Application of nanoparticles for the delivery of drugs to the brain

Abstract The blood–brain barrier (BBB) represents an insurmountable obstacle for the delivery of a large number of drugs to the central nervous system (CNS). One of the possibilities to overcome this barrier is drug delivery to the brain using nanoparticles. Drugs that have been transported into the brain and led to significant pharmacological effects after intravenous injection using this carrier include the hexapeptide dalargin, the dipeptide kytorphin, loperamide, tubocurarine, doxorubicin, and the NMDA receptor antagonists MRZ 2/576 and MRZ 2/596. In order to achieve a significant transport across the blood–brain barrier the coating of the nanoparticles with polysorbate 80 (Tween® 80) or other polysorbates with 20 polyoxyethylene units was required. Other surfactants were less successful. The most promising results were obtained with doxorubicin for the treatment of brain tumours. Intravenous injection of polysorbate 80-coated nanoparticles loaded with doxorubicin (5 mg/kg) achieved very high brain levels of 6 μg/g brain tissue while all the controls, including uncoated nanoparticles and doxorubicin solutions mixed with polysorbate, did not reach the analytical detection limit of 0.1 μg/g. Moreover, experiments with the extremely aggressive glioblastoma 101/8 transplanted intracranially showed a long term survival for 6 months of up to 40% of the rats after intravenous injection of the polysorbate 80-coated nanoparticle preparation (3×1.5 mg/kg). The surviving animals were sacrificed after this time and showed total remission by histological investigation. Untreated controls died within 10–20 days, the animals in the doxorubicin control and uncoated doxorubicin nanoparticle groups died between 10–50 days. The mechanism of the drug transport across the blood–brain barrier with the nanoparticles appears to be endocytotic uptake by the brain capillary endothelial cells followed either by release of the drugs in these cells and diffusion into the brain or by transcytosis. After injection of the nanoparticles, apolipoprotein E (apo E) or apo B adsorb on the particle surface and then seem to promote the interaction with the LDL receptor followed by endocytotic uptake. The nanoparticles thus would mimic the uptake of naturally occurring lipoprotein particles. This hypothesis was supported by the achievement of an antinociceptive effect using dalargin-loaded poly(butyl cyanoacrylate) nanoparticles with adsorbed apo E or loperamide-loaded albumin nanoparticles with covalently bound apo E.