Manganese (II) Chelate Functionalized Copper Sulfide Nanoparticles for Efficient Magnetic Resonance/Photoacoustic Dual-Modal Imaging Guided Photothermal Therapy

Abstract

The integration of diagnostic and therapeutic functionalities into one nanoplatform shows great promise in cancer therapy. In this research, manganese (II) chelate functionalized copper sulfide nanoparticles were successfully prepared using a facile hydrothermal method. The obtained ultrasmall nanoparticles exhibit excellent photothermal effect and photoaoustic activity. Besides, the high loading content of Mn(II) chelates makes the nanoparticles attractive T1 contrast agent in magnetic resonance imaging (MRI). In vivo photoacoustic imaging (PAI) results showed that the nanoparticles could be efficiently accumulated in tumor site in 24 h after systematic administration, which was further validated by MRI tests. The subsequent photothermal therapy of cancer in vivo was achieved without inducing any observed side effects. Therefore, the copper sulfide nanoparticles functionalized with Mn(II) chelate hold great promise as a theranostic nanomedicine for MR/PA dual-modal imaging guided photothermal therapy of cancer.

Keywords: Copper sulfide nanoparticles; Magnatic resonance imaging; Nanotheranostic agent; Photoacoustic imaging; Photothermal therapy..

Figure 1

Schematic illustration of CuS@MPG NPs: (A) the structure; (B) multifunction for MR/PA dual-modal imaging guided PTT through i.v. injection.

Figure 2

Characterization of CuS@MPG NPs: (A) TEM images and particle size distribution based on TEM results (Inset); (B) HRTEM images; (C) UV-vis-NIR spectra; (D) Photos of CuS@MPG NPs dispersed in water, PBS, fetal bovine serum (FBS), RMPI-1640 culture media containing 10% FBS and DMEM culture media containing 10% FBS.

Figure 3

(A) In vitro T₁-weighted MRI images of CuS@MPG NPs aqueous solutions with increasing concentrations of Mn(II). (B) Linear relationship between T₁ relaxation rate (1/T₁) and Mn(II) concentrations in CuS@MPG NPs aqueous solutions. (C) Normalized PA signal and absorbance of CuS@MPG NPs solutions as a function of wavelength. (D) PA signal intensity as a function of optical densities (OD) at 808 nm.

Figure 4

(A) The temperature of the aqueous dispersion of CuS@MPG NPs with different concentrations changed as time. (B) Plot of temperature elevation (ΔT) of CuS@MPG NPs and PEG-CuS NPs over a period of 5 min versus OD at 808 nm. (C) In vitro cytotoxicity of CuS@MPG NPs and PEG-CuS NPs to MDA-MB-231 cells. (D) Photothermal cytotoxicity to MDA-MB-231 cells as a function of laser irradiation time and NPs concentration.

Figure 5

(A) PA images collected by MOST imaging system before (pre) and at various time points (1 h, 3 h, 5 h, 8 h, 24 h) after i.v. injection of CuS@MPG NPs. (B) PA signals in the tumor region as a function of time post-injection. (C) T₁-weighted MRI images before (pre) and 24 h after i.v. injection of CuS@MPG NPs. (D) MR signals in the tumor region pre-injection and 24 h post-injection (P < 0.05, Student's t-test).

Figure 6

In vivo photothermal therapy using CuS@MPG NPs. (A) Temperature evolution on tumors of MDA-MB-231 tumor-bearing mice with and without CuS@MPG NPs monitored with a thermometer during laser treatment. (B) The infrared thermal images from tumor region in laser-only group and agent+laser group, respectively (808 nm laser, 0.64 W/cm² for 10 min. The thermal images were taken in the last second of laser irradiation). (C) The tumor growth curves and (D) body weights of mice bearing MDA-MB-231 tumors after different treatments indicated (n = 5). (E) Representative photographs of mice in four groups 21 days after treatments. (F) Histological examination of vital organs (heart, liver, spleen, lung and kidney) of mice in agent+laser group at 21th day after treatments. Untreated healthy mouse was used as control. Scale bar = 50 µm.