Zuojia Liu

Folic acid as delivery vehicles: targeting folate conjugated fluorescent nanoparticles to tumors imaging.

Herein, folic acid (FA) conjugated with AuNPs were introduced into the cancer cell imaging via the specific interaction between FA and the folate receptor on the cell surface. FA protected gold nanoparticles (AuNPs) was synthesized and labeled with fluorescein isothiocynate (FITC) to form the FITC-FA-AuNPs (FFANPs). As over-expressed folic acid receptor in some cancer cells and folic acid can specifically and selectively combine, the FFANPs can bind to the FR expressed on tumor cells such as HeLa cells (human epithelial cervical cancer) and CERF-CEM cells (T cell line, human acute lymphoblastic leukemia). As a result, cancer cell imaging can be achieved. To ascertain the FR target ability, it has been acquired by FR-targeted images using synthetic FFANPs. The formation of FITC-FA can be identified by MS. FCM was carried out to study the cell uptake of FFANPs. The cell toxicity (3-[4,5-dimethylthiazolyl-2]-2, 5-diphenyltetrazolium bromide, MTT) assay demonstrated that the FITC-labeled conjugate had only little effect on the cytotoxicity to the cells, which further proved the applicability of the method in tumor cell imaging.

The enhancement of transfection efficiency of cationic liposomes by didodecyldimethylammonium bromide coated gold nanoparticles.

The development of transfection enhancement of liposomes with attributes of high stability and easy handling in gene therapy is challenging. In this study, we report didodecyldimethylammonium bromide (DDAB, a cationic lipid) coated gold nanoparticles (DDAB-AuNPs), which can enhance the transfection efficiency generated by two kinds of commercially available cationic liposomes: Lipotap and DOTAP. It showed that DDAB-AuNPs at the optimal concentrations could produce more than 2 times increase when measuring the number of cells expressed green fluorescent protein and 48-fold increase for luciferase levels after transfection, respectively. The electrophoretic mobility shift assay (EMSA) and confocal laser scanning microscopy (CLSM) experiments showed that more DNA molecules binding to the lipoplexes after adding DDAB-AuNPs. In addition, the flow cytometry (FCM) results indicated that DDAB-AuNPs increased cellular uptake efficiency of DNA molecules, which might account for the enhancement of transfection efficiency. It has also been found that the DDAB-AuNPs could decrease the cytotoxicity of liposomes to the cells.

Affinity and Specificity of Levamlodipine-Human Serum Albumin Interactions: Insights into Its Carrier Function

The affinity and specificity of drugs with human serum albumin (HSA) are crucial factors influencing the bioactivity of drugs. To gain insight into the carrier function of HSA, the binding of levamlodipine with HSA has been investigated as a model system by a combined experimental and theoretical/computational approach. The fluorescence properties of HSA and the binding parameters of levamlodipine indicate that the binding is characterized by one binding site with static quenching mechanism, which is related to the energy transfer. As indicated by the thermodynamic analysis, hydrophobic interaction is the predominant force in levamlodipine-HSA complex, which is in agreement with the computational results. And the hydrogen bonds can be confirmed by computational approach between levamlodipine and HSA. Compared to predicted binding energies and binding energy spectra at seven sites on HSA, levamlodipine binding HSA at site I has a high affinity regime and the highest specificity characterized by the largest intrinsic specificity ratio (ISR). The binding characteristics at site I guarantee that drugs can be carried and released from HSA to carry out their specific bioactivity. Our concept and quantification of specificity is general and can be applied to other drug-target binding as well as molecular recognition of peptide-protein, protein-protein, and protein-DNA interactions.

