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We describe biodegradable mesoporous hybrid nanoparticles (NPs) in the presence of proteins and their applications for drug delivery. We synthesized oxamide phenylene-based mesoporous organosilica nanoparticles (MON) in the absence of a silica source which had remarkably high organic content and high surface areas. Oxamide functions provided biodegradability in the presence of trypsin model proteins. MON displayed exceptionally high payloads of hydrophilic and hydrophobic drugs (up to 84 wt %), and a unique zero premature leakage without the pore capping, unlike mesoporous silica. MON were biocompatible and internalized into cancer cells for drug delivery. [ABSTRACT FROM AUTHOR]

Despite the worldwide interest generated by periodic mesoporous organosilica (PMO) bulk materials, the design of PMO nanomaterials with controlled morphology remains largely unexplored and their properties unknown. In this work, we describe the first study of PMO nanoparticles (NPs) based on meta-phenylene bridges, and we conducted a comparative structure-property relationship investigation with para-phenylene-bridged PMO NPs. Our findings indicate that the change of the isomer drastically affects the structure, morphology, size, porosity and thermal stability of PMO materials. We observed a much higher porosity and thermal stability of the para-based PMO which was likely due to a higher molecular periodicity. Additionally, the para isomer could generate multipodal NPs at very low stirring speed and upon this discovery we designed a phenylene-ethylene bridged PMO with a controlled Janus morphology. Unprecedentedly high payloads could be obtained from 40 to 110 wt % regardless of the organic bridge of PMOs. Finally, we demonstrate for the first time the co-delivery of two cargos by PMO NPs. Importantly, the cargo stability in PMOs did not require the capping of the pores, unlike pure silica, and the delivery could be autonomously triggered in cancer cells by acidic pH with nearly 70 % cell killing. [ABSTRACT FROM AUTHOR]

Mesoporous silica nanoparticles (MSNPs) are functionalized with molecular-recognition sites by anchoring a triazine or uracil fragment on the surface. After loading these MSNPs with dyes (propidium iodide or rhodamine B) or with a drug (camptothecin, CPT) they are capped by the complementary fragments, uracil and adenine, respectively, linked to the bulky cyclodextrin ring. These MSNPs are pH-sensitive and indeed, the dye release was observed at acidic pH by continuously monitored fluorescence spectroscopy studies. On the other hand, no dye leakage occurred at neutral pH, hence meeting the non-premature requirement to minimize side effects. In vitro studies were performed and confocal microscopy images demonstrate the internalization of the MSNPs and also dye release in the cells. To investigate the drug-delivery performance, the cytotoxicity of CPT-loaded nanoparticles was tested and cell death was observed. A remarkably lower amount of loaded CPT in the MSNPs (more than 40 times less) proved to be as efficient as free CPT. These results not only demonstrate the drug release after pore opening under lysosomal pH, but they also show the potential use of these MSNPs to significantly decrease the amount of the administered drug. [ABSTRACT FROM AUTHOR]

Mesoporous silica nanoparticles with a cubic ( Ia3 d) pore structure are derivatized with light-activated nanoimpellers to control the release of loaded guest molecules under external photo-control. The nanoimpellers consist of azobenzene derivatives that are attached to the interiors of the three-dimensional interconnected pores, and undergo photoisomerization that results in dynamic wagging motions of the unbound termini and drives the expulsion of molecules from the pores. Stimulated release experiments monitored by fluorescence spectroscopy demonstrate that the nanoimpeller-functionalized MCM-48 particles are able to trap and release both hydrophilic and hydrophobic cargo molecules under external photocontrol in aqueous, non-aqueous, and intracellular environments. [ABSTRACT FROM AUTHOR]

A therapy of cancer cells: Two‐photon‐triggered camptothecin delivery (see picture) with nanoimpellers was studied in MCF‐7 breast cancer cells. A fluorophore with a high two‐photon absorption cross‐section was first incorporated in the nanoimpellers. Fluorescence resonance energy transfer (FRET) from the fluorophore to the azobenzene moiety was demonstrated. [ABSTRACT FROM AUTHOR]

Porous silicon nanoparticles (PSiNPs) are attractive carriers for targeted drug delivery in nanomedicine. For in vivo applications, the biodegradation property of PSiNPs provides a pathway for their safe clearance from the body. Particles sizes of 80-120 nm are of particular interest as they are important for cellular applications, such as drug delivery for cancer therapy, because these nanoparticles can take advantage of the enhanced permeability and retention effect to deliver drug preferentially to tumors with leaky vasculature, yet large enough to avoid renal clearance. However, the biodegradability rate of such particles is often too fast, which limits particle half-life and potentially reduces their in vivo delivery efficiency. In this work, we focus on the degradation of nanoscale particles and study the effect of both thermal oxidation and silica coating on the stability of PSiNPs in phosphate buffered saline solution (a close mimic of a basic biological fluid). Using thermal oxidation, the half-life of PSiNPs can be varied from 10 min up to 3 h. Using silica coating, the half-life can be extended further to 8 h. The particles produced using both these techniques can be functionalized using standard silica surface chemistries developed for applications in drug delivery. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A:3416-3421, 2012. [ABSTRACT FROM AUTHOR]

