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Orthotopic glioblastoma xenografts are paramount for evaluating the effect of innovative anti-cancer treatments. In longitudinal studies, tumor growth (or regression) of glioblastoma can only be monitored by noninvasive imaging. For this purpose, bioluminescence imaging (BLI) has gained popularity because of its low cost and easy access. In the context of the development of new nanomedicines for treating glioblastoma, we were using luciferase-expressing GL261 cell lines. Incidentally, using BLI in a specific GL261 glioblastoma model with cells expressing both luciferase and the green fluorescent protein (GL261-luc-GFP), we observed an apparent spontaneous regression. By contrast, the magnetic resonance imaging (MRI) analysis revealed that the tumors were actually growing over time. For other models (GL261 expressing only luciferase and U87 expressing both luciferase and GFP), data from BLI and MRI correlated well. We found that the divergence in results coming from different imaging modalities was not due to the tumor localization nor the penetration depth of light but was rather linked to the instability in luciferase expression in the viral construct used for the GL261-luc-GFP model. In conclusion, the use of multi-modality imaging prevents possible errors in tumor growth evaluation, and checking the stability of luciferase expression is mandatory when using BLI as the sole imaging modality.

Orthotopic glioblastoma xenografts are paramount for evaluating the effect of innovative anti-cancer treatments. In longitudinal studies, tumor growth (or regression) of glioblastoma can only be monitored by noninvasive imaging. For this purpose, bioluminescence imaging (BLI) has gained popularity because of its low cost and easy access. In the context of the development of new nanomedicines for treating glioblastoma, we were using luciferase-expressing GL261 cell lines. Incidentally, using BLI in a specific GL261 glioblastoma model with cells expressing both luciferase and the green fluorescent protein (GL261-luc-GFP), we observed an apparent spontaneous regression. By contrast, the magnetic resonance imaging (MRI) analysis revealed that the tumors were actually growing over time. For other models (GL261 expressing only luciferase and U87 expressing both luciferase and GFP), data from BLI and MRI correlated well. We found that the divergence in results coming from different imaging modalities was not due to the tumor localization nor the penetration depth of light but was rather linked to the instability in luciferase expression in the viral construct used for the GL261-luc-GFP model. In conclusion, the use of multi-modality imaging prevents possible errors in tumor growth evaluation, and checking the stability of luciferase expression is mandatory when using BLI as the sole imaging modality.

Glioblastoma (GBM) recurrences are inevitable, and mainly originate from residual tumor cells and the presence of glioma stem cells (GSC) around the resection cavity borders. We previously showed that the local treatment of GBM with nanomedicine-based Lauroyl-gemcitabine lipid nanocapsules (GemC12-LNC) hydrogel delayed tumor onset in various preclinical models and can be used as a scaffold to deliver multiple drugs. However, it does not inhibit tumor relapse in the long-term. In this work, we aim at encapsulating an anti-GSC molecule in the GemC12-LNC hydrogel to eliminate both GBM cells and GSC. We performed a screening on GBM cell lines (GL261 and U-87 MG) and patient-derived GSC (GBM9) to select the anti-GSC molecule that could act synergically with GemC12. Based on our results, salinomycin (Sal) and curcumin (Cur) were selected for further development. Both GemC12-Sal-LNC and GemC12-Cur LNC showed similar size (55 nm), zeta potential (- 2 mV) and viscoelastic properties compared to the GemC12-LNC hydrogel. Encapsulation efficiency was above 95 %. Moreover, the GemC12-Sal-LNC hydrogel was stable for at least 6 months and released both drugs over 30 days in vitro. Both hydrogels inhibited the growth of GL261 and U-87 MG spheroids. Flow cytometry analysis showed that Sal reduced the GSC population in GL261 and U-87 MG cells. Our results show that the co-encapsulation of Sal in the GemC12-LNC hydrogel can reduce both GBM cells and GSC, and therefore might be promising to avoid the onset of GBM recurrences.

Background\ud Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Despite the gold standard treatment combining surgical resection, radiation and adjuvant plus concomitant chemotherapy with the alkylating agent temozolomide (TMZ), the prognosis remains poor (5-year survival rate < 10%). Over the last three decades, a vast array of drug delivery systems (DDS) have been developed for the local treatment of GBM, with the majority of the characterization being undertaken in pre-clinical models. We aimed to gain an overview of the potential efficacy of such local delivery systems in comparison to the systemic drug administration.\ud \ud Methods\ud In this paper, a systematic search of Pubmed, Web of Science, and Scopus was performed using pre-determined search terms. Studies were assessed for eligibility based on specific inclusion and exclusion criteria. A total of fifteen publications were included for analysis of local vs systemic group median survival, tumor volume and adverse events, with five brought forward for a meta-analysis.\ud \ud Results\ud The majority of studies showed local delivery to be more efficacious than systemic administration, regardless of the drug, animal model, type of DDS used, or duration of the study. The meta-analysis also showed that the mean difference between median survival ratios was statistically significantly in favor of local delivery.\ud \ud Conclusion\ud Preclinical evidence shows that there is a firm rationale for further developing DDS for local therapeutic delivery to GBM and other brain cancers.

