Delivery of host cell-directed therapeutics for intracellular pathogen clearance

Abstract

Intracellular pathogens present a major health risk because of their innate ability to evade clearance. Their location within host cells and ability to react to the host environment by mutation or transcriptional changes often enables survival mechanisms to resist standard therapies. Host-directed drugs do not target the pathogen, minimizing the potential development of drug resistance; however, they can be difficult to deliver efficiently to intracellular sites. Vehicle delivery of host-mediated response drugs not only improves drug distribution and toxicity profiles, but can reduce the total amount of drug necessary to clear infection. In this article, we will review some host-directed drugs and current drug delivery techniques that can be used to efficiently clear intracellular infections.

Keywords::

• Ac-DEX
• autophagy
• dose sparing
• drug delivery
• druggable target
• host-mediated response
• inflammatory cytokines
• innate immunity
• intracellular pathogens
• macrophages
• multiple-resistant strains
• Toll-like receptors

Financial & competing interests disclosure

Arno Therapeutics, Inc. the company that licenses AR-12, has provided grant support to the College of Medicine and the College of Pharmacy at The Ohio State University. The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Intracellular pathogens have the ability to rapidly mutate due to exposure to suboptimal concentrations of pathogen-targeting drugs, resulting in antibiotic resistant strains.

• • Host-directed drugs allow for a decreased chance of pathogen mutability.

• • Encapsulated drugs are shielded, which minimizes side effects in the host.

• • Dose sparing allows for a smaller dosage of drug with the same or greater effects.

• • Targeted drug delivery allows for enhanced uptake into macrophages and/or dendritic cells.

• • Encapsulation of drug increases the stability of the compound and lessens the need for a cold chain.

• • Encapsulation allows drugs with solubility problems to be distributed systemically.

• • Stimulation of Toll-like receptors allows for an exceptional immune response to combat infections.

• • Combination therapies allow for smaller amounts of drug and increased pathogen clearance.

Notes