Bosutinib high density lipoprotein nanoformulation has potent tumour radiosensitisation effects

Abstract

Disruption of the cell cycle is among the most effective approach to increase tumour cells’ radio-sensitivity. However, the presence of dose-limiting side effects hampers the clinical use of tyrosine kinase inhibitors targeting the cell cycle. Towards addressing this challenge, we identified a bosutinib nanoformulation within high density lipoprotein nanoparticles (HDL NPs) as a promising radiosensitiser. Bosutinib is a kinase inhibitor clinically approved for the treatment of chronic myeloid leukemia that possesses radiosensitising properties through cell cycle checkpoint inhibition. We found that a remarkably high bosutinib loading (> 10%) within HDL NPs could be reliably achieved under optimal preparation conditions. The radiosensitisation activity of the bosutinib-HDL nanoformulation was first assessed in vitro in UM-SCC-1 head and neck squamous cell carcinoma (HNSCC) cells, which confirmed efficient disruption of the radiation induced G2/M cell cycle arrest. Interestingly, the bosutinib nanoformulation out-performed free bosutinib, likely because of the specific affinity of HDL NPs with tumour cells. The combination of bosutinib-HDL NPs and radiotherapy significantly controlled tumour growth in an immunocompetent murine HNSCC model. The bosutinib-HDL nanoformulation also enhanced the radiation induced immune response through the polarisation of tumour associated macrophages towards proinflammatory phenotypes.

Carriers for hydrophobic drug molecules: lipid-coated hollow mesoporous silica particles, and the influence of shape and size on encapsulation efficiency

“…Many anticancer drugs including bosutinib, dasatinib, tamoxifen, and curcumin are hydrophobic, leading to poor retention times within the human body. [1][2][3][4][5] Given their chemi-cal design to favorably interact with specific receptors located in the lipid-rich cell membrane or intracellular compartments of cells, it is imperative to discover new carrier systems enabling their optimum encapsulation and transport. [6][7][8][9][10] Ultrafine carriers capable of containing hydrophobic molecules are ideally suited to enhance blood circulation and drug uptake.…”