Doxorubicin-Polysorbate 80 Conjugates: Targeting Effective and Sustained Delivery to the Brain

Targeting therapeutic agents to the brain to treat the 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 mice 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. 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 to controls. In vitro cytotoxicity assay using U251 human glioblastoma cells showed an IC50 value of 38.10 µg/mL 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. Tumor spheroid assay and in vivo experiments in Swiss albino mice demonstrated the possibility of DOX-PS80 conjugate crossing the BBB and delivering the drug molecules to the target site for treating CNS disorders.