Polyethylenimine (PEI) in gene therapy: Current status and clinical applications

Jens Casper; Susanne H Schenk; Elahehnaz Parhizkar; Pascal Detampel; Ali Dehshahri; Jörg Huwyler

doi:10.1016/j.jconrel.2023.09.001

Polyethylenimine (PEI) in gene therapy: Current status and clinical applications

J Control Release. 2023 Oct:362:667-691. doi: 10.1016/j.jconrel.2023.09.001. Epub 2023 Sep 18.

Authors

Jens Casper¹, Susanne H Schenk¹, Elahehnaz Parhizkar², Pascal Detampel¹, Ali Dehshahri³, Jörg Huwyler⁴

Affiliations

¹ Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
² Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
³ Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: dehshahria@sums.ac.ir.
⁴ Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: joerg.huwyler@unibas.ch.

PMID: 37666302
DOI: 10.1016/j.jconrel.2023.09.001

Abstract

Polyethlyenimine (PEI) was introduced 1995 as a cationic polymer for nucleic acid delivery. PEI and its derivatives are extensively used in basic research and as reference formulations in the field of polymer-based gene delivery. Despite its widespread use, the number of clinical applications to date is limited. Thus, this review aims to consolidate the past applications of PEI in DNA delivery, elucidate the obstacles that hinder its transition to clinical use, and highlight potential prospects for novel iterations of PEI derivatives. The present review article is divided into three sections. The first section examines the mechanism of action employed by PEI, examining fundamental aspects of cellular delivery including uptake mechanisms, release from endosomes, and transport into the cell nucleus, along with potential strategies for enhancing these delivery phases. Moreover, an in-depth analysis is conducted concerning the mechanism underlying cellular toxicity, accompanied with approaches to overcome this major challenge. The second part is devoted to the in vivo performance of PEI and its application in various therapeutic indications. While systemic administration has proven to be challenging, alternative localized delivery routes hold promise, such as treatment of solid tumors, application as a vaccine, or serving as a therapeutic agent for pulmonary delivery. In the last section, the outcome of completed and ongoing clinical trials is summarized. Finally, an expert opinion is provided on the potential of PEI and its future applications. PEI-based formulations for nucleic acid delivery have a promising potential, it will be an important task for the years to come to introduce innovations that address PEI-associated shortcomings by introducing well-designed PEI formulations in combination with an appropriate route of administration.

Keywords: Cationic polymer; Clinical trials; Gene delivery; Gene therapy; Nanoparticle; PEI; Polyplex; Polytheylenimine.

Publication types

Review