title: pH and amphiphilic structure direct supramolecular behavior in biofunctional assemblies.
abstract: Supramolecular self-assembly offers promising new ways to control nanostructure morphology and respond to external stimuli. A pH-sensitive self-assembled system was developed to both control nanostructure shape and respond to the acidic microenvironment of tumors using self-assembling peptide amphiphiles (PAs). By incorporating an oligo-histidine H6 sequence, we developed two PAs that self-assembled into distinct morphologies on the nanoscale, either as nanofibers or spherical micelles, based on the incorporation of the aliphatic tail on the N-terminus or near the C-terminus, respectively. Both cylinder and sphere-forming PAs demonstrated reversible disassembly between pH 6.0 and 6.5 upon protonation of the histidine residues in acidic solutions. These PAs were then characterized and assessed for their potential to encapsulate hydrophobic chemotherapies. The H6-based nanofiber assemblies encapsulated camptothecin (CPT) with up to 60% efficiency, a 7-fold increase in CPT encapsulation relative to spherical micelles. Additionally, pH-sensitive nanofibers showed improved tumor accumulation over both spherical micelles and nanofibers that did not change morphologies in acidic environments. We have demonstrated that the morphological transitions upon changes in pH of supramolecular nanostructures affect drug encapsulation and tumor accumulation. Our findings also suggest that these supramolecular events can be tuned by molecular design to improve the pharmacologic properties of nanomedicines.
authors.affiliation: Institute for BioNanotechnology in Medicine and ∥Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.
authors.forename: Tyson J
authors.initials: TJ
authors.lastname: Moyer
authors.forename: Joel A
authors.initials: JA
authors.lastname: Finbloom
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Toft
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Stupp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D006639:Histidine; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D057139:Nanofibers / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D006639:Histidine