Search

Glioblastoma (GBM) is a highly deadly brain tumor that does not respond satisfactorily to conventional treatment. The non-alkylating agent gemcitabine (GEM) has been proposed for treating GBM. It can overcome MGMT protein-mediated resistance, a major limitation of conventional therapy with the alkylating agent temozolomide (TMZ). However, GEM's high systemic toxicity and poor permeability across the blood-brain barrier (BBB) pose significant challenges for its delivery to the brain. Thus, mucoadhesive poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) coated with chitosan (CH), suitable for intranasal GEM delivery, were proposed in this work. A central composite design (CCD) was implemented for NPs optimization, and NPs with appropriate characteristics for intranasal administration were obtained. in vitro studies revealed that the NPs possess excellent mucoadhesive properties and the ability to selectively release GEM in the simulated tumor tissue environment. in vitro studies using two human GBM cell lines (U215 and T98G) revealed the NPs' ability to promote GEM's antiproliferative activity to sensitize cells to the effect of TMZ. The findings of this work demonstrate that the developed CH-GEM-NPs are suitable delivery systems for GEM, both as a single therapy and as a chemosensitizer to the GBM gold standard therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Temozolomide (TMZ) is one of the best choices for treating glioblastoma. However, due to the short plasma half-life, only 20-30 % brain bioavailability can be achieved using traditional formulations. In the present study, PEGylated liposomes and lyotropic liquid crystals (LLCs) were developed and investigated to prolong the plasma circulation time of TMZ. Industrially feasible membrane extrusion and modified hot melt emulsification techniques were utilized during the formulation. Liposomes and LLCs in the particle size range of 80-120 nm were obtained with up to 50 % entrapment efficiency. The nanocarriers were found to show a prolonged release of up to 72 h. The cytotoxicity studies in glioblastoma cell lines revealed a ∼1.6-fold increased cytotoxicity compared to free TMZ. PEGylated liposomes and PEGylated LLCs were found to show a 3.47 and 3.18-fold less cell uptake in macrophage cell lines than uncoated liposomes and LLCs, respectively. A 1.25 and 2-fold increase in the plasma t 1/2 was observed with PEGylated liposomes and PEGylated LLCs, respectively, compared to the TMZ when administered intravenously. Extending plasma circulation time of TMZ led to significant increase in brain bioavailability. Overall, the observed improved pharmacokinetics and biodistribution of TMZ revealed the potential of these PEGylated nanocarriers in the efficient treatment of glioblastoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Recent developments in pharmacogenomics have created opportunities for predicting temozolomide response in gliomas. Temozolomide is the main first-line alkylating chemotherapeutic drug together with radiotherapy as standard treatments of high-risk gliomas after surgery. However, there are great individual differences in temozolomide response. Besides the heterogeneity of gliomas, pharmacogenomics relevant genetic polymorphisms can not only affect pharmacokinetics of temozolomide but also change anti-