Fabrication of self-assembling nanofibers with optimal cell uptake and therapeutic delivery efficacy

• Published in: Bioactive materials 2017-12, Vol.2 (4), p.260-268
• Main Authors: Xu, Dawei, Samways, Damien S.K., Dong, He
• Format: Article
• Language: English
• Subjects: Bioactive polymers and gel; Cell penetrating peptide; Cell uptake; Drug delivery; Membrane activity; Supramolecular assembly
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2017.09.001

Effective strategies to fabricate finite organic nanoparticles and understanding their structure-dependent cell interaction is highly important for the development of long circulating nanocarriers in cancer therapy. In this contribution, we will capitalize on our recent development of finite supramolecular nanofibers based on the self-assembly of modularly designed cationic multidomain peptides (MDPs) and use them as a model system to investigate structure-dependent cell penetrating activity. MDPs self-assembled into nanofibers with high density of cationic charges at the fiber-solvent interface to interact with the cell membrane. However, despite the multivalent charge presentation, not all fibers led to high levels of membrane activity and cellular uptake. The flexibility of the cationic charge domains on self-assembled nanofibers plays a key role in effective membrane perturbation. Nanofibers were found to sacrifice their dimension, thermodynamic and kinetic stability for a more flexible charge domain in order to achieve effective membrane interaction. The increased membrane activity led to improved cell uptake of membrane-impermeable chemotherapeutics through membrane pore formation. In vitro cytotoxicity study showed co-administering of water-soluble doxorubicin with membrane-active peptide nanofibers dramatically reduced the IC50 by eight folds compared to drug alone. Through these detailed structure and activity studies, the acquired knowledge will provide important guidelines for the design of a variety of supramolecular cell penetrating nanomaterials not limited to peptide assembly which can be used to probe various complex biological processes. In this work, we will demonstrate the design and optimization of cell penetrating activity and therapeutic delivery efficacy of self-assembling nanofibers based on modularly designed cationic multidomain peptides. [Display omitted] •We establish a supramolecular nanoplatform for the construction of finite anisotropic nanofibers with tunable nanostructure and cell penetrating activity.•We confirmed the effective membrane activity of selected nanofibers to destabilize the cell membrane and identified that the flexibility of the cationic charge domains on self- assembled nanofiber plays a key role in effective membrane perturbation.•We showed the utility of nanofiber as a highly effective chemotherapeutic enhancer to facilitate the transport of membrane-impermeable drug molecules across the cell membrane to m