Lactic acid modified rare earth-based nanomaterials for enhanced radiation therapy by disturbing the glycolysis

Abstract

Deficient deposition of X-rays and strong capacity of repairing damage DNA of cancer cells limit the effect of radiation therapy (RT). Herein, we synthesize CsLu₂F₇ nanoparticles with lactic acid (LA) ligands (CsLu₂F₇-LA) to overcome these limitations. The high-Z atoms of Lu and Cs can deposit more X-rays for generating enhanced hydroxyl radicals (·OH). Meanwhile, the LA ligand will guide CsLu₂F₇-LA to target monocarboxylic acid transporter (MCT) and impede the transportation of free LA, leading to decreased glycolysis and DNA damage repair. Consequently, the curative effect of RT will be enhanced and the strategy of LA accumulation induced radiosensitization is proved by in vivo and in vitro experiments, which will bring prospects for enhanced RT with nanomedicine.

Keywords: Glycolysis; Lactic acid; Nanomedicine; Radiation therapy; Rare earth.

Fig. 1

Illustration of a synthetic procedure of CsLu₂F₇-LA and b the mechanism that CsLu₂F₇-LA enhance the effect of RT

Fig. 2

Characterization of nanomaterials. a TEM image of CsLu₂F₇-OA. b TEM image of CsLu₂F₇-LA. c HAADF image of CsLu₂F₇-LA. d Cs, e Lu and f F Elements mapping of CsLu₂F₇-LA. g EDS spectrum of CsLu₂F₇-LA. h XPS spectrum of CsLu₂F₇-LA. i XRD pattern of CsLu₂F₇-OA and CsLu₂F₇-LA

Fig. 3

Experiments in vitro. a 143B cells viability of different concentrations of LA (n = 6, mean ± SD). b HUVEC cells viability of different concentrations of CsLu₂F₇-LA (n = 6, mean ± SD). c 143B cells viability of different concentrations of CsLu₂F₇-LA (n = 6, mean ± SD). d 143B cell pH staining of control group and CsLu₂F₇-LA group. Scale bar: 50 μm. e Relative intensity of BCECF in control group and CsLu₂F₇-LA group (n = 3, mean ± SD). f Relative content of ATP in control group and CsLu₂F₇-LA group (n = 3, mean ± SD). Two asterisks indicate P < 0.01, three asterisks indicate P < 0.001, and four asterisks indicate P < 0.0001 according to Student’s two-tailed t-test

Fig. 4

Experiments in vitro. a Survival fraction of cell colony formation assay (n = 3, mean ± SD, single asterisk indicates P < 0.05 according to Student’s two-tailed t-test). b Photographs of cell colony formation assay. c Relative intensity of PI in each group (n = 3, mean ± SD, two asterisks indicate P < 0.01 according to Student’s two-tailed t-test). d Calcein-AM and PI staining of each group. e The yield of ·OH of each group measured by 2,7-Dichlorodi-hydrofluorescein diacetate (DCFH-DA) staining. f Cell γ-H2AX staining of each group. Scale bar: 100 μm

Fig. 5

Experiments in vivo. a Illustration of the experimental design. b The weights of tumor-bearing mice of each group (6 Gy, n = 5, mean ± SD). c Relative tumor volume of each group (6 Gy, n = 5, mean ± SD, triple asterisks indicate P < 0.001 according to Student’s two tailed t-test). d H&E staining, Ki67 staining and TUNEL staining of tumor sections. Scale bar: 100 μm