Supramolecular self assembly of nanodrill-like structures for intracellular delivery

N. Ashwanikumar, Justin S. Plaut, Barmak Mostofian, Siddharth Patel, Peter Kwak, Conroy Sun, Kerry McPhail, Daniel Zuckerman, Sadik Esener, Gaurav Sahay

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Despite recent advances in the supramolecular assembly of cell-penetrating peptide (CPP) nanostructures, the tuning of size, shape, morphology and packaging of drugs in these materials still remain unexplored. Herein, through sequential ligation of peptide building blocks, we create cell-penetrating self-assembling peptide nanomaterials (CSPNs) with the capability to translocate inside cells. We devised a triblock array of Tat48-59 [HIV-1 derived transactivator of transcription48-59] based CPPs, conjugated to up to four Phenylalanine (Phe) residues through an amphiphilic linker, (RADA)2. We observed that the sequential addition of Phe leads to the transition of CSPN secondary structures from a random coil, to a distorted α-helix, a β-sheet, or a pure α-helix. This transition occurs due to formation of a heptad by virtue of even number of Phe. Atomic force microscopy revealed that CSPNs form distinct shapes reminiscent of a "drill-bit". CSPNs containing two, three or four Phe, self-assemble into "nanodrill-like structures" with a coarse-twisted, non-twisted or fine-twisted morphology, respectively. These nanodrills had a high capacity to encapsulate hydrophobic guest molecules. In particular, the coarse-twisted nanodrills demonstrate higher internalization and are able to deliver rapamycin, a hydrophobic small molecule that induced autophagy and are capable of in vivo delivery. Molecular dynamics studies provide microscopic insights into the structure of the nanodrills that can contribute to its morphology and ability to interact with cellular membrane. CSPNs represent a new modular drug delivery platform that can be programmed into exquisite structures through sequence-specific fine tuning of amino acids.

Original languageEnglish (US)
JournalJournal of Controlled Release
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Nanostructures
Phenylalanine
Peptides
Drug Packaging
Cell-Penetrating Peptides
Mandrillus
Trans-Activators
Atomic Force Microscopy
Autophagy
Sirolimus
Molecular Dynamics Simulation
Ligation
HIV-1
Amino Acids
Membranes
Pharmaceutical Preparations

Keywords

  • Cell penetrating peptides
  • Intracellular delivery
  • Nanodrills
  • Supramolecular assembly

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Ashwanikumar, N., Plaut, J. S., Mostofian, B., Patel, S., Kwak, P., Sun, C., ... Sahay, G. (Accepted/In press). Supramolecular self assembly of nanodrill-like structures for intracellular delivery. Journal of Controlled Release. https://doi.org/10.1016/j.jconrel.2018.02.041

Supramolecular self assembly of nanodrill-like structures for intracellular delivery. / Ashwanikumar, N.; Plaut, Justin S.; Mostofian, Barmak; Patel, Siddharth; Kwak, Peter; Sun, Conroy; McPhail, Kerry; Zuckerman, Daniel; Esener, Sadik; Sahay, Gaurav.

In: Journal of Controlled Release, 01.01.2018.

Research output: Contribution to journalArticle

Ashwanikumar, N. ; Plaut, Justin S. ; Mostofian, Barmak ; Patel, Siddharth ; Kwak, Peter ; Sun, Conroy ; McPhail, Kerry ; Zuckerman, Daniel ; Esener, Sadik ; Sahay, Gaurav. / Supramolecular self assembly of nanodrill-like structures for intracellular delivery. In: Journal of Controlled Release. 2018.
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