Gaolin Liang

Multifunctional yolk-shell nanoparticles: A potential MRI contrast and anticancer agent

We report a new type of multifunctional nanomaterials, FePt@Fe2O3 yolk-shell nanoparticles, that exhibit high cytotoxicity originated from the FePt yolks and strong MR contrast enhancement resulting from the Fe2O3 shells. Encouraged by the recently observed high cytotoxicity of FePt@CoS2 yolk-shell nanoparticles, we used Fe2O3 to replace CoS2 as the shells to further explore the applications of the yolk-shell nanostructures. The ultralow IC50 value (238 +/- 9 ng of Pt/mL) of FePt@Fe2O3 yolk-shell nanoparticles likely originates from the fact that the slow oxidation and release of FePt yolks increases the cytotoxicity. Moreover, compared with two commercial magnetic resonance imaging (MRI) contrast agents, MION and Sinerem, the FePt@Fe2O3 yolk-shell nanoparticle showed stronger contrast enhancement according to their apparent transverse relaxivity values (r2* = 3.462 (microg/mL)(-1) s(-1)). The bifunctional FePt@Fe2O3 yolk-shell nanoparticles may serve both as an MRI contrast agent and as a potent anticancer drug. This work indicates that these unique yolk-shell nanoparticles may ultimately lead to new designs of multifunctional nanostructures for nanomedicine.

A biocompatible condensation reaction for controlled assembly of nanostructures in living cells

Through controlled synthesis and molecular assembly, biological systems are able to organize molecules into supramolecular structures that carry out sophisticated processes. Although chemists have reported a few examples of supramolecular assembly in water, the controlled covalent synthesis of large molecules and structures in vivo has remained challenging. Here we report a condensation reaction between 1,2-aminothiol and 2-cyanobenzothiazole that occurs in vitro and in living cells under the control of pH, disulfide reduction and enzymatic cleavage. In vitro, the size and shape of the condensation products, and nanostructures subsequently assembled, were different in each case and could thus be controlled by tuning the structure of the monomers. Direct imaging of the products obtained in the cells revealed their locations – near the Golgi bodies under enzymatic cleavage control – demonstrating the feasibility of a controlled and localized reaction in living cells. This intracellular condensation process enabled the imaging of the proteolytic activity of furin.

D-glucosamine-based supramolecular hydrogels to improve wound healing.

A simple supramolecular hydrogel based on D-glucosamine, a naturally occurring aminosaccharide, promises new biomaterials for applications such as wound healing.

Conjugates of naphthalene and dipeptides produce molecular hydrogelators with high efficiency of hydrogelation and superhelical nanofibers

Here we report a new class of molecular hydrogelators based on the conjugates of dipeptide and (naphthalen-2-yloxy)acetic acid. They form hydrogels efficiently—the lowest concentration for them to gel water is 0.07 wt%. Two hydrogelators show the ability to form helical nanofibers within the hydrogels, and the chirality of the hydrogelators apparently dictates the handedness of the nanofibers—D-peptide and L-peptide afford left-handed and right-handed self-assembled nanofibers in the hydrogels, respectively. Moreover, MTT assay of the viability of cells indicates that these molecular hydrogelators are biocompatible.

Rational Design of a Tetrameric Protein to Enhance Interactions between Self‐Assembled Fibers Gives Molecular Hydrogels

Molecular hydrogels have attracted extensive research interest in recent years because of their inherent properties (e.g., formation by the self-assembly of small molecules and their gel–sol/sol–gel phase transitions can be easily manipulated by external stimulus). They have shown great potential in fields such as three-dimensional (3D) cell culture and controlled drug delivery. During the formation of a molecular hydrogel, a small molecule (molecular hydrogelator) needs to selfassemble into a 3D matrix of nanofibers, nanorods, or nanospheres that can hold water molecules within the cavities of the 3D matrix. To form the 3D matrix, there should be strong or at least medium interactions between self-assembled nanostructures. Otherwise, nanostructures with weak interactions between them will only form dispersions or solutions in the aqueous phase. Actually, there are many examples of this kind of self-assembled system that lack strong interactions between the self-assembled structures. This type of solution/dispersion containing self-assembled nanostructures could change to a hydrogel if the interaction between the nanostructures could be enhanced. For example, several groups have demonstrated that zinc and calcium ions can be used to cross-link self-assembled nanofibers to form molecular hydrogels. In this study, we rationally designed a fusion protein with four binding sites and used the protein– peptide interaction to enhance interactions between selfassembled nanofibers, thus leading to the formation of molecular hydrogels (Figure 1). There are only a few examples of polymeric hydrogels formed by specific protein–peptide interactions. Specific protein–peptide interaction has also been used to direct self-

In Vivo Bioluminescence Imaging of Furin Activity in Breast Cancer Cells Using Bioluminogenic Substrates

Furin, a proprotein convertases family endoprotease, processes numerous physiological substrates and is overexpressed in cancer and inflammatory conditions. Noninvasive imaging of furin activity will offer a valuable tool to probe furin function over the course of tumor growth and migration in the same animals in real time and directly assess the inhibition efficacy of drugs in vivo. Here, we report successful bioluminescence imaging of furin activity in xenografted MBA-MB-468 breast cancer tumors in mice with bioluminogenic probes. The probes are conjugates of furin substrate, a consensus amino acid motif R-X-K/R-R (X, any amino acid), with the firefly luciferase substrate D-aminoluciferin. In the presence of the luciferase reporter, the probes are unable to produce bioluminescent emission without furin activation. Blocking experiments with a furin inhibitor and control experiments with a scrambled probe showed that the bioluminescence emission in the presence of firefly luciferase is furin-dependent and specific. After furin activation, a 30-fold increase in the bioluminescent emission was observed in vitro, and on average, a 7-8-fold contrast between the probe and control was seen in the same tumor xenografts in mice. Direct imaging of furin activity may facilitate the study of furin function in tumorigenicity and the discovery of new drugs for furin-targeted cancer therapy.

