A novel doxorubicin loaded folic acid conjugated PAMAM modified with borneol, a nature dual-functional product of reducing PAMAM toxicity and boosting BBB penetration.

Abstract Effective targeting drug delivery system for glioma treatment is still greatly challenged by the existence of the blood–brain barrier (BBB) and the intracranial overspreading of anti-tumor drug. Herein, we presented a dual-functional glioma targeting delivery of doxorubicin based on the PAMAM G5 dendrimer, modified with folic acid (FA) to target tumor cell, also borneol (BO), a well known safe material derived from traditional Chinese medicine, to facilitate the BBB permeability and reduce the toxicity of naked PAMAM. The intracranial transportation and glioma targeting ability were evaluated on the BBB model and C6 glioma cells in vitro . Also, pharmacokinetics and biodistribution were studied on C6 glioma-bearing rats in vivo . It indeed reduced the cytotoxicity of PAMAM against both HBMEC and C6 cells by coupling BO on the surface, while efficiently boosted BBB permeability with the improvement of transportation ratio by 2 folds to the BO-unmodified conjugates. Furthermore, conjugated FA increased total uptake amount by C6 cells leading to strong inhibition with the 3-fold lower IC 50 value than FA-unmodified DOX conjugate. In comparison with DOX solution, FA-BO-PAMAM/DOX exhibited significantly prolonged half-life time and increased area under the curve and improved DOX accumulation in brain tumor. The tumor growth inhibition, in vivo , was significantly increased up to 57.4%. The median survival time of xenograft rats after administering FA-BO-PAMAM/DOX (28 days) was significantly prolonged compared to free DOX (18 days, P