Shizhen Chen

Design and Synthesis of Fluorinated Dendrimers for Sensitive F-19 MRI

To achieve high sensitivity for (19)F MRI, a class of novel dendritic molecules with multiple pseudosymmetrical fluorines was designed and efficiently synthesized. Through iterative bromination and Williamson ether synthesis under mild conditions, a fluorinated dendrimer with 540 pseudosymmetrical fluorines was conveniently prepared without performing the group protection in a convergent way. The dendrimer is characterized by a strong (19)F NMR peak and short relaxation times. Eventually, an appreciably enhanced (19)F MRI at an extremely low concentration (18.5 μM) was achieved, which demonstrated the potential utility of such dendritic molecules in highly sensitive (19)F MRI.

MRI-visible liposome nanovehicles for potential tumor-targeted delivery of multimodal therapies

Real-time diagnosis and monitoring of disease development, and therapeutic responses to treatment, are possible by theranostic magnetic resonance imaging (MRI). Here we report the synthesis of a multifunctional liposome, which contains Gd-DOTA (an MRI probe), paclitaxel and c(RGDyk) (a targeted peptide). This nanoparticle overcame the insolubility of paclitaxel, reduced the side effects of FDA-approved formulation of PTX-Cre (Taxol®) and improved drug delivery efficiency to the tumor. c(RGDyk) modification greatly enhanced the cytotoxicity of the drug in tumor cells A549. The T1 relaxivity in tumor cells treated with the targeted liposome formulation was increased 16-fold when compared with the non-targeted group. In vivo, the tumors in mice were visualized using T1-weighted imaging after administration of the liposome. Also the tumor growth could be inhibited well after the treatment. Fluorescence images in vitro and ex vivo also showed the targeting effect of this liposome in tumor cells, indicating that this nanovehicle could limit the off-target side effects of anticancer drugs and contrast agents. These findings lay the foundation for further tumor inhibition study and application of this delivery vehicle in cancer therapy settings.

Discovery of a 19F MRI sensitive salinomycin derivative with high cytotoxicity towards cancer cells

Salinomycin is a promising anti-cancer agent which selectively targets cancer stem cells. To improve its potency and selectivity, an analog library of salinomycin was generated by site-specific modification and CuAAc derivatization. Through a cytotoxicity analysis of the library, a fluorinated analog with high potency, selectivity, and (19)F MRI sensitivity was discovered as a novel theranostic agent.

Increasing Cancer Therapy Efficiency through Targeting and Localized Light Activation

Currently, the potential of cancer therapy is compromised by a variety of problems related to tumor specificity, drug access, and limited efficacy. We report a novel approach to improve the effectiveness of cancer treatment utilizing a light-responsive nanoconstruct. Effectiveness is increased by enhancing drug absorption through heating and the production of free radicals. Treatment specificity is increased through chemical targeting of the nanoconstruct and localization of light delivery to the tumor. When reaching the tumor, magnetic resonance imaging is enhanced and near-infrared fluorescence is activated upon drug release, making it possible to visualize the localized treatment at both the tissue and cellular levels. This dual-modality imaging nanoconstruct enables the synergistic treatment and observable evaluation of solid tumors with dramatically improved efficacy, giving rise to a promising new approach for cancer therapy and evaluation.

Synthesis and biological evaluation of 20-epi-amino-20-deoxysalinomycin derivatives

To improve the druggability of salinomycin, a 20-epi-amino-20-deoxysalinomycin derivatives library was synthesized with high efficacy from which a few salinomycin derivatives with high potency and selectivity were identified through comprehensive cytotoxicity assay, including a fluorine-19 magnetic resonance sensitive tool molecule. Using a K-ras cellular model, salinomycin and its derivatives showed different molecular mode of action from literature reports. These results would be valuable for developing salinomycin-based cancer therapy.

