Decreased circulation time offsets increased efficacy of PEGylated nanocarriers targetingfolate receptors of glioma

Abstract

Liposomal and other nanocarrier based drug delivery vehicles can localize to tumoursthrough passive and/or active targeting. Passively targeted liposomal nanocarriersaccumulate in tumours via ‘leaky’ vasculature through the enhanced permeability andretention (EPR) effect. Passive accumulation depends upon the circulation time andthe degree of tumour vessel ‘leakiness’. After extravasation, actively targetedliposomal nanocarriers efficiently deliver their payload by receptor-mediated uptake.However, incorporation of targeting moieties can compromise circulation time inthe blood due to recognition and clearance by the reticuloendothelial system,decreasing passive accumulation. Here, we compare the efficacy of passively targeteddoxorubicin-loaded PEGylated liposomal nanocarriers to that of actively targetedliposomal nanocarriers in a rat 9L brain tumour model. Although folate receptor(FR)-targeted liposomal nanocarriers had significantly reduced blood circulation timecompared to PEGylated liposomal nanocarriers; intratumoural drug concentrationsboth at 20 and 50 h after administration were equal for both treatments. Bothtreatments significantly increased tumour inoculated animal survival by 60–80%compared to non-treated controls, but no difference in survival was observedbetween FR-targeted and passively targeted nanocarriers. Therefore, alternateapproaches allowing for active targeting without compromising circulation time may beimportant for fully realizing the benefits of receptor-mediated active targeting ofgliomas.