Injectable nanomedicine hydrogel for local chemotherapy of glioblastoma after surgical resection.

Glioblastoma (GBM) treatment includes, when possible, surgical resection of the tumor followed by radiotherapy and oral chemotherapy with temozolomide, however recurrences quickly develop around the resection cavity borders leading to patient death. We hypothesize that the local delivery of Lauroyl-gemcitabine lipid nanocapsule based hydrogel (GemC12-LNC) in the tumor resection cavity of GBM is a promising strategy as it would allow to bypass the blood brain barrier, thus reaching high local concentrations of the drug. The cytotoxicity and internalization pathways of GemC12-LNC were studied on different GBM cell lines (U251, T98-G, 9L-LacZ, U-87 MG). The GemC12-LNC hydrogel was well tolerated when injected in mouse brain. In an orthotopic xenograft model, after intratumoral administration, GemC12-LNC significantly increased mice survival compared to the controls. Moreover, its ability to delay tumor recurrences was demonstrated after perisurgical administration in the GBM resection cavity. In conclusion, we demonstrate that GemC12-LNC hydrogel could be considered as a promising tool for the post-resection management of GBM, prior to the standard of care chemo-radiation.

To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?

Tumor targeting by nanomedicine-based therapeutics has emerged as a promising approach to overcome the lack of specificity of conventional chemotherapeutic agents and to provide clinicians the ability to overcome shortcomings of current cancer treatment. The major underlying mechanism of the design of nanomedicines was the Enhanced Permeability and Retention (EPR) effect, considered as the "royal gate" in the drug delivery field. However, after the publication of thousands of research papers, the verdict has been handed down: the EPR effect works in rodents but not in humans! Thus the basic rationale of the design and development of nanomedicines in cancer therapy is failing making it necessary to stop claiming efficacy gains via the EPR effect, while tumor targeting cannot be proved in the clinic. It is probably time to dethrone the EPR effect and to ask the question: what is the future of nanomedicines without the EPR effect? The aim of this review is to provide a general overview on (i) the current state of the EPR effect, (ii) the future of nanomedicine and (iii) the strategies of modulation of the tumor microenvironment to improve the delivery of nanomedicine.

Anticancer drug-loaded hydrogels as drug delivery systems for the local treatment of glioblastoma.

Among central nervous system tumors, Glioblastoma (GBM) is the most common, aggressive and neurological destructive primary brain tumor in adults. Standard care therapy for GBM consists in surgical resection of the accessible tumor (without causing neurological damage) followed by chemoradiation. However, several obstacles limit the assessment of tumor response and the delivery of cytotoxic agents at the tumor site, leading to a lack of effectiveness of conventional treatments against GBM and fatal outcome. Despite the efforts of the scientific community to increase the long-term benefits of GBM therapy, at the moment GBM remains incurable. Among the strategies that have been adopted in the last two decades to find new and efficacious therapies for the treatment of GBM, the local delivery of chemotherapeutic drugs in the tumor resection cavity emerged. In this review, our aim is to provide an overview on hydrogels loaded with anticancer drugs for the treatment of GBM recently used in preclinical and clinical studies, their advantages and major limitations for clinical translation. This review is divided in three parts: the first one describes the context of GBM and its current treatments, with a highlight on the role of local delivery in GBM treatment and the development of GBM resection murine models. Then, recent developments in the use of anticancer drug-loaded hydrogels for the treatment of GBM will be detailed. The final section will be focused on the limitations for in vivo studies, clinical translation and the clinical perspectives to the development of hydrogels.

Lauroyl-gemcitabine-loaded lipid nanocapsule hydrogel for the treatment of glioblastoma.

The local delivery of chemotherapeutic agents is a very promising strategy for the treatment of glioblastoma (GBM). Gemcitabine is a chemotherapeutic agent that has a different mechanism of action compared to alkylating agents and shows excellent radio-sensitizing properties. So, we developed an injectable gel-like nanodelivery system consisting in lipid nanocapsules loaded with anticancer prodrug lauroyl-gemcitabine (GemC12-LNC) in order to obtain a sustained and local delivery of this drug in the brain. In this study, the GemC12-LNC has been formulated and characterized and the viscoelastic properties of the hydrogel were evaluated after extrusion from 30G needles. This system showed a sustained and prolonged in vitro release of the drug over one month. GemC12 and the GemC12-LNC have shown increased in vitro cytotoxic activity on U-87 MG glioma cells compared to the parent hydrophilic drug. The GemC12-LNC hydrogel reduced significantly the size of a subcutaneous human GBM tumor model compared to the drug and short-term tolerability studies showed that this system is suitable for local treatment in the brain. In conclusion, this proof-of-concept study demonstrated the feasibility, safety and efficiency of the injectable GemC12-LNC hydrogel for the local treatment of GBM.

Dual anticancer drug/superparamagnetic iron oxide-loaded PLGA-based nanoparticles for cancer therapy and magnetic resonance imaging.

We developed dual paclitaxel (PTX)/superparamagnetic iron oxide (SPIO)-loaded PLGA-based nanoparticles for a theranostic purpose. Nanoparticles presented a spherical morphology and a size of 240 nm. The PTX and iron loading were 1.84 ± 0.4 and 10.4 ± 1.93 mg/100 mg respectively. Relaxometry studies and phantom MRI demonstrated their efficacy as T2 contrast agent. Significant cellular uptake by CT26 cells of nanoparticles was shown by Prussian blue staining and fluorescent microscopy. While SPIO did not show any toxicity in CT-26 cells, PTX-loaded nanoparticles had a cytotoxic activity. PTX-loaded nanoparticle (5 mg/kg) with or without co-encapulated SPIO induced in vivo a regrowth delay of CT26 tumors. Together these multifunctional nanoparticles may be considered as future nanomedicine for simultaneous molecular imaging, drug delivery and real-time monitoring of therapeutic response.