ABSTRACT
Here, we report the design, synthesis and efficacy of a new class of ultrasound (US)-sensitive self-assembled peptide-based nanoparticle. Peptisomes are prepared via templated assembly of a de novo designed peptide at the interface of fluorinated nanodroplets. Utilizing peptide assembly allows for facile particle synthesis, direct incorporation of bioactive sequences displayed from the particle corona, and the ability to easily encapsulate biologics during particle preparation using a mild solvent exchange procedure. Further, nano-peptisome size can be precisely controlled by simply modulating the starting peptide and fluorinated solvent concentrations during synthesis. Biomolecular cargo encapsulated within the particle core can be directly delivered to the cytoplasm of cells upon US-mediated rupture of the carrier. Thus, nano-peptisomes represent a novel class of US-activated carriers that can shuttle cell-impermeable biomacromolecules into cells with spatial and temporal precision.
Subject(s)
Nanoparticles/chemistry , Phalloidine/chemistry , Ultrasonics , A549 Cells , Humans , Microscopy, Fluorescence , Optical Imaging , Phalloidine/chemical synthesisSubject(s)
Actins/chemistry , Biological Products/chemical synthesis , Fluorescent Dyes/chemistry , Glutamic Acid/chemical synthesis , Phalloidine/chemical synthesis , Actins/metabolism , Amanita/chemistry , Cyclization , Fluorescent Dyes/metabolism , Glutamic Acid/analogs & derivatives , Microscopy, Fluorescence , Models, Chemical , Phalloidine/analogs & derivatives , Protein BindingABSTRACT
Herein we report a solid-phase synthetic approach to [Ala7]-phalloidin (1). Prior syntheses of phallotoxins were carried out using solution-phase routes that required large scale and preclude library production. The route presented here consists of solution-phase preparation of key orthogonally protected amino acid building blocks, followed by a solid-phase peptide synthesis sequence, featuring two resin-bound macro-cyclization reactions. The final product mixture was composed of two atropisomeric compounds, one designated "natural" (1) and the other designated "non-natural" (1'). The structures of these species were modeled using restrained energy minimization with NMR-derived restraints.