A europium–lipoprotein nanocomposite for highly-sensitive MR-fluorescence multimodal imaging

A novel reconstituted high-density lipoprotein (rHDL) nanocomposite has been prepared for highly-sensitive magnetic resonance (MR)-fluorescence multimodal imaging. Such a nanocomposite is able to enhance the MR sensitivity up to 129 fold in comparison to the traditional small molecule MRI agent based on paramagnetic chemical exchange saturation transfer (PARACEST). It has also demonstrated specific targeting to macrophage cells, which shows great potential for the detection of atherosclerosis.

Detection and Differentiation of Cys, Hcy and GSH mixtures by 19 F NMR Probe

Simultaneous detection and differentiation of biomolecules is of significance in biological research. Biothiols such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) play an important role in regulating the vital functions of living organisms. However, existing methods for simultaneous detection and differentiation of Cys, Hcy, and GSH are still challenging because of their similarity in structure and chemical properties. Herein we report a probe that simultaneously detects and discriminates between mixtures of Cys, Hcy and GSH using 19F nuclear magnetic resonance (NMR). This 19F NMR probe responds rapidly to biothiols through the Michael addition reaction and subsequent intramolecular cyclization reaction allowing differentiation between Cys, Hcy and GSH through 19F NMR chemical shift. We demonstrate that this 19F NMR probe is a powerful method for analysis of complex mixtures.

pH-Responsive theranostic nanocomposites as synergistically enhancing positive and negative magnetic resonance imaging contrast agents

BackgroundThe rational design of theranostic nanoprobe to present responsive effect of therapeutic potency and enhanced diagnostic imaging in tumor milieu plays a vital role for efficient personalized cancer therapy and other biomedical applications. We aimed to afford a potential strategy to pose both T1- and T2-weighted MRI functions, and thereby realizing imaging guided drug delivery and targeted therapy.ResultsTheranostic nanocomposites Mn-porphyrin&Fe3O4@SiO2@PAA-cRGD were fabricated and characterized, and the nanocomposites were effectively used in T1- and T2-weighted MRI and pH-responsive drug release. Fluorescent imaging also showed that the nanocomposites specifically accumulated in lung cancer cells by a receptor-mediated process, and were nontoxic to normal cells. The r2/r1 ratio was 20.6 in neutral pH 7.4, which decreased to 7.7 in acidic pH 5.0, suggesting the NCs could act as an ideal T1/T2 dual-mode contrast agent at acidic environments of tumor. For in vivo MRI, T1 and T2 relaxation was significantly accelerated to 55 and 37%, respectively, in the tumor after i.v. injection of nanocomposites.ConclusionThe synthesized nanocomposites exhibited highly sensitive MRI contrast function no matter in solution, cells or in vivo by synergistically enhancing positive and negative magnetic resonance imaging signals. The nanocomposites showed great potential for integrating imaging diagnosis and drug controlled release into one composition and providing real-time imaging with greatly enhanced diagnostic accuracy during targeted therapy.

Potential detection of cancer with fluorinated silicon nanoparticles in 19F MR and fluorescence imaging

Fluorescence is widely used for cell imaging due to its high sensitivity and rich color choices but limited for in vivo imaging because of its low light penetration. Meanwhile, magnetic resonance imaging (MRI) is widely applied for in vivo diagnosis but not suitable for cell imaging because of its low resolution. As a result of rare background in living organisms, 19F-MRI stands out in several fields of clinical application. Herein, we report a one-pot microwave synthesis of fluorinated silicon nanoparticles (19FSiNPs), for detection of cancer cells and tumors. Based on the quantum effects of the nano-sized nanoparticles, 19FSiNPs can act as a label free dye for ultracontrast cell fluorescence imaging. Our experiments demonstrated that these nanoprobes significantly enhanced in vivo19F/1H MRI contrast in rats with non-small cell lung tumors. Moreover, the resulting 19FSiNPs exhibited high water dispersibility and excellent biocompatibility, which make them promising for both cell imaging and in vivo imaging applications.