Non-toxic polymer nanovectors for improved delivery of dexamethasone

Benjamin C Ede,Allison Blair,Paraskevi Diamanti,David S Williams

doi:10.1038/s41598-021-96797-4

Abstract

Dexamethasone (Dex) is a highly insoluble front-line drug used in cancer therapy. Data from clinical trials indicates that the pharmacokinetics of Dex vary considerably between patients and prolonging drug exposure rather than increasing absolute dose may improve efficacy. Non-toxic, fully biodegradable Dex loaded nanovectors (NV) were formulated, via simple direct hydration within 10 min, as a vehicle to extend exposure and distribution in vivo. Dex-NV were just as effective as the free drug against primary human leukemia cells in vitro and in vivo. Importantly, high levels of DMSO solvent were not required in the NV formulations. Broad distribution of NV was seen rapidly following inoculation into mice. NV accumulated in major organs, including bone marrow and brain, known sanctuary sites for ALL. The study describes a non-toxic, more easily scalable system for improving Dex solubility for use in cancer and can be applied to other medical conditions associated with inflammation.

Highlights

Dexamethasone (Dex) is a highly insoluble front-line drug used in cancer therapy
Using an optimised protocol for the direct hydration of NV, it was established that the upper limit of Dex encapsulation was 5 wt% with 100% loading efficiency, confirmed using dynamic light scattering (DLS)
Relevant concentrations of Dex (0.25–0.5 mg/mL) giving 2.5–5 mg/kg doses in mice were encapsulated, which contained ≤ 0.5% dimethyl sulfoxide (DMSO) to enhance its dissolution during the direct hydration process (Fig. 1A)

Summary

Introduction

Dexamethasone (Dex) is a highly insoluble front-line drug used in cancer therapy. Data from clinical trials indicates that the pharmacokinetics of Dex vary considerably between patients and prolonging drug exposure rather than increasing absolute dose may improve efficacy. Relevant concentrations of Dex (0.25–0.5 mg/mL) giving 2.5–5 mg/kg doses in mice (equivalent to 5–10 mg/m2 in humans) were encapsulated, which contained ≤ 0.5% DMSO to enhance its dissolution during the direct hydration process (Fig. 1A). Once ≥ 0.1% human CD45+ cells were detected in peripheral blood (PB) aspirates, separate cohorts of animals were treated with Dex-NV, free Dex (IP, 2.5 mg/kg,) or placebo daily, for 5 days/week over a 4 week period.

Results

Conclusion