Oxygen Vacancies Enhanced CeO2:Gd Nanoparticles for Sensing a Tumor Vascular Microenvironment by Magnetic Resonance Imaging.

The specific characteristics of the tumor vascular microenvironment such as microvascular permeability and water diffusion have been demonstrated to play essential roles in the evaluation of infiltration of tumors. However, at present, there are few contrast agents (CAs) for magnetic resonance imaging to enhance the sensitivity for acquiring this vital information. Herein, we develop Gd-doped (CeO2:Gd) nanoparticles as CAs to detect the tumor vascular microenvironment with high sensitivity. The lattice oxygen vacancies on the surface of CeO2:Gd nanoparticles could bind considerable water molecules to improve the r1 value, achieving an excellent dynamic contrast-enhanced perfusion weighted imaging performance for the measurement of microvascular permeability. Diffusion limiting of water molecules by oxygen vacancies of CeO2:Gd nanoparticles further enhances the diffusion-weighted magnetic resonance imaging signal in vitro and in vivo. Excitingly, the strategy is not only essential for obtaining tumor vascular microenvironment information but also offers a way for further research in the design of magnetic resonance CAs.

Polyethylene glycol-poly(ε-benzyloxycarbonyl-l-lysine)-conjugated VEGF siRNA for antiangiogenic gene therapy in hepatocellular carcinoma.

A polyethylene glycol-poly(ε-benzyloxycarbonyl-l-lysine) (PEG-SS-PLL) block copolymer based on a disulfide-linked, novel biodegradable catiomer bearing a PEG-sheddable shell was developed to avoid "PEG dilemma" in nanoparticle intracellular tracking of PEG-PLL where PEG was nondegradable. However, PEG-SS-PLL catiomers have not been used to deliver small interfering VEGF RNA (siVEGF) in antiangiogenesis gene therapy. In this study, we aimed to investigate whether this novel biodegradable catiomer can deliver siVEGF into cancer cells and at the same time have an antitumor effect in a xenograft mouse model. It was found that PEG-SS-PLL efficiently delivered siVEGF with negligible cytotoxicity, and significantly decreased the expression of VEGF at both the messenger-RNA and protein levels both in vitro and in vivo, and thus tumor growth was inhibited. Our findings demonstrated that PEG-SS-PLL/siVEGF could potentially be applied to antiangiogenesis gene therapy for hepatocellular carcinoma.

Biodegradable gadolinium-chelated cationic poly(urethane amide) copolymers for gene transfection and magnetic resonance imaging.

Theranostic nano-polyplexes containing gene and imaging agents hold a great promise for tumor diagnosis and therapy. In this work, we develop a group of new gadolinium (Gd)-chelated cationic poly(urethane amide)s for gene delivery and T1-weighted magnetic resonance (MR) imaging. Cationic poly(urethane amide)s (denoted as CPUAs) having multiple disulfide bonds, urethane and amide linkages were synthesized by stepwise polycondensation reaction between 1,4-bis(3-aminopropyl)piperazine and a mixture of di(4-nitrophenyl)-2, 2'-dithiodiethanocarbonate (DTDE-PNC) and diethylenetriaminepentaacetic acid (DTPA) dianhydride at varied molar ratios. Then, Gd-chelated CPUAs (denoted as GdCPUAs) were produced by chelating Gd(III) ions with DTPA residues of CPUAs. These GdCPUAs could condense gene into nanosized and positively-charged polyplexes in a physiological condition and, however, liberated gene in an intracellular reductive environment. In vitro transfection experiments revealed that the GdCPUA at a DTDE-PNC/DTPA residue molar ratio of 85/15 induced the highest transfection efficiency in different cancer cells. This efficiency was higher than that yielded with 25kDa branched polyethylenimine as a positive control. GdCPUAs and their polyplexes exhibited low cytotoxicity when an optimal transfection activity was detected. Moreover, GdCPUAs may serve as contrast agents for T1-weighted magnetic resonance imaging. The results of this work indicate that biodegradable Gd-chelated cationic poly(urethane amide) copolymers have high potential for tumor theranostics.

Green synthetic, multifunctional hybrid micelles with shell embedded magnetic nanoparticles for theranostic applications.

The objective of this study is to design and develop a green-synthetic, multifunctional hybrid micelles with shell embedded magnetic nanoparticles for theranostic applications. The hybrid micelles were engineered based on complex micelles self-assembled from amphiphilic block copolymers Pluronic F127 and peptide-amphiphile (PA) pal-AAAAHHHD. The reason to choose PA is due to its amphiphilic character and the coordination capability for Fe(3+) and Fe(2+). The PA incorporation allows the in situ growth of the magnetic iron oxide nanoparticles onto the complex micelles, to yield the nanostructures with shell embedded magnetic nanoparticles at an ambient condition without any organic solvents. The anticancer drug doxorubicin (DOX) can be efficiently loaded into the hybrid micelles. Interestingly, the magnetic nanoparticles anchored on the shell were found to significantly retard the DOX release behavior of the drug loaded hybrid micelles. It was proposed that a cross-linking effect of the shell by magnetic nanoparticles is a key to underlie the above intriguing phenomenon, which could enhance the stability and control the drug diffusion of the hybrid micelles. Importantly, in vitro and in vivo magnetic resonance imaging (MRI) revealed the potential of these hybrid micelles to be served as a T2-weighted MR imaging contrast enhancer for clinical diagnosis.

Bioreducible polyethylenimine-delivered siRNA targeting human telomerase reverse transcriptase inhibits HepG2 cell growth in vitro and in vivo.

One new siRNA sequence was found efficient for human telomerase reverse transcriptase (hTERT) gene silencing in vitro in five types of human cancer cells. Then, a biodegradable polyethylenimine containing multiple disulfide bonds (SS-PEI) was successfully applied as a potent non-viral carrier for intracellular delivery of the hTERT siRNA in vitro and in vivo. The SS-PEI could strongly bind siRNA to form nano-sized and positively-charged complexes, but which were readily destabilized to sufficiently release siRNA in a reducing environment. Transfection experiments showed that the complexes of SS-PEI/hTERT siRNA were able to transfect HepG2 cells in vitro, inducing reduced levels of hTERT mRNA and hTERT protein, decreased telomerase activity, cell growth inhibition and significant cell apoptosis. Besides, treatment with the complexes of SS-PEI/hTERT siRNA could inhibit HepG2 tumor growth in a xenograft mouse model. Importantly, the SS-PEI revealed relatively low cytotoxicity in vitro and at an appropriate dose had no adverse effect on liver and kidney functions in vivo. The results of this study indicate that SS-PEI/siRNA-induced hTERT gene silencing provides a promising method for human cancer gene therapy.