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Paclitaxel nanoparticles for the potential treatment of brain tumors
Joanna M Koziara1, Paul R Lockman, David D Allen
1Division of Pharmaceutical Sciences, Center for Pharmaceutical Science and Technology, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536-0082, USA.
Abstract:
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.
Insights
Novel nanoparticles enhance paclitaxel (PX) brain uptake for brain tumor therapy. Paclitaxel nanoparticles (PX NPs) overcome blood-brain barrier limitations and p-glycoprotein efflux, improving tumor cell toxicity.
Area of Science:
- Nanotechnology
- Neuro-oncology
- Pharmacology
Background:
- Primary brain tumors and metastases have poor prognoses due to limited chemotherapy efficacy.
- The blood-brain barrier restricts cytotoxic agent delivery to the brain.
- Paclitaxel's efficacy is hindered by poor brain penetration and Cremophor EL side effects, partly due to p-glycoprotein (p-gp) efflux.
Purpose of the Study:
- To develop paclitaxel-loaded nanoparticles (PX NPs) to improve brain tumor treatment.
- To enhance paclitaxel delivery across the blood-brain barrier.
- To investigate the effect of nanoparticles on paclitaxel's interaction with p-gp.
Main Methods:
- Paclitaxel was entrapped in cetyl alcohol/polysorbate nanoparticles (PX NPs).
- PX NPs were characterized for size, stability, entrapment efficiency, and release profile.
- Cytotoxicity was assessed using U-118 and HCT-15 cell lines; brain uptake was evaluated using an in situ rat brain perfusion model.
Main Results:
- Nanoparticle formulation demonstrated favorable physicochemical properties.
- PX NPs significantly increased paclitaxel brain uptake compared to the free drug.
- PX NPs exhibited enhanced cytotoxicity against p-gp expressing tumor cells.
Conclusions:
- Entrapment of paclitaxel in nanoparticles enhances its brain uptake and anti-tumor activity.
- PX NPs may overcome p-gp mediated efflux, leading to improved drug delivery to brain tumors.
- This nanoparticle approach holds promise for improving outcomes in brain tumor patients.
