Self‐Assembling Nanofibers Inhibit Inflammation in a Murine Model of Crohn's‐Disease‐Like Ileitis

Abstract

Inflammatory bowel diseases are characterized by chronic inflammation, leading to the destruction of gastrointestinal tract tissue. Strategies specifically utilized to manage intestinal inflammation in patients afflicted with Crohn's disease (CD) are met with numerous obstacles. These include treatment‐specific physiological side effects and the development of resistance to biological and pharmacological therapies. As an alternative treatment approach, high aspect ratio supramolecular anti‐inflammatory peptide amphiphiles (AIF‐PAs) are engineered to mitigate small intestinal inflammation within the established, preclinical CD‐like ilieitis senescence accelerated mouse (SAMP1)/YitFcsJ murine model. Data derived from this study demonstrate ileitis that the direct injection of AIF‐PAs into inflammatory small intestinal skip lesions minimizes pathologic change in tissue architecture and intestinal physiology. When compared to untreated or saline injected control animals, AIF‐PAs substantially reduce lesion size and tissue‐specific inflammation, inciting cytokines tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), interleukin (IL)‐1β, and IL‐13 along with a concomitant decrease including in tissue proinflammatory innate and adaptive immune cells. Finally, this is accompanied by increased small bowel intestinal transit that aligns with improved gross intestinal pathology scoring. Taken together, this study provides evidence that AIF‐PAs may serve as a novel stand‐alone or combinatorial therapy to enhance efficacy in order to treat localized intestinal inflammation related to CD.

Discovery of Y-Shaped Supramolecular Polymers in a Self-Assembling Peptide Amphiphile System

“…Nanostructured supramolecular polymers (SPs) can be viewed as one-dimensional assemblies with a high degree of internal order. − Depending upon their chemical structures and assembly pathways, the resultant SPs can assume various morphologies such as nanofibers, nanoribbons, and nanotubes, among others. − The one dimensionality at the supramolecular level is largely rooted in the directional, strong, associative interactions at the molecular level, such as hydrogen bonding and π–π stacking, − yet it could also be a result of achieving an optimal interfacial surface area stabilized by a spontaneous curvature that favors a cylindrical packing geometry. , For molecular building units such as peptide amphiphiles that contain a β-sheet-forming peptide motif, the complex interplay of enthalpic interactions stemming from its peptidic traits and those from its amphiphilic features allows for access to a diverse array of SPs of varying sizes and shapes; ,− however, Y-junctions, or three-way connections that have been theoretically predicted and experimentally observed as a topological defect in cylinder-forming traditional surfactant systems, − have not been identified as stable structures in peptide-based supramolecular polymeric systems.…”

Biomimetic Extracellular Scaffolds by Microfluidic Superstructuring of Nanofibers

“…Other PA morphologies do not (Figure S12). This morphological similarity between PA SBs and dECM, combined with the ability to tailor the biological signals present on PA, ,− suggests that SBs can serve as morphological mimics of dECM with reduced batch-to-batch variability and greater structural uniformity than naturally derived scaffolds. ,− …”

Evolving Experimental Platforms to Evaluate Ulcerative Colitis

“…Self-assembling PAs have demonstrated utility in a wide range of settings and applications. [144][145][146][147][148][149][150] PAs are comprised of a hydrophobic alkyl segment attached to a peptide domain that includes a β-sheet forming segment (Figure 4). In aqueous environments, these molecules self-assemble through hydro-phobic collapse of the alkyl domain in combination with hydrogen bonding in the β-sheet domain to produce high aspect-ratio nanofibers.…”

“…[144,147] Recently, Bury et al have demonstrated the efficacy of PAs that express a potent anti-inflammatory peptide, known as TxPAs, in the established mouse model (SAMP1/YitFc) of CD-like ileitis. [150] As a proof of concept study, inflammatory lesions identified in the ileum of SAMP1/YitFc mice were directly injected with the Tx-PA. Several key inflammatory metrics were positively modulated by Tx-PA treatment. Observed was a statistically significant reduction in mean lesion size of the treatment group (Tx-PA) when comparing treatment PA controls [(un-injected (NO INJ); saline-injected (SAL), and control PA (C-PA) mice)].…”

“…All data were considered statistically significant. [150] Although the system described herein was not targeted to UC but rather CD, the concepts and application can be extrapolated to conditions of moderate to severe UC in the form of endoscopic delivery or lavage to Due to its unique ability for individual nanomolecules to undergo self-assembly and form nanofibers combined with its unique packing ability, PAs can deliver highly potent anti-inflammatory molecules, for example, in a fraction of the physical space that conventional UC treatments. Furthermore, PAs are highly reproducible, non-toxic, and biodegradable.…”