Idarubicin-loaded chitosan nanobubbles to improve survival and decrease drug side effects in hepatocellular carcinoma.

BACKGROUND: Drug delivery strategies using chitosan nanobubbles (CS-NBs) could be used to reduce drug side effects and improve outcomes in hepatocellular carcinoma (HCC) treatment. To enhance their action, a targeting agent, such as the humanized anti-GPC3 antibody GC33 (condrituzumab), could be attached to their surface. Here, we investigated the use of idarubicin-loaded CS-NBs for HCC treatment and a GC33-derived minibody (that we named 4A1) to enhance CS-NB delivery. METHODS: Various CS-NB formulations were prepared with or without 4A1 conjugation and idarubicin loading. RESULTS: CS-NBs had a positive charge and a diameter of about 360 nm. In in-vitro experiments using the HCC-like HUH7 cell line, CS-NBs showed a cytotoxic effect once loaded with idarubicin. In-vivo biodistribution in HUH7 tumor-bearing xenograft mice demonstrated that CS-NBs can accumulate in the tumor mass. This effect was enhanced by 4A1 conjugation (p = 0.0317). In HUH7 tumor-bearing xenograft mice, CS-NBs loaded with idarubicin and conjugated or not conjugated with 4A1 were both able to slow tumor growth, to increase mouse survival time compared to free idarubicin (p = 0.00044 and 0.0018, respectively) as well as to reduce drug side effects. CONCLUSIONS: CS-NBs loaded with idarubicin can be a useful drug delivery strategy for HCC treatment.