No abstract

We report the observation of intermediate structures in the self-assembly of the peptide KFE8 (FKFEFKFE), designed with alternating polar and nonpolar amino acids. Self-assembly was followed over time using atomic force microscopy (AFM), transmission electron microscopy (TEM), and circular dichroism (CD). Molecular dynamics simulations suggest that these intermediates are left-handed double helical β-sheets. These findings have implications in the study of β-sheet fibril formation, and in the molecular design of materials.

We have investigated the supramolecular structure of helical ribbons formed during self-assembly of a ␤-sheet peptide using computer simulation. We tested a wide range of molecular packing geometries consistent with the experimental dimensions to identify the most stable structure, and then systematically changed the helical geometry to investigate its energy landscape. The effect of pH was incorporated by scaling the amount of charge on the side chains based on the electrostatic double layer theory. Our results suggest that these left-handed helical ribbons are comprised of a double ␤-sheet and that the experimentally measured dimensions correspond to a local energy minimum. Side chain interactions are found to be critical in determining the stability and curvature of the helix. Our approach has general applicability to the study of self-assembled nanostructures from ␤-sheet peptides where high resolution data are not yet available.

Nanoparticle (NP)-mediated drug delivery typically relies on cargo release to occur passively or in response to environmental stimuli. Here we present a delivery method based on light-activated disruption of intracellular vesicles after internalization of biofunctionalized mesoporous silica nanoparticles loaded with cargo. This method combines the power of targeted delivery with the spatiotemporal control of light activation. As an example, we delivered a cell-impermeable fluorescent compound exclusively to the cytosol of multidrug resistant cancer cells in a mixed population. KeywordsMesoporous silica; nanoparticles; P-glycoprotein; drug delivery; photodynamic therapy; endosomeThe potential of nanomaterials for drug delivery has been extensively explored in recent years. [1][2][3][4] Such efforts have been driven to a large extent by the need to reduce side effects in anticancer drugs (such as doxorubicin's severe cardiotoxicity) via tissue-specific targeting. 5 Beyond enhanced targetability, NP-encapsulation of drugs may also provide protection against premature degradation and enable efficient delivery of substances with poor inherent solubility or membrane permeability. Important determinants of the success of NP-mediated drug delivery are biocompatibility, circulation time, immunogenicity, specific targeting, © 2010 American Chemical Society * To whom correspondence should be addressed. dclapham@enders.tch.harvard.edu. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscripttiming of cargo release and, ideally, access to intracellular compartments. Careful tuning of NP size, especially in the 10-100 nm range, enables control of circulation time, 6,7 as well as passive tumor accumulation due to the "enhanced permeability and retention" effect. 8 Particle size also affects NP cellular uptake. 9 A highly desirable feature of NP-based delivery platforms is precise temporal control of compound release. This can be regulated by incorporating release mechanisms triggered by environmental stimuli such as pH, 10 temperature, 11 or enzymatic reactions. 12 Another important way to control payload delivery for membrane-impermeable drugs is to regulate access to the cytosol, which usually requires escape from the endolysosomal compartment where particles are clustered following receptor-mediated endocytosis. Here we present a method for precise spatial and temporal control over cytosolic delivery of compounds that would otherwise be cell-impermeable by incorporating a light-triggered endosomal escape mechanism within a cell targetable mesoporous silica carrier.Among potential nanocarriers, mesoporous silicate materials 13-15 have demonstrated great potential for biomedical applications due to their biocompatibility, ease of functionalization, and large surface-to-volume ratio. 16 They have been successfully used to deliver drugs, 17,18 proteins 19 and nucleic acids. 20,21 Most recent efforts have been focused on their biological targeting in order to achieve site-specific delivery. 16,22 Size contro...

No abstract