RRC ID 71926
Author Dehghankelishadi P, Maritz MF, Dmochowska N, Badiee P, Cheah E, Kempson I, Berbeco RI, Thierry B.
Title Formulation of simvastatin within high density lipoprotein enables potent tumour radiosensitisation.
Journal J Control Release
Abstract Preclinical, clinical and epidemiologic studies have established the potent anticancer and radiosensitisation effects of HMG-CoA reductase inhibitors (statins). However, the low bioavailability of oral statin formulations is a key barrier to achieving effective doses within tumour. To address this issue and ascertain the radiosensitisation potential of simvastatin, we developed a parenteral high density lipoprotein nanoparticle (HDL NP) formulation of this commonly used statin. A scalable method for the preparation of the simvastatin-HDL NPs was developed using a 3D printed microfluidic mixer. This enables the production of litre scale amounts of particles with minimal batch to batch variation. Simvastatin-HDL NPs enhanced the radiobiological response in 2D/3D head and neck squamous cell carcinoma (HNSCC) in vitro models. The simvastatin-HDL NPs radiosensitisation was comparable to that of 10 and 5 times higher doses of free drug in 2D and 3D cultures, respectively, which could be partially explained by more efficient cellular uptake of the statin in the nanoformulation as well as by the inherent biological activity of the HDL NPs on the cholesterol pathway. The radiosensitising potency of the simvastatin-HDL nanoformulation was validated in an immunocompetent MOC-1 HNSCC tumour bearing mouse model. This data supports the rationale of repurposing statins through reformulation within HDL NPs. Statins are safe and readily available molecules including as generic, and their use as radiosensitisers could lead to much needed effective and affordable approaches to improve treatment of solid tumours.
Volume 346
Pages 98-109
Published 2022-6-1
DOI 10.1016/j.jconrel.2022.04.017
PII S0168-3659(22)00211-5
PMID 35447296
MeSH Animals Cholesterol, HDL Head and Neck Neoplasms* / drug therapy Head and Neck Neoplasms* / radiotherapy Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use Lipoproteins, HDL Mice Simvastatin / pharmacology Simvastatin / therapeutic use Squamous Cell Carcinoma of Head and Neck / drug therapy
IF 7.727
DNA material mVenus-hGeminin(1/110) / pCSII-EF (RDB15271) mCherry-hCdt1(30/120)/ pCSII-EF (RDB15273)