Doxorubicin-Polysorbate 80 conjugates: targeting effective and sustained delivery to the brain†

Abstract

Targeting therapeutic agents to the brain to treat central nervous system (CNS) diseases is a major challenge due to the blood–brain barrier (BBB). In this study, an attempt was made to deliver a model drug such as doxorubicin (DOX), to the brain in a mouse model through DOX-Polysorbate 80 (DOX-PS80) conjugates. DOX was successfully conjugated with the non-ionic surfactant Polysorbate 80 (PS80) by carbamate linkage and the conjugate was characterized by different spectroscopic techniques, such as FTIR, UV-Visible and NMR. The DOX conjugation efficacy was found to be 43.69 ± 4.72%. The in vitro cumulative release of DOX from the conjugates was found to be 4.9 ± 0.8% in PBS of pH 7.3 and 3.9 ± 0.6% in simulated cerebrospinal fluid (CSF) of pH 7.3 at the end of 10 days. An in vitro BBB permeability assay was carried out using bEnd.3 cells and DOX-PS80 conjugate showed a 3-fold increase in BBB permeability compared with controls. In vitro cytotoxicity assay using U251 human glioblastoma cells showed an IC₅₀ value of 38.10 μg mL⁻¹ for DOX-PS80. Cell uptake studies revealed that DOX-PS80 was effectively taken up (90%) by the bEnd.3 and U251 cells and localized in cytoplasm at the end of 24 h. Pharmacokinetic parameters for DOX-PS80 were evaluated using in silico studies. Tumor spheroid assay and in vivo experiments in Swiss albino mouse demonstrated the possibility of DOX-PS80 conjugate crossing the BBB and delivering the drug molecules to the target site for treating CNS disorders.