Paclitaxel nanoparticles for the potential treatment of brain tumors

• Published in: Journal of controlled release Vol. 99; no. 2; pp. 259 - 269
• Main Authors: Koziara, Joanna M., Lockman, Paul R., Allen, David D., Mumper, Russell J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 30.09.2004; Elsevier
• Subjects: Adjuvants, Pharmaceutic - chemistry; Adjuvants, Pharmaceutic - pharmacokinetics; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blood–brain barrier; Brain metastases; Brain Neoplasms - drug therapy; Brain perfusion; Brain uptake; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Pharmaceutical - methods; Fatty Alcohols - chemistry; General pharmacology; Glycerol - analogs & derivatives; Glycerol - chemistry; Glycerol - pharmacokinetics; Humans; Inhibitory Concentration 50; Male; Medical sciences; Nanostructures - chemistry; Nanostructures - ultrastructure; P-glycoprotein; Paclitaxel - chemistry; Paclitaxel - metabolism; Paclitaxel - therapeutic use; Pharmaceutical technology. Pharmaceutical industry; Pharmaceutical Vehicles - chemistry; Pharmaceutical Vehicles - pharmacokinetics; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polysorbates - chemistry; Rats; Rats, Inbred F344; Technology, Pharmaceutical - methods; Tritium; P-glycoprotein; Brain metastases; Brain perfusion; Brain uptake; Blood–brain barrier; Antineoplastic agent; Intracranial; Nervous system diseases; Pharmaceutical technology; Nanoparticle; Brain cancer; P Glycoprotein; Malignant tumor; Blood brain barrier; Uptake; Cerebral disorder; Treatment; Blood-brain barrier; Perfusion; Taxane derivatives; Central nervous system disease; Paclitaxel; Antimitotic
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2004.07.006

Despite the advances in tumor therapy, patients with primary brain tumors and brain metastases have a very poor prognosis. Low responses to chemotherapy are mainly attributed to impermeability of the blood–brain barrier to cytotoxic agents. Paclitaxel has been shown to be active against gliomas and various brain metastases. However, its use in treatment of brain tumors is limited due to low blood–brain barrier permeability and serious side effects associated with administration of the paclitaxel solvent, Cremophor EL®. Lack of paclitaxel brain uptake is thought to be associated with the p-glycoprotein (p-gp) efflux transporter. In this work, paclitaxel (PX) was entrapped in novel cetyl alcohol/polysorbate nanoparticles. Paclitaxel nanoparticles (PX NPs) were characterized by means of size, short-term stability, drug entrapment efficiency, and release profile. The PX NP cytotoxicity profile was monitored using two different cell lines, U-118 and HCT-15. Brain uptake of PX NPs was evaluated using an in situ rat brain perfusion model. The results suggest that entrapment of paclitaxel in nanoparticles significantly increases the drug brain uptake and its toxicity toward p-glycoprotein expressing tumor cells. It was hypothesized that PX NPs could mask paclitaxel characteristics and thus limit its binding to p-gp, which consequently would lead to higher brain and tumor cell uptake of the otherwise effluxed drug.