Remarkable shape memory effect of a natural biopolymer in aqueous environment

Remarkable water-stimulated shape memory effect was revealed in a natural biopolymer of peacocks tail covert feathers of which the innate shape can almost be fully recovered after severe deformation by a short hydration step. The shape memory effect manifests a good stability of high recovery rate and ratio during cycles of deformation and subsequent recovery. Both strength and energy absorption efficiency of medullary foam can be recovered despite the apparent decrease in the first deformation stroke caused by structural damage. A kinetic model developed from non-equilibrium thermodynamic fluctuation theory was adopted to describe the shape recovery process by considering the viscoelastic relaxation. The effects of hydration on mechanical properties, recovery kinetics, activation process and dynamic mechanical behaviors were also evaluated. Mechanisms were explored based on the lubrication, swelling effect and structural changes of macromolecular chains or segments in terms of their mobility. This study is expected to aid in understanding the responses of natural biological materials to environmental stimuli and to provide useful information for synthetic shape memory materials from the bio-inspiration perspective.

A Potent Lead Induces Apoptosis in Pancreatic Cancer Cells

Pancreatic cancer is considered a lethal and treatment-refractory disease. To obtain a potent anticancer drug, the cytotoxic effect of 2-(benzo[d]oxazol-3(2H)-ylmethyl)- 5-((cyclohexylamino)methyl)benzene-1,4-diol, dihydrochloride (NSC48693) on human pancreatic cancer cells CFPAC-1, MiaPaCa-2, and BxPC-3 was assessed in vitro. The proliferation of CFPAC-1, MiaPaCa-2, and BxPC-3 is inhibited with IC50 value of 12.9±0.2, 20.6±0.3, and 6.2±0.6 µM at 48 h, respectively. This discovery is followed with additional analysis to demonstrate that NSC48693 inhibition is due to induction of apoptosis, including Annexin V staining, chromatins staining, and colony forming assays. It is further revealed that NSC48693 induces the release of cytochrome c, reduces mitochondrial membrane potential, generates reactive oxygen species, and activates caspase. These results collectively indicate that NSC48693 mainly induces apoptosis of CFPAC-1, MiaPaCa-2, and BxPC-3 cells by the mitochondrial-mediated apoptotic pathway. Excitingly, the study highlights an encouraging inhibition effect that human embryonic kidney (HEK-293) and liver (HL-7702) cells are more resistant to the antigrowth effect of NSC48693 compared to the three cancer cell lines. From this perspective, NSC48693 should help to open up a new opportunity for the treatment of patients with pancreatic cancer.

In situ labeling and imaging of cellular protein via a bi-functional anticancer aptamer and its fluorescent ligand

In this article, we reported a novel approach for in situ labeling and imaging HeLa cancer cells utilizing a bifunctional aptamer (AS1411) and its fluorescent ligand, protoporphyrin IX (PPIX). In the presence of potassium ion, AS1411 folded to G-quadruplex structure, binded fluorescent ligand (PPIX) with fluorescent enhancement, and targeted the nucleolin overexpressed by cancer cells. Consequently, bioimaging of cancer cells specifically were realized by laser scanning confocal microscope. The bioimaging strategy with AS1411-PPIX complex was capable to distinguish HeLa cancer cells from normal cells unambiguously, and fluorescence imaging of cancer cells was also realized in human serum. Moreover, the bioimaging method was very facile, effective and need not any covalent modification. These results illustrated that the useful approach can provide a novel clue for bioimaging based on non-covalent bifunctional aptamer in clinic diagnosis.

Water-assisted self-healing and property recovery in a natural dermal armor of pangolin scales.

Self-healing capacity, of which the inspiration comes from biological systems, is significant for restoring the mechanical properties of materials by autonomically repairing damages. Clarifying the naturally occurring self-healing behaviors and mechanisms may provide valuable inspiration for designing synthetic self-healing materials. In this study, water-assisted self-healing behavior was revealed in a natural dermal armor of pangolin scales. The indentation damages which imitate the injury caused by predatory attack can be continuously mitigated through hydration. The healing kinetics was characterized according to the variations of indentation crater dimension and quantitatively described in terms of the viscoelastic behavior of biopolymer. The mechanical properties of original, damaged, and recovered scales in both dry and wet states were systematically evaluated by three-point bending and compared through statistical analysis. The hydration effects and mechanisms were explored by examining the dynamic mechanical properties and thermal behaviors. The promoted self-healing process can be attributed to the improved flexibility of macromolecules in the biopolymer. This study may stimulate useful self-healing strategies in bio-inspired design and aid in developing high-performance synthetic self-healing materials.

Hybrid of gold nanostar and indocyanine green for targeted imaging-guided diagnosis and phototherapy using low-density laser irradiation

Phototherapy is widely studied with the development of photothermal nanomaterials. However, the laser power density for reaching effective phototherapy is still high and dangerous for normal tissues. In this research, based on multi-functional polydopamine, we proposed a general strategy to design diverse core-shell nanoparticles with different surface charges, and synthesized a targeted nanoplatform, AuNS@PDA-PEI-FA (APP), by coupling gold nanostar (AuNS) with polyethylenimine-folate (PEI-FA). Owing to the electrostatic interaction, the as-prepared APP can anchor a negatively-charged photosensitizer, indocyanine green (ICG), for photothermal and photodynamic synergistic cancer therapy. The APP-ICG is able to realize the targeted phototherapy for tumor cells even at the low power laser density of 0.33 W cm-2 both in vitro and in vivo. Furthermore, APP-ICG is not only a treatment nanoplatform but also a diagnosis agent. The integrative diagnosis results can be acquired by dual imaging technologies: the near-infrared fluorescence images and the photothermal images acquired by an in vivo imaging system and a thermal imaging camera, respectively. This new nanoplatform is a good diagnosis and treatment system and has the potential for further theranostics application.

Structure and mechanical behaviors of protective armored pangolin scales and effects of hydration and orientation

As natural flexible dermal armor, pangolin scales provide effective protection against predatory threats and possess other notable properties such as anti-adhesion and wear-resistance. In this study, the structure, mechanical properties, deformation and damage behaviors of pangolin scales were systematically investigated with the effects of hydration and orientation evaluated. The scales are divided into three macro-layers constituted by overlapping keratin tiles with distinct lamellar arrangements which are further composed of lower-ordered lamellae. Both hardness and strength are significantly decreased by hydration; while the plasticity is markedly improved concomitantly, and as such, the mechanical damages are mitigated. The tensile strength invariably approximates to one third of hardness in value. The tensile deformation is dominated by lamellae stretching and pulling out under wet condition, which is distinct from the trans-lamellar fracture in dry samples. The compressive behaviors are featured by pronounced plasticity in both dry and wet scales; and notable strain-hardening capacity is introduced by hydration, especially along the thickness direction wherein kinking occurs. Inter-lamellar cracking is effectively alleviated in wet samples compared with the dry ones and both of them deform by macroscopic buckling. This study may help stimulate possible inspiration for the design of high-performance synthetic armor materials by mimicking pangolin scales.

Rational Drug Design: The Search for Ras Protein Hydrolysis Intermediate Conformation Inhibitors with Both Affinity and Specificity

Computer-aided drug design (CADD) plays significant roles in all stages of todays drug discovery. Many CADD technologies and methods were employed in finding promising hits against different targets during the past several decades. In this review, the most common molecular modeling methods applied to computer-aided drug design are discussed. However, how to effectively integrate these computational methods and then combine them with experiments to improve the hit rate is still a challenge. In addition, the present study reviews the ISR (intrinsic specificity ratio) as a novel concept and quantitative criterion for binding specificity to be applied as a complement in addition to binding affinity for finding new leads. Using Ras protein as a case study, Molecular modeling calculations and the subsequent biological testings for the hits are performed, the specificity of these hits is also studies against the normal and cancer cells aiming at discovering the novel chemical compounds with minimal side effects. Herein, the case study also includes the evaluations for tumor-specific cytotoxicity on different cell lines. The current results suggest that ISR is useful for quantitative assessment of specificity of small molecules.