Mammalian target of rapamycin (mTOR) is a key regulator of eukaryotic cell growth. In particular, mTORC1, one of the two complexes that contain mTOR, is involved in the regulation of protein synthesis, proliferation, cell cycle and autophagy. Hyperactivation of the mTOR signaling pathway is observed in human cancer. A variety of approaches including deletion analysis, yeast genetic screens and mining of human cancer genome databases were taken that resulted in the identification of activating mutations of TOR. These studies suggest that the FAT, FRB and kinase domains are the three regions of TOR where activating mutations can be identified. Within the kinase domain, the mutations are clustered in three hot spots that are all located in the kinase active site that was deduced by the alignment with PI3K. One of the hot spots corresponds to the region where PI3K oncogenic mutations have been identified. These results are beginning to provide important insights into the mechanism of activation of mTOR. [ABSTRACT FROM AUTHOR]

Silica thin films and nanoparticles prepared using sol–gel chemistry are derivatized with active molecules to generate new functional materials. The mild conditions associated with sol–gel processing allow for the incorporation of a range of dopants including organic or inorganic dyes, biomolecules, surfactants, and molecular machines. Silica nanoparticles embedded with inorganic nanocrystals, and films containing living cells have also been synthesized. Silica templated with surfactants to create mesostructure contains physically and chemically different regions that can be selectively derivatized using defined techniques to create dynamic materials. Using two different techniques, donor–acceptor pairs can be doped into separated regions simultaneously and photo-induced electron transfer between the molecules can be measured. Mesoporous silica materials are also useful supports for molecular machines. Machines including snap-tops and nanoimpellers that are designed to control the release of guest molecules trapped within the pores are described. Mesoporous silica nanoparticles are promising materials for drug delivery and other biomedical applications because they are nontoxic and can be taken up by living cells. Through appropriate design and synthesis, multifunctional mesoporous silica nanoparticles for sophisticated bio-applications are created. [ABSTRACT FROM AUTHOR]

Rheb GTPase is a key player in the control of growth, cell cycle and nutrient uptake that is conserved from yeast to humans. To further our understanding of the Rheb pathway, we sought to identify hyperactivating mutations in the Schizosaccharomyces pombe Rheb, Rhb1. Hyperactive forms of Rhb1 were found to result from single amino acid changes at valine-17, serine-21, lysine-120 or asparagine-153. Expression of these mutants confers resistance to canavanine and thialysine, phenotypes which are similar to phenotypes exhibited by cells lacking the Tsc1/Tsc2 complex that negatively regulates Rhb1. The thialysine-resistant phenotype of the hyperactive Rhb1 mutants is suppressed by a second mutation in the effector domain. Purified mutant proteins exhibit dramatically decreased binding of GDP, while their GTP binding is not drastically affected. In addition, some of the mutant proteins show significantly decreased GTPase activities. Thus the hyperactivating mutations are expected to result in an increase in the GTP-bound/GDP-bound ratio of Rhb1. By using the hyperactive mutant, Rhb1K120R, we have been able to demonstrate that Rhb1 interacts with Tor2, one of the two S. pombe TOR (Target of Rapamycin) proteins. These fission yeast results provide the first evidence for a GTP-dependent association of Rheb with Tor. [ABSTRACT FROM AUTHOR]

Protein farnesylation is important for a number of physiological processes, including proliferation and cell morphology. The Schizosaccharomyces pombe mutant, cpp1–, defective in farnesylation, exhibits distinct phenotypes, including morphological changes and sensitivity to the arginine analogue, canavanine. In this work, we report a novel phenotype of this mutant, enrichment of G0/G1 phase cells. This phenotype results mainly from the inability to farnesylate the Rheb G-protein, as normal cell cycle progression can be restored to the mutant by expressing a mutant form of SpRheb (SpRheb-CVIL) that can bypass farnesylation. In contrast, a farnesylation-defective mutant of SpRheb (SpRheb-SVIA) is incapable of restoring the normal cell cycle profile to the cpp1– mutant. Inhibition of SpRheb expression leads to the accumulation of cells at the G0/G1 phase of the cell cycle. This growth arrest phenotype of the sprheb– disruption can be complemented by the introduction of wild-type sprheb+. The complementation is dependent on farnesylation, as the farnesylation-defective SpRheb-SVIA mutant is incapable of complementing the sprheb– disruption. Other mutants of SpRheb, E40K and S20N, are also incapable of complementing the sprheb– disruption. Furthermore, efficient complementation can be obtained by the expression of human Rheb but not Saccharomyces cerevisiae Rheb. Our findings suggest that protein farnesylation is important for cell cycle progression of S. pombe cells and that farnesylated SpRheb is critical in this process. [ABSTRACT FROM AUTHOR]

Examines the characteristics of the geranylgeranyl transferase type I from Schizosaccharomyces pombe. Post-translational C-terminal modification of several small GTPases; Genes encoding subunits of each phenyltransferase; Reconstitution of the GGTase I activity.

Nanotechnology Biodegradable hybrid materials that combine high porosity and drug payload without drug leakage are in high demand. In their Communication on page 14806 ff., N. M. Khashab and et al. report the first completely biodegradable mesoporous hybrid nanovectors in the presence of proteases. Oxamide‐phenylene‐based mesoporous organosilica nanoparticles were synthesized with oxamide functions to enable the biodegradability in the presence of trypsin. Exceptionally high payloads of drugs (up to 84 wt%) and a unique zero premature leakage without the pore capping were observed. [ABSTRACT FROM AUTHOR]