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors as Promising Therapeutic Drugs for Diabetes: Status and Development

Glucocorticoids (GC) play a fundamental role in controlling physiologic homeostasis and, when present in excess, can have a detrimental impact on glucose control, blood pressure and lipid levels. The oxidoreductase 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mainly catalyzes the intracellular regeneration of active GCs (cortisol, corticosterone) from inert inactive 11-keto forms (cortisone) in liver, adipose tissue and brain, amplifying local GC action. Multiple lines of evidence have indicated that 11beta-HSD1-mediated intracellular cortisol production may have a pathogenic role in type 2 diabetes and its co-morbidities. The 11beta-HSD1 becomes a novel target for anti-type 2 diabetes drug developments, and inhibition of 11beta-HSD1 offers a potential therapy to attenuate the type 2 diabetes. In the past several years, a lot of 11beta-HSD1 inhibitors have been designed, synthesized, screened and discovered. Lowering intracellular glucocorticoid concentrations through administration of small molecule 11beta-HSD1 selective inhibitors, significantly attenuates the signs and symptoms of disease in preclinical animal models and clinical trials of diabetes and metabolic syndrome. Among published inhibitors, DIO-902 from DiObex Inc. and INCB13739 from Incyte Inc. are now being investigated under Phase 2B clinical trials. However, the selectivity of current selective 11beta-HSD1 inhibitors has been just focused on the difference between 11beta-HSD1 and 11beta-HSD2. They inhibit the bi-directional activities of 11beta-HSD1, both 11beta-HSD1 reductase (major) and oxidase (minor). In our lab, we have recently found novel chemicals that not only inhibit 11beta-HSD1 reductase activity but also increase its oxidase activity without inhibition against 11beta-HSD2. We propose that this dual modulation on 11beta-HSD1 may provide a better therapeutic strategy for type 2 diabetes.

Controlled intracellular self-assembly of gadolinium nanoparticles as smart molecular MR contrast agents

Herein we developed a new “smart” Gd-based MR contrast agent (i.e., 1) which is susceptive to furin, a protease overexpressed in tumor. Under the action of furin, 1 condenses to form dimers (1-Ds) and the latter self-assemble into gadolinium nanparticles (Gd-NPs). Relaxivity of 1-D is more than 2 folds of those of 1 and magnevist at 1.5 T, and 1.4 folds of that of 1 at 3 T. Intracellular condensation of 1 in furin-overexpressed MDA-MB-468 cells was proven with direct two-photon laser microscopy (TPLM) fluorescence imaging of the cells incubated with the europium analog of 1 (i.e., 2). Intracellular Gd-NPs of 1 were uncovered and characterized for the first time. MRI of MDA-MB-468 tumors showed that 1 has enhanced MR contrast within the tumors than that of its scrambled control 1-Scr.

Enzymatic control of the self-assembly of small molecules: a new way to generate supramolecular hydrogels

This highlight summarizes recent advances in the enzymatic formation of supramolecular hydrogels, a new method for the creation of biofunctional soft matter. Using phosphatase, thermolysin, β-lactamase, and phosphatase/kinase as examples, we illustrate the design and application of enzyme catalyzed or regulated formation of supramolecular hydrogels. This approach provides a new strategy to detect the presence of enzymes, screen enzyme inhibitors, assist biomineralization, assay the types of bacteria, and aid the development of smart drug delivery systems. The strategy of using enzymes to control the self-assembly of small molecules described in this highlight will lead to the further development of new materials for biomedical applications and improve understanding of molecular self-assembly in water.

Intracellular Self-Assembly of Taxol Nanoparticles for Overcoming Multidrug Resistance†

Multidrug resistance (MDR) remains the biggest challenge in treating cancers. Herein we propose the intracellular self-assembly of nanodrugs as a new strategy for overcoming MDR. By employing a biocompatible condensation reaction, we rationally designed a taxol derivative Ac-Arg-Val-Arg-Arg-Cys(StBu)-Lys(taxol)-2-cyanobenzothiazole (CBT-Taxol) which could be subjected to furin-controlled condensation and self-assembly of taxol nanoparticles (Taxol-NPs). In vitro and in vivo studies indicated that, compared with taxol, CBT-Taxol showed a 4.5-fold or 1.5-fold increase in anti-MDR effects, respectively, on taxol-resistant HCT 116 cancer cells or tumors without being toxic to the cells or the mice. Our results demonstrate that structuring protease-susceptible agents and assembling them intracellularly into nanodrugs could be a new optimal strategy for overcoming MDR.