Abstract B33: PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma
Authors: Gaudin Alice , Song Eric , Amanda King , Desmaele Didier , Couvreur Patrick , Saltzman Mark 
Published: March 2017

Given its deadly prognosis, new treatments for glioblastoma multiforme (GBM) are desperately needed. Despite major progress in the development of new chemotherapeutic drugs and improved surgical technique, GBM prognosis remains grim, with a median survival of 15 months, mainly due to the almost invariable tumor recurrence. Convection-enhanced delivery (CED) of nanoparticles (NPs) has been proposed as an efficient way to deliver chemotherapeutic drugs locally into the tumor bed and to enhance treatment of intracranial tumors. Gemcitabine is an antimetabolite, and an effective inhibitor of DNA synthesis, that is used as a first line treatment for a wide variety of solid tumors. Gemcitabine has demonstrated efficacy against human glioma cell lines in vitro, but its clinical effectiveness is limited by its inability to cross the blood-brain barrier (BBB) after systemic delivery, its rapid deamination in the brain interstitial space to its inactive difluorodeoxyuridine metabolite, and its limited uptake by brain tumor cells. Here we propose to use CED to circumvent the BBB, and to administer the chemotherapeutic drug gemcitabine in a squalene-based nanoparticulate form, which is designed to protect the drug from metabolism, to provide a sustained release of the drug, and to enhance its cellular internalization.

SQGem NPs were prepared by the nanoprecipitation technique, and presented a diameter of around 120 nm when measured by DLS, with a negative surface charge of around -20 mV. Modification of the surface of SQGem NPs using different amounts of polyethylene glycol (PEG) was performed by incorporating squalenoyl-PEG (SQPEG) to the formulation, providing SQGem/SQPEG NPs. The PEGylated NPs retained the physico-chemical properties of SQGem NPs, and the addition of PEG prevented the aggregation of the particles in aCSF. The stabilized formulations presented significantly larger volumes of distribution (Vd) in the healthy brain and the tumor-bearing brain after administration by CED. We further demonstrated that the combination of a non-distributing formulation and a distributing formulation offered the possibility of tuning the volume distribution of the nanoparticles in the brain tissue, and thus controlling the local drug concentration. To evaluate the effect of PEGylation on therapeutic efficacy, Fischer 344 rats were implanted with RG2 cells, and treated by CED using different SQGem/SQPEG formulations. Given the dual action of gemcitabine as chemotherapeutic and radiosensitizer, we also evaluated the addition of radiation to the treatment schedule. Overall, all formulations increased survival compared to free drug. Finally, as a first step toward clinical translation, we incorporated ultra-small iron particles oxide (USPIO) to the SQGem/SQPEG NPs formulation, to add the possibility of tracking the particles during CED using MRI. These NPs retained suitable characteristics to be administered by CED and were able to distribute in the brain tissue.

This study demonstrates for the first time the safe administration of SQGem NPs by CED, providing significant survival improvement compared to the free drug. It also demonstrates a new method to optimize drug distribution by modulating surface properties of the nanoparticles. The administration by CED of optimized SQGem NPs formulations is expected to increase survival and could, in the future, change the way that GBM patients are treated in the US and around the world.

Citation Format: Alice Gaudin, Eric Song, King Amanda, Didier Desmaele, Patrick Couvreur, Mark Saltzman. PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B33.