Application of chloroquine as an endosomal escape enhancing agent: new frontiers for an old drug

ABSTRACT

Introduction

Adequate transfection efficiency is indispensable to safe and effective delivery of therapeutically active agents, particularly in cancer. Endosomal escape is regarded as a critical and determining step devoted a significant number of studies of the drug/gene delivery field.

Areas covered

This paper critically reviews the fundamental properties of chloroquine (CQ), its pharmacokinetics, pharmacodynamics, and clinical applications and the present knowledge of CQ application as an endosomal escape enhancing agent. Different approaches to enhance the endosomal escape process of nanoparticles have been introduced including use of endosomal escape enhancing agents. Application of CQ as either a pre-treatment modality in which cells or animals are exposed to CQ prior to the main treatment or a component of co-delivery systems where CQ and other anti-cancer agents are simultaneously entered the cancer cells, is discussed with recent studies.

Expert opinion

CQ is founded to intervene with the natural process of endosomal maturation. Moreover, CQ seems to increase the effectiveness of gene delivery by its electrostatic interaction with negatively charged components of the transferred genetic molecules. Endosomal escape might be regarded as the bottleneck of efficient gene delivery and CQ as an effective and available endosomal escape enhancing agent deserves more sophisticated studies.

KEYWORDS:

• Chloroquine
• endosomal escape
• nanotechnology
• nanoparticle
• drug delivery
• gene delivery

Article highlights

• Practical application of many drug/gene delivery systems is limited due to the their poor endosomal escape capacity.

• To date, four well-known mechanisms have been proposed for the efficient endosomal escape of non-viral delivery systems: (1) pore formation, (2) fusion, (3) photochemical disruption, and (4) pH-buffering effect.

• A number of strategies have been introduced so far to address the problem of poor endosomal escape including use of endosomal escape enhancing agents.

• The endocytosis process of nanoparticles is highly dependent on the physicochemical parameters of the nanoparticles. These parameters include, but not limited to, size, surface charge, elasticity, and hydrophobicity of the nanoparticles.

• CQ exerts the endosomal escape enhancing property through several mechanisms such as inhibition of lysosomal acidification, increasing the osmotic pressure, and decreasing the activity of P-gp.

• Among the available endosomal escape enhancing agents, CQ seems to be a promising candidate by being physicochemically stable, inexpensive, and effective.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.