Simple Summary Glioblastoma is one of the deadliest brain cancers, and despite the efforts made in the last few years, the life expectancy of patients is still low. In most cases, even with the best treatments available, the tumor will eventually return. One of the main causes of this appears to be a fraction of cancer cells that are known as glioma stem cells. They have different characteristics than normal cancer cells, and some drugs can eliminate them. However, using such drugs is not always safe or effective, and nanomedicine can have improved effects as well as additional benefits. This review focuses on the nanomedicine strategies that have been employed in the last 5 years and their relative advantages, which make nanomedicine a promising approach for the eradication of glioma stem cells. Abstract The standard of care therapy of glioblastoma (GBM) includes invasive surgical resection, followed by radiotherapy and concomitant chemotherapy. However, this therapy has limited success, and the prognosis for GBM patients is very poor. Although many factors may contribute to the failure of current treatments, one of the main causes of GBM recurrences are glioma stem cells (GSCs). This review focuses on nanomedicine strategies that have been developed to eliminate GSCs and the benefits that they have brought to the fight against cancer. The first section describes the characteristics of GSCs and the chemotherapeutic strategies that have been used to selectively kill them. The second section outlines the nano-based delivery systems that have been developed to act against GSCs by dividing them into nontargeted and targeted nanocarriers. We also highlight the advantages of nanomedicine compared to conventional chemotherapy and examine the different targeting strategies that have been employed. The results achieved thus far are encouraging for the pursuit of effective strategies for the eradication of GSCs.

The purpose of this study was to investigate the feasibility of an intravenously administered combinational therapy using lipid nanocapsules (LNCs) as a drug delivery carrier for the treatment of different cancers. Therefore, we encapsulated 6 anticancer drugs within LNCs. Their size was approximately 50 nm. Except for oxaliplatin, their encapsulation efficiency, which was measured by different analytical methods, varied between 75% for SN38 to 100% for regorafenib. The in vitro studies showed a nonsignificant difference between the cytotoxicity of free and encapsulated drugs and a significant decrease in haemolysis by encapsulation in LNCs. Finally, the in vivo experiment showed that a combinational regimen of SN38-LNCs and regorafenib-LNCs abates CT26 murine colorectal cancer growth and increases median survival time.

A photopolymerizable hydrogel-based local drug delivery system was developed for the postsurgical treatment of glioblastoma (GBM). We aimed for a local drug combination therapy with paclitaxel (PTX) and temozolomide (TMZ) within a hydrogel to synergistically inhibit tumor growth. The in vitro cytotoxicity of TMZ was assessed in U87MG cells. We demonstrated the synergistic effect of PTX and TMZ on U87MG cells by clonogenic assay. Treatment with TMZ did not induce O6-methylguanine-DNA methyltransferase related drug resistance in tumor-bearing mice. PTX had sustained release for at least 1 month in vivo in healthy mice brains. The drug combination was tolerable and suppressed tumor growth more efficiently than the single drugs in the U87MG orthotopic tumor model. The PTX and TMZ codelivery hydrogel showed superior antitumor effects and can be considered a promising approach for the postsurgical treatment of GBM.

Lauroyl-gemcitabine lipid nanocapsules (GemC12-LNC) hydrogel, administered intratumorally or perisurgically in the tumor resection cavity, increases animal survival in several orthotopic GBM models. We hypothesized that GemC12-LNC can be used as nanodelivery platform for other drugs, to obtain a combined local therapeutic approach for GBM. Paclitaxel (PTX) was selected as a model molecule and PTX-GemC12-LNC formulation was evaluated in terms of physicochemical and mechanical properties. The PTX-GemC12-LNC hydrogel stability and drug release were evaluated over time showing no significant differences compared to GemC12-LNC. The drug combination was evaluated on several GBM cell lines showing increased cytotoxic activity compared to the original formulation and synergy between PTX and GemC12. Our results suggest that GemC12-LNC hydrogel can be used as nanodelivery platform for dual drug delivery to encapsulate active agents with different mechanisms of action to achieve a better antitumor efficacy against GBM or other solid tumors.