Preclinical autophagy modulatory nanomedicines: big challenges, slow advances

ABSTRACT

Introduction

Autophagy is a critical housekeeping pathway to remove toxic protein aggregates, damaged organelles, providing cells with bioenergetic substrates needed to survive under adverse conditions. Since altered autophagy is associated with diverse diseases, its pharmacological modulation is considered of therapeutic interest. Nanomedicines may reduce the toxicity and improve the activity of toxic autophagy modulatory drugs (amd).

Areas covered

The status of the most relevant anti-tumor, anti-inflammatory, and anti-infectious treatments mediated by autophagy modulatory nanomedicines (amN) published in the last 5 years is discussed.

Expert opinion

Antitumor and anti-inflammatory treatments may be improved by administering amN for selective, massive, and targeted delivery of amd to diseased tissues. The use of amN as antimicrobial agent remains almost underexploited. Assessing the effect of amN on the complex autophagy machinery operating under different basal diseases, however, is not a trivial task. Besides structural reproducibility, nanomedicines must grant higher efficiency, and lower adverse effects than conventional medication. Simplicity of design, carefully chosen (scalable) preparation techniques, and rigorous monitoring of preclinical efficacy and nanotoxicity will improve the chances of clinical success. Currently, available data are not sufficient to envisage a fast-succeeding translation. Application of quality by design criteria would help to reach such milestones.

KEYWORDS:

• Nanomedicines
• autophagy
• endocytosis
• targeted delivery
• toxicity
• quality by design

Article highlights

• Autophagy is a catabolic mechanism of sequestration, degradation and intracellular recycling conserved among eukaryotes.

• An overview is provided on preclinical efficacy of amN published in the last 5 years, which alone or in combination with other therapeutic drugs, modify pharmacokinetics, biodistribution and pharmacodynamics of amd.

• Most amN are anti-cancer agents and consist of either autophagy inhibitory nanomedicines for delivery of chloroquine and hydroxychloroquine combined with anti-cancer drugs or autophagy inducing nanomedicines for delivery of rapamycin alone (as antiangiogenic agent) or combined with anti-cancer drugs.

• Autophagy inducing nanomedicines as antibacterial agents deserve a deeper exploration, because of their potential to reduce the use of antibiotics.

• More rigorous preclinical assays, including nanotoxicity estimation and feasibility of industrial scaling up are major factors that limit the translation into clinics of autophagy modulatory nanomedicines.

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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 funded by the Research Office from the Quilmes National University and National Council for Scientific and Technological Research (CONICET).