Paclitaxel nanoparticles for the potential treatment of brain tumors.
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.
Koziara
Joanna M
JM
Division of Pharmaceutical Sciences, Center for Pharmaceutical Science and Technology, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536-0082, USA.
Lockman
Paul R
PR
Allen
David D
DD
Mumper
Russell J
RJ
D000277:Adjuvants, Pharmaceutic / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005233:Fatty Alcohols / Q000737:chemistry; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure; D017239:Paclitaxel / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D014677:Pharmaceutical Vehicles / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics; D011136:Polysorbates / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344; D013678:Technology, Pharmaceutical / Q000379:methods; D014316:Tritium
D000277:Adjuvants, Pharmaceutic; D000970:Antineoplastic Agents; D005233:Fatty Alcohols; D014677:Pharmaceutical Vehicles; D011136:Polysorbates; D014316:Tritium; D011092:Polyethylene Glycols; C000515:cremophor EL; C043444:octadecyl polyoxyethylene ether; C005031:cetyl alcohol; D017239:Paclitaxel; D005990:Glycerol