MRI-visible and pH-sensitive nanomicelles for targeting delivery of sorafenib to hepatocellular carcinoma
10.3760/cma.j.issn.1005-1201.2019.11.014
- VernacularTitle: MRI可视化pH敏感纳米胶束用于肝癌靶向输送索拉非尼的可行性
- Author:
Mingyue CAI
1
;
Ge LYV
2
;
Qin YANG
2
;
Liteng LIN
1
;
Jingjun HUANG
1
;
Zhimei ZHOU
1
;
Yong HUANG
1
;
Hui LIAN
1
;
Mingji HE
1
;
Kangshun ZHU
1
Author Information
1. Department of Minimally Invasive Interventional Radiology, Department of Radiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
2. Department of Interventional Radiology and Vascular Surgery, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
- Publication Type:Journal Article
- Keywords:
Magnetic resonance imaging;
Carcinoma, hepatocellular;
Molecular targeted therapy;
Nanomedicine;
Sorafenib
- From:
Chinese Journal of Radiology
2019;53(11):1005-1011
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To synthesize a folic acid (FA)-modified pH-sensitive nanomicelle containing sorafenib (SF) and superparamagnetic iron oxide (SPIO), and to access its visibility in MRI and anti-cancer efficacy on hepatocellular carcinoma (HCC) in vitro.
Methods:The copolymer FA-PEG-Pasp (DBA/DIP) of FA, poly(ethylene glycol), N,N-dibutylethylenediamine and N,N-diisopropylethylenediamine grafted poly (L-aspartic acid) were prepared. SF and SPIO were encapsulated inside the copolymer to synthesize the targeting micelle FA-PEG-PAsp (DBA/DIP)-SPIO/SF (FPASS). The folate-free micelle[PEG-PAsp (DBA/DIP)-SPIO/SF (PASS)] was used as nontargeting micelle. The physicochemical properties and drug release behavior of the micelles were analyzed. MRI of HepG2 cells incubated with FPASS and PASS with different Fe concentrations and Prussian blue staining of cells treated with the micelles (Fe concentration of 20 μg/ml) was performed to assess the drug delivery capability and imaging function of the micelles. For the FA competitive inhibition assay in these experiments, HepG2 cells were pre-treated with an excess amount of free FA prior to the incubation with FPASS. Cell viability, cell apoptosis, cell cycle and tube formation assays were conducted for evaluating the anti-HCC effects of the micelles. Comparison between groups was analyzed by one-way ANOVA, and multiple comparisons correction was performed by LSD test.
Results:The diameters of FPASS and PASS were (102.3±5.2) nm and (107.1±5.7) nm, respectively; the δ potentials of them were (29.7±1.6) mV and (31.5±1.4) mV, respectively. The T2 relaxivity of both the micelles was (5.2±0.4) ml·μg-1·s-1, which was much higher than that of water soluble Fe3O4 nanoparticles [(2.3±0.1) ml·μg-1·s-1; F=76.45, P<0.01]. SF released from the micelles was much faster at pH5.0 than at pH7.4, which indicated that the micelles had a pH-triggered drug release behavior. MRI of HepG2 cell samples revealed the signal intensity on T2WI images and the T2 value on T2-map images decreased with the increasing Fe concentrations in the micelles. At the same Fe concentration (5, 10, 20 and 40 μg/ml), the cells of FPASS group exhibited a more significant decrease in T2 signal intensity and T2 value compared with those of PASS group or FA competitive inhibition group (F=8.69, 14.03, 27.27, 32.25 and 19.80, 45.76, 113.20, 66.80; P<0.01). Prussian blue staining verified the existing of SPIO in the cytoplasm of cells. Compared with PASS, FPASS presented significantly higher anticancer effects on inducing apoptosis, causing G0/G1 phase arrest on HepG2 cells and inhibiting tube formation on human umbilical vein endothelial cells (t=7.905, 4.399 and 3.454, respectively; P<0.01).
Conclusions:The pH-sensitive nanomicelle FPASS was successfully constructed. This micelle possessed a hypersensitive MRI-visible function and a targeting SF delivery capability which may contribute to a significant anti-HCC effect.
