A peptide for transcellular cargo delivery: Structure-function relationship and mechanism of action

Alexander Komin; Maxim I Bogorad; Ran Lin; Honggang Cui; Peter C Searson; Kalina Hristova

doi:10.1016/j.jconrel.2020.05.030

A peptide for transcellular cargo delivery: Structure-function relationship and mechanism of action

J Control Release. 2020 Aug 10:324:633-643. doi: 10.1016/j.jconrel.2020.05.030. Epub 2020 May 28.

Authors

Alexander Komin¹, Maxim I Bogorad¹, Ran Lin², Honggang Cui², Peter C Searson³, Kalina Hristova⁴

Affiliations

¹ Institute for Nanobiotechnology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA; Department of Materials Science and Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
² Institute for Nanobiotechnology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
³ Institute for Nanobiotechnology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA; Department of Materials Science and Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA. Electronic address: searson@jhu.edu.
⁴ Institute for Nanobiotechnology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA; Department of Materials Science and Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA. Electronic address: kh@jhu.edu.

Abstract

The rate of transport of small molecule drugs across biological barriers, such as the blood-brain barrier, is often a limiting factor in achieving a therapeutic dose. One proposed strategy to enhance delivery across endothelial or epithelial monolayers is conjugation to cell-penetrating peptides (CPPs); however, very little is known about the design of CPPs for efficient transcellular transport. Here, we report on transcellular transport of a CPP, designated the CL peptide, that increases the delivery of small-molecule cargoes across model epithelium approximately 10-fold. The CL peptide contains a helix-like motif and a polyarginine tail. We investigated the effect of cargo, helix-like motif sequence, polyarginine tail length, and peptide stereochemistry on cargo delivery. We showed that there is an optimal helix-like motif sequence (RLLRLLR) and polyarginine tail length (R₇) for cargo delivery. Furthermore, we demonstrated that the peptide-cargo conjugate is cleaved by cells in the epithelium at the site of a two-amino acid linker. The cleavage releases the cargo with the N-terminal linker amino acid from the peptide prior to transport out of the epithelium. These studies provide new insight into the sequence requirements for developing novel CPPs for transcellular delivery of cargo.

Keywords: Cell-penetrating peptides; Drug delivery; Microvessel; Peptide proteolysis; Polyarginine; Transcellular transport.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Biological Transport
Cell-Penetrating Peptides* / metabolism
Drug Delivery Systems
Structure-Activity Relationship

Substances

Cell-Penetrating Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding