Potent therapeutic efficacy of intranasally deliverable paclitaxel modified with pH-sensitive and PEGylated polymeric micelle against glioblastoma

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and common type of brain tumor. Conventional therapies for GBM, such as surgery or radiotherapy, have shown inadequate therapeutic effect. Similarly, a large fraction of chemotherapeutics are ineffective against GBM due to the blood-brain barrier (BBB) preventing effective delivery of these drugs to the brain. To overcome these obstacles, an intranasally administrable and multifunctional drug-loaded polymeric micelle composed of a pH-sensitive PPCBA-PEI-Arg (PPA) polymer conjugated with PEGylated paclitaxel (PEG-PTX; PPP) was synthesized to treat GBM. PPP was more soluble in an aqueous solution than parental PTX and was more effectively internalized into the GBM cells. Further, PPP elicited a more potent cancer cell killing effect than PTX under physiological pH condition, which was further augmented under the mildly acidic condition that emulated the tumor microenvironment. Intranasal administration of PPP into orthotopic GBM tumor xenograft-bearing mice led to more efficient delivery of the drug to the brain tissues compared to parental PTX delivered via intranasal or intravenous route, thus resulting in superior inhibition of GBM growth. Collectively, these findings demonstrated that intranasal delivery of PTX via pH-sensitive and PEGylated polymeric micelles can be an effective approach for the treatment of aggressive GBM.

Keywords: Arginine; Blood brain barrier; Brain cancer; Intranasal delivery; Paclitaxel; Piperazine; Polyethylene glycol; Polyethylenimine (PEI); pH-sensitive polymers.