhancement by a Th lattice. b),c) Comparisons of DEF curves of Th and Hf lattices under X-ray (b) or γ-ray (c) irradiation.

Figure 2.

a) Synthesis of Th-DBP. b),c) TEM (b) and SEM (c) images of Th-DBP (Scale bars = 100 nm). d) Number-averaged sizes of Th-DBP and Hf-DBP. (e) PXRD patterns of Th-DBP (as synthesized and after incubation in PBS for 3 days) along with the simulated pattern for UiO-69.

Figure 3.

a),b) Total ROS signals of PBS, Hf-DBP, and Th-DBP by DCFH assays after different doses of X-ray (a) or γ-ray (b) radiation, n = 6. c),d) Total ROS signals (c) and surface CRT expressions (d) of CT26 cells after incubation with Hf-DBP or Th-DBP and irradiated with 2 Gy X-ray or 4 Gy γ-ray, n = 3. e), f) Percentages of early apoptotic, late apoptotic, and necrotic CT26 cells after incubation with Hf-DBP or Th-DBP and irradiated with 2 Gy X-ray (e) or 4 Gy γ-ray (f), n = 3. **, p<0.01, ***, p<0.001, and ****, p<0.0001.

Figure 4.

a)-d) Linear-quadratic dose-fitting curves for surviving fractions (SF, log scale) of CT26 cells after X-ray (a) and γ-ray (b) irradiation and Panc02 cells after X-ray (c) and γ-ray (d) irradiation in clonogenic assays. e)-f) Linear dose-fitting curves for growth rate inhibition indices (GRI log scale) of CT26 cells after X-ray (e) and γ-ray (f) irradiation and Panc02 cells after X-ray (g) and γ-ray (h) irradiation in growth rate inhibition assays.

Figure 5.

a),b) Growth curves of subcutaneous CT26 tumors in BALB/c mice (a) and Panc02 tumors in C57BL/6 mice (b) after treatment with Th-DBP or Hf-DBP followed by X-ray irradiation, n = 5. Black arrows indicate nMOF injection whereas red arrows indicate irradiation. The CT26 tumors were irradiated with 2 Gy X-ray/fraction on 3 consecutive days and the Panc02 tumors were irradiated with 4 Gy X-ray/fraction on 3 consecutive days. (+) and (−) denote with and without irradiation, respectively. c) CT images showing intratumoral retention of Th-DBP and Hf-DBP at day 0, day 2, and day 7 post particle administration in Panc02 tumor-bearing C57BL/6 mice (scale bar = 5 mm). d) Hematoxylin-eosin (H&E) staining and processed Ki67 and γ-H2AX staining of excised CT26 tumors 1 day after the last radiation dose (Scale bars = 50 μm, the 3,3’-diaminobenzidine (DAB)-positive cells were marked red, and the DAB-negative cells were marked blue). *, p<0.05 and **, p<0.01.