Science and Mathematics Faculty Publications

Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide

Document Type

Article

Publication Date

2-3-2020

Journal Title

Molecular Pharmaceutics

ISSN

15438392

Volume

17

Issue

2

First Page

461

Last Page

471

DOI

10.1021/acs.molpharmaceut.9b00883

Abstract

Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, “drug-like” molecules. Here, we explore the ability of a tumor-targeted delivery system centered on the use of a pH-low insertion peptide (pHLIP) to directly deliver moderately polar, multi-kDa molecules into tumor cells. A pHLIP is a short, pH-responsive peptide capable of inserting across a cell membrane to form a transmembrane helix at acidic pH. pHLIPs target the acidic tumor microenvironment with high specificity, and a drug attached to the inserting end of a pHLIP can be translocated across the cell membrane during the insertion process. We investigate the ability of wildtype pHLIP to deliver peptide nucleic acid (PNA) cargoes of varying sizes across lipid membranes. We find that pHLIP effectively delivers PNAs up to ∼7 kDa into cells in a pH-dependent manner. In addition, pHLIP retains its tumor-targeting capabilities when linked to cargoes of this size, although the amount delivered is reduced for PNA cargoes greater than ∼6 kDa. As drug-like molecules are traditionally restricted to sizes of ∼500 Da, this constitutes an order-of-magnitude expansion in the size range of deliverable drug candidates.

Keywords

pHLIP, tumor-targeted drug delivery, tumor acidity, transmembrane insertion, membrane permeability, drug size

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