AbstractThe introduction of controlled self-assembly into living organisms opens up desired biomedical applications in wide areas including bioimaging/assays, drug delivery, and tissue engineering. Besides the enzyme-activated examples reported before, controlled self-assembly under integrated stimuli, especially in the form of sequential input, is unprecedented and ultimately challenging. This study reports a programmable self-assembling strategy in living cells under sequentially integrated control of both endogenous and exogenous stimuli. Fluorescent polymerized vesicles are constructed by using cholinesterase conversion followed by photopolymerization and thermochromism. Furthermore, as a proof-of-principle application, the cell apoptosis involved in the overexpression of cholinesterase in virtue of the generated fluorescence is monitored, showing potential in screening apoptosis-inducing drugs. The approach exhibits multiple advantages for bioimaging in living cells, including specificity to cholinesterase, red emission, wash free, high signal-to-noise ratio.

•Mixed micelles composed of a pH-sensitive prodrug and TPGS were prepared.•The mixed micelles show increased cytotoxicity against drug resistant cancer cells.•The pH-sensitive prodrug and TPGS synergistically enhance cytotoxicity.In this study, we prepared mixed micelles composed of a pH-sensitive poly(ethylene glycol)-doxorubicin conjugate prodrug and d-alpha-tocopheryl polyethylene glycol succinate (TPGS). The average hydrodynamic size of the mixed micelles was approximately 144 nm, measured by dynamic light scattering. In an MTT assay the pH-sensitive prodrug was non-cytotoxic at low concentration but inhibited drug-resistant cancer cell (MCF-7/ADR) growth at high dose. The mixed micelles showed concentration-dependent cytotoxicity and significantly increased the cytotoxicity of the prodrug in MCF-7/ADR cells. Confocal laser scanning images revealed that higher concentrations of doxorubicin were successfully delivered into cell nuclei, enabling effective drug-induced cell death. Fluorescence microscopy indicated that there was less escape of the internalized doxorubicin from cells. Therefore, the enhanced drug efficacy in MCF-7/ADR cells is most likely attributed to a synergistic effect of drug-release from the pH-sensitive prodrug inside cells and suppression of P-glycoprotein efflux activity by TPGS.Download high-res image (119KB)Download full-size image

Stimuli-responsive drug release nanoparticles are of particular interest due to their enhanced effects and reduced systemic toxicities in the area of cancer therapeutics. The effect of these nanoparticles on the cellular microenvironment has not yet been clearly defined. In this context, redox-responsive nanoparticles were synthesized with disulfide-containing linkages. These nanoparticles depleted the cellular GSH level and modulated the cellular redox microenvironment to more oxidizing conditions. The resulting drug-encapsulated nanoparticles showed improved cytotoxicity, apoptosis, and invasion inhibition of metastatic cancer cells. Moreover, these improvements had a direct correlation with the cellular redox status modulated by nanoparticles. The present study provides a new strategy for designing redox-responsive drug carriers to improve the sensitivity of cells to anticancer drugs and enhance the therapeutic efficacy in metastatic cancer.

The detailed mechanism of the cyanide-catalyzed synthesis of benzoxazole from 2-aminophenol and benzaldehyde was investigated in depth using density functional theory (DFT). The metal-free aerobic oxidative process as well as the dehydrogenation detail were examined and described. Cyanide anion was proved to assist the oxygen atoms to undergo an aerobic dehydrogenation rather than direct cyclization which was predicted according to Baldwin’s 5-exotet rule. The dehydrogenation pathway was thermodynamically favored over cyclization with an activation energy difference of 24.2 kcal/mol. Another point noteworthy was the observation that a trace amount of water could reduce the activation energy effectively during the condensation step (ΔΔG⧧ = 22.3 kcal/mol).

Here we present the special self-assembly properties of the amphiphilic macromolecules made from G1 PAMAM dendrimers partially modified with cholic acid. These cholic acid-derived macromolecules can self-assemble in both apolar and polar solvents. The aggregates of these macromolecules in toluene can partially extract hydrophilic molecules from water to toluene. The macromolecules in aqueous solutions can form multiple morphological aggregates which are nanoparticles below pH 10.0 and microparticles above pH 13.0. The nanoparticles release methotrexate, an anticancer drug, in a pH-dependent manner. The results indicate that the solvent-controlled self-assemblies may make the macromolecules good candidates for pH-controlled drug release carriers with good cell membrane permeability. This macromolecule may have potential applications in intracellular drug delivery systems.

To improve the efficacy and bioacceptability of polyamidoamine (PAMAM) in potential biomedical applications, the PAMAM dendrimers (first generation) were partially modified with cholic acid. 1H NMR studies and acid−base titration show that two cholic acid molecules are linked to one PAMAM. The modified PAMAM dendrimers self-assemble to form dendritic multimolecular micelles in aqueous solutions, with a diameter of 120 nm measured by dynamic light scattering. These micelles can encapsulate hydrophobic drug molecules in aqueous media and exhibit pH sensitivity. The in vitro results demonstrate that the anticancer activity of camptothecin is significantly enhanced at low drug dose after being encapsulated by these micelles in the presence of serum. Therefore, the dendritic multimolecular micelles based on low generation dendrimers may have potential applications in the delivery of drugs.

The effect of a peripheral disulfide bridge substituent on the phenolic O−H bond dissociation energy (BDE) and the ionization potential (IP) of naphthyridine diol has been studied by density functional theory (DFT) calculation. Compared with naphthalene diol, the substituent of a peripheral disulfide bridge group is very efficient in reducing the BDE, whereas the insertion of nitrogen atoms into the naphthalenic ring only slightly changes the BDE of O−H bond but dramatically enhances the IP. It is similar with the stereoelectronic effect of the heterocyclic ring for the well-known α-tocopherol antioxidant and leads to a highly delocalized spin distribution. With the incorporation of these two aspects, a potential antioxidant is expected to be more active and more stable than α-tocopherol.

A detailed theoretical study on the rearrangement of 2-(1,6-methano[10]annulenyl)-3,3-dimethylmethylenecyclopropane 1 to a mixture of two diastereomeric 1,6-methano[10]annulenylisopropylidenecyclopropanes, 3 and 5, is presented in this paper. The computational results reproduce experimental findings and confirm the conjecture that the rearrangement proceeds through the biradical intermediate 2, which is greatly stabilized by the 1,6-methano[10]annulenyl group and is long-lived enough to undergo a rotation before ring closure. In addition, the origin of the stereochemistry observed in the rearrangement has been discussed.

The Conductor-like Polarizable Continuum Model (CPCM) in conjunction with the radii of UAHF, UAKS, Pauling, Bondi and KLAMT was used to calculate the pKa values of benzo-quinuclidine series in aqueous solvent. Comparison of calculated pKa’s and experimental data indicates that the accuracy of the CPCM model predominantly depends on the choice of cavity models. The most accurate pKa’s were obtained from the use of CPCM with UAKS or UAHF cavity, producing a mean absolute deviation of 0.39 and 0.40 pKa units, respectively. These methods are suitable for calculating the pKa’s of the relatively large ammonium ions in aqueous solution.Structures of 9H-9,10(1′,2′)-benzenoacridinium ion solvated with one water molecule.

Stimuli-responsive drug release nanoparticles are of particular interest due to their enhanced effects and reduced systemic toxicities in the area of cancer therapeutics. The effect of these nanoparticles on the cellular microenvironment has not yet been clearly defined. In this context, redox-responsive nanoparticles were synthesized with disulfide-containing linkages. These nanoparticles depleted the cellular GSH level and modulated the cellular redox microenvironment to more oxidizing conditions. The resulting drug-encapsulated nanoparticles showed improved cytotoxicity, apoptosis, and invasion inhibition of metastatic cancer cells. Moreover, these improvements had a direct correlation with the cellular redox status modulated by nanoparticles. The present study provides a new strategy for designing redox-responsive drug carriers to improve the sensitivity of cells to anticancer drugs and enhance the therapeutic efficacy in metastatic cancer.