Glioblastoma (GBM) is a lethal brain cancer with a very difficult therapeutic approach and ultimately frustrating results. Currently, therapeutic success is mainly limited by the high degree of genetic and phenotypic heterogeneity, the blood brain barrier (BBB), as well as increased drug resistance. Temozolomide (TMZ), a monofunctional alkylating agent, is the first line chemotherapeutic drug for GBM treatment. Yet, the therapeutic efficacy of TMZ suffers from its inability to cross the BBB and very short half-life (~2 h), which requires high doses of this drug for a proper therapeutic effect. Encapsulation in a (nano)carrier is a promising strategy to effectively improve the therapeutic effect of TMZ against GBM. Although research on liposomes as carriers for therapeutic agents is still at an early stage, their integration in GBM treatment has a great potential to advance understanding and treating this disease. In this review, we provide a critical discussion on the preparation methods and physico-chemical properties of liposomes, with a particular emphasis on TMZ-liposomal formulations targeting GBM developed within the last decade. Furthermore, an overview on liposome-based formulations applied to translational oncology and clinical trials formulations in GBM treatment is provided. We emphasize that despite many years of intense research, more careful investigations are still needed to solve the main issues related to the manufacture of reproducible liposomal TMZ formulations for guaranteed translation to the market.

Two new series of heterocyclic derivatives with potential anticancer activity, in which a pyrrolo[1,2-b]pyridazine or a pyrrolo[2,1-a]phthalazine moiety was introduced in place of the 3′-hydroxy-4′-methoxyphenyl ring of phenstatin have been synthesised and their structure-activity relationship (SAR) was studied. Fourteen of the new compounds were evaluated for their in vitro cytotoxic activity by National Cancer Institute (NCI) against 60 human tumour cell lines panel. The best five compounds in terms of in vitro growth inhibition were screened in the second stage five dose-response studies, three of them showing a very good antiproliferative activity with GI₅₀<100 nM on several cell lines including colon, ovarian, renal, prostate, brain and breast cancer, melanoma and leukemia. Docking experiments on the biologically active compounds showed a good compatibility with the colchicine binding site of tubulin.

Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a.

Investigating the interaction between liposomes and proteins is of paramount importance in the development of liposomal formulations with real potential for bench-to-bedside transfer. Upon entering the body, proteins are immediately adsorbed on the liposomal surface, changing the nanovehicles’ biological identity, which has a significant impact on their biodistribution and pharmacokinetics and ultimately on their therapeutic effect. Albumin is the most abundant plasma protein and thus usually adsorbs immediately on the liposomal surface. We herein report a comprehensive investigation on the adsorption of model protein bovine serum albumin (BSA) onto liposomal vesicles containing the zwitterionic lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), in combination with either cholesterol (CHOL) or the cationic lipid 1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP). While many studies regarding protein adsorption on the surface of liposomes with different compositions have been performed, to the best of our knowledge, the differential responses of CHOL and DOTAP upon albumin adsorption on vesicles have not yet been investigated. UV–vis spectroscopy and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a strong influence of the phospholipid membrane composition on protein adsorption. Hence, it was found that DOTAP-containing vesicles adsorb proteins more robustly but also aggregate in the presence of BSA, as confirmed by DLS and TEM. Separation of liposome–protein complexes from unadsorbed proteins performed by means of centrifugation and size exclusion chromatography (SEC) was also investigated. Our results show that neither method can be regarded as a golden experimental setup to study the protein corona of liposomes. Yet, SEC proved to be more successful in the separation of unbound proteins, although the amount of lipid loss upon liposome elution was higher than expected. In addition, coarse-grained molecular dynamics simulations were employed to ascertain key membrane parameters, such as the membrane thickness and area per lipid. Overall, this study highlights the importance of surface charge and membrane fluidity in influencing the extent of protein adsorption. We hope that our investigation will be a valuable contribution to better understanding protein–vesicle interactions for improved nanocarrier design.