Dynamic Contrast-Enhanced MRI Assessing Antifibrotic Therapeutic Effects of Pancreatic Fibrosis with Curcumin - An Experimental Study at 11.7 T.

RATIONALE AND OBJECTIVES: Pancreatic fibrosis is the hallmark of chronic pancreatitis (CP), which is associated with microcirculatory disturbance. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess the perfusion and permeability of the pancreas by providing information about microcirculation. We hypothesize that DCE-MRI parameters can be utilized to assess pancreatic fibrosis and may furthermore provide an opportunity to evaluate response to antifibrotic treatment with curcumin. Our study was to evaluate the feasibility of quantitative DCE-MRI in assessing pancreatic fibrosis and the antifibrotic effect of curcumin in a rat model of CP. MATERIALS AND METHODS: Pancreatic fibrosis was induced by injecting dibutyltin dichloride (DBTC). Seventy rats were randomized to five groups: the control group (n = 10); DBTC for 2 weeks (n = 15); DBTC for 4 weeks (n = 15); DBTC + curcumin for 2 weeks (n = 15); DBTC + curcumin for 4 weeks (n = 15). DCE-MRI was performed at an 11.7 T MR scanner. DCE-MRI quantitative parameters (Ktrans, Ve, and Vp) were derived from an extended Tofts model. Fibrosis content and DCE-MRI parameters were compared among the above groups (one-way analysis of variance). The correlations between DCE-MRI parameters and pancreatic fibrosis content as well as the expression of α-SMA were computed by Spearman correlation coefficients. RESULTS: Fifty-three rats survived and underwent MR imaging. Ktrans in rats 4 weeks after DBTC injection was significantly lower than DBTC 2 weeks rats and control rats (0.30 ± 0.06 min vs 0.49 ± 0.09 vs 0.62 ± 0.09, respectively). Vp in DBTC 4 weeks rats was also significantly lower than control rats (0.048 ± 0.010 min-1 vs 0.065 ± 0.011 min-1, respectively). Ktrans and Vp significantly correlated with fibrosis content of pancreas (r = -0.619 and -0.450, all P < 0.001), and the expression of α-SMA (r = -0.688 and -0.402, all P < 0.01). Ktrans and Vp in rats with daily curcumin treatment for 4 weeks were significantly higher than DBTC 4 weeks rats (Ktrans, 0.51 ± 0.09 vs 0.30 ± 0.06; Vp, 0.064 ± 0.015 vs 0.048 ± 0.010). CONCLUSION: DCE-MRI parameters (Ktrans and Vp) have the potential to noninvasively assess pancreatic fibrosis and the antifibrotic treatment response of curcumin.

Molecular Engineered Squaraine Nanoprobe for NIR-II/Photoacoustic Imaging and Photothermal Therapy of Metastatic Breast Cancer.

Various squaraine dyes have been developed for biological imaging. Nevertheless, squaraine dyes with emission in the second window (NIR-II, 1000-1700 nm) have few reports largely due to the short of a simple and universal design strategy. In this contribution, molecular engineering strategy is explored to develop squaraine dyes with NIR-II emission. First, NIR-I squaraine dye SQ2 is constructed by the ethyl-grafted 1,8-naphtholactam as donor units and square acid as acceptor unit in a donor-acceptor-donor (D-A-D) structure. To red-shift the fluorescence emission into NIR-II window, malonitrile, as a forceful electron-withdrawing group, is introduced to strengthen square acid acceptor. As a result, the fluorescence spectrum of acceptor-engineered squaraine dye SQ1 exhibits a significant red-shift into NIR-II window. To translate NIR-II fluorophores SQ1 into effective theranostic agents, fibronectin-targeting SQ1 nanoprobe was constructed and showed excellent NIR-II imaging performance in angiography and tumor imaging, including lung metastatic foci in deep tissue. Furthermore, SQ1 nanoprobe can be used for photoacoustic imaging and photothermal ablation of tumors. This research demonstrates that the donor-acceptor engineering strategy is feasible and effective to develop NIR-II squaraine dyes.

An ALP-activatable and mitochondria-targeted probe for prostate cancer-specific bimodal imaging and aggregation-enhanced photothermal therapy.

Tumor-derived alkaline phosphatase (ALP) is over-expressed in metastatic prostate cancer. The development of selective probes for ALP detection is therefore critical for early diagnosis and therapy of metastatic prostate cancer. Herein, we develop a mitochondria-targeted near-infrared activatable fluorescent/photoacoustic (NIR FL/PA) probe for the selective detection of prostate cancer-derived ALP and aggregation-enhanced photothermal therapy. Upon dephosphorylation, the probes are activated and they provide a red-shifted strong absorption and emission in the NIR window and thus enable NIR FL and PA imaging of ALP activity in tumor tissues. Particularly, the activated probes self-assemble in situ into a supramolecular network structure which induces cell apoptosis and significantly enhances the photothermal therapy efficacy.

Beyond the Roles in Biomimetic Chemistry: An Insight into the Intrinsic Catalytic Activity of an Enzyme for Tumor-Selective Phototheranostics.

Protein-assisted biomimetic synthesis has been an emerging offshoot of nanofabrication in recent years owing to its features of green chemistry, facile process, and ease of multi-integration. As a result, many proteins have been used for biomimetic synthesis of varying kinds of nanostructures. Although the efforts on exploring new proteins and investigating their roles in biomimetic chemistry are increasing, the most essential intrinsic properties of proteins are largely neglected. Herein we report a frequently used enzyme (horseradish peroxidase, HRP) to demonstrate the possibility of enzymatic activity retaining after accomplishing the roles in biomimetic synthesis of ultrasmall gadolinium (Gd) nanodots and stowing its substrate 2,2'-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid ammonium salt) (ABTS), denoted as Gd@HRPABTS. It was found that ca. 70% of the enzymatic activity of HRP was preserved. The associated changes of protein structure with chemical treatments were studied by spectroscopic analysis. Leveraging on the highly retained catalytic activity, Gd@HRPABTS exerts strong catalytic oxidation of peroxidase substrate ABTS into photoactive counterparts in the presence of intrinsic H2O2 inside the tumor, therefore enabling tumor-selective catalytic photoacoustic (PA) imaging and photothermal therapy (PTT). In addition, the MR moiety of Gd@HRPABTS provides guidance for PTT and further diagrams that Gd@HRPABTS is clearable from the body via kidneys. Preliminary toxicity studies show no observed adverse effects by administration of them. This study demonstrates beyond the well-known roles in biomimetic chemistry that HRP can also preserve its enzymatic activity for tumor catalytic theranostics.

Enzyme-triggered self-assembly of gold nanoparticles for enhanced retention effects and photothermal therapy of prostate cancer.

A peptide-modified gold nanoparticle was developed for tumour-targeted therapy. Triggered by alkaline phosphatase, the CREKA-YPFFK(Nph) peptide can self-assemble and further result in accumulation of gold nanoparticles in tumour cells. The large-sized gold nanoparticle aggregates cannot escape from the tumour tissue, therefore realizing the goal of tumour-specific targeting, enhanced retention and photothermal effects.