Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

Abstract

In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires advanced synthetic platforms to improve our understanding of the impact of mechanical cues on drug sensitivity in AML. By use of a synthetic, self-assembling peptide hydrogel (SAPH) of modifiable stiffness and composition, a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs has been developed and utilized. AML cell proliferation was dependent on SAPH stiffness, which was optimized to facilitate colony growth. Three candidate FDA-approved drugs were initially screened against the THP-1 cell line and mAF9 primary cells in liquid culture, and EC50 values were used to inform drug sensitivity assays in the peptide hydrogel models. Salinomycin demonstrated efficacy in both an ‘early-stage’ model in which treatment was added shortly after initiation of AML cell encapsulation, and an ‘established’ model in which time-encapsulated cells had started to form colonies. Sensitivity to Vidofludimus treatment was not observed in the hydrogel models, and Atorvastatin demonstrated increased sensitivity in the ‘established’ compared to the ‘early-stage’ model. AML patient samples were equally sensitive to Salinomycin in the 3D hydrogels and partially sensitive to Atorvastatin. Together, this confirms that AML cell sensitivity is drug- and context-specific and that advanced synthetic platforms for higher throughput are valuable tools for pre-clinical evaluation of candidate anti-AML drugs.

High-throughput formulation of reproducible 3D cancer microenvironments for drug testing in myelogenous leukemia

“…Despite the superior physiological relevance of the 3D culture, reliable 3D leukemia CME models remain scarce. Recently, James et al (James et al, 2023) reported a 3D cell culture model with the leukemic cells embedded in an external peptide-based hydrogel mimicking the properties of the ECM. Authors used multi-well plates to study the responses of various types of leukemic cell lines embedded in a peptide hydrogel layer to several anti-cancer drugs supplied from the external media.…”

Ameliorating Old Drugs with New Tricks in the Nano Realms

“…In a preclinical evaluation, a synthetic, self-assembling peptide hydrogel (SAPH) of variable stiffness and composition was utilized to screen repurposed and FDA-approved drugs for acute myeloid leukemia (AML). 62 It had acted as a 3D model of the bone marrow niche. The candidate drugs were salinomycin (antibacterial), vidofludimus (multiple sclerosis drug), and atorvastatin (anticholesterol drug).…”

“…Apart from drug delivery, hydrogels have emerged as 3D surrogate platforms in various disease models and applications like scaffolds and cell transplantation. In a preclinical evaluation, a synthetic, self-assembling peptide hydrogel (SAPH) of variable stiffness and composition was utilized to screen repurposed and FDA- approved drugs for acute myeloid leukemia (AML) . It had acted as a 3D model of the bone marrow niche.…”

Diversity of Bioinspired Hydrogels: From Structure to Applications

“…In vivo tests represent a determinant step for hydrogel applications. Interdisciplinary studies for hydrogel design, characterization, and in vitro investigations [55,92,116,189,380,381], along with access to preclinical and clinical studies to ensure safety and efficacy of new materials [98,271,[382][383][384][385], will accelerate the application of new concepts and revolutionary materials. Last but not least, education regarding the protection of nature, which generously offers us a variety of biomolecules, must be promoted beyond the academic framework.…”