Weakly basic small molecule drugs like clofazimine can be used as building blocks for endowing cells with unnatural structural and functional elements. Here, we describe how clofazimine represents a first-in-class mechanopharmaceutical device, serving to construct inert, inactive and stimulus responsive drug depots within the endophagolysosomal compartment of cells of living organisms. Upon oral administration, clofazimine molecules self-assemble into stable, membrane-bound, crystal-like drug inclusions (CLDI) that accumulate within macrophages to form a "smart" biocompatible, pathogen activatable mechanopharmaceutical device. Upon perturbation of the mechanism maintaining pH and ion homeostasis of these CLDIs, the inert encapsulated drug precipitates are destabilized, releasing bioactive drug molecules into the cell and its surrounding. The resulting increase in clofazimine solubility activates this broad-spectrum antimicrobial, antiparasitic, antiviral or cytotoxic agent within the infected macrophage. We present a general, molecular design strategy for using clofazimine and other small molecule building blocks for the cytoplasmic construction of mechanopharmaceutical devices, aimed at rapid deployment during infectious disease outbreaks, for the purpose of pandemic prevention.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901583 | PMC |
http://dx.doi.org/10.1016/j.jconrel.2022.05.029 | DOI Listing |
J Control Release
July 2022
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Weakly basic small molecule drugs like clofazimine can be used as building blocks for endowing cells with unnatural structural and functional elements. Here, we describe how clofazimine represents a first-in-class mechanopharmaceutical device, serving to construct inert, inactive and stimulus responsive drug depots within the endophagolysosomal compartment of cells of living organisms. Upon oral administration, clofazimine molecules self-assemble into stable, membrane-bound, crystal-like drug inclusions (CLDI) that accumulate within macrophages to form a "smart" biocompatible, pathogen activatable mechanopharmaceutical device.
View Article and Find Full Text PDFPharmaceutics
December 2021
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution.
View Article and Find Full Text PDFSci Rep
April 2019
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Macrophages are immune cells responsible for tissue debridement and fighting infection. Clofazimine, an FDA-approved antibiotic, accumulates and precipitates as rod-shaped, crystal-like drug inclusions within macrophage lysosomes. Drug treatment as well as pathophysiological states could induce changes in macrophage mechanical property which in turn impact their phenotype and function.
View Article and Find Full Text PDFPharm Res
November 2018
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
Purpose: Clofazimine (CFZ) is an FDA-approved, poorly soluble small molecule drug that precipitates as crystal-like drug inclusions (CLDIs) which accumulate in acidic cytoplasmic organelles of macrophages. In this study, we considered CLDIs as an expandable mechanopharmaceutical device, to study how macrophages respond to an increasingly massive load of endophagolysosomal cargo.
Methods: First, we experimentally tested how the accumulation of CFZ in CLDIs impacted different immune cell subpopulations of different organs.
Pharm Res
November 2018
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109, USA.
Purpose: Drug-induced liver injuries (DILI) comprise a significant proportion of adverse drug reactions leading to hospitalizations and death. One frequent DILI is granulomatous inflammation from exposure to harmful metabolites that activate inflammatory pathways of immune cells of the liver, which may act as a barrier to isolate the irritating stimulus and limit tissue damage.
Methods: Paralleling the accumulation of CFZ precipitates in the liver, granulomatous inflammation was studied to gain insight into its effect on liver structure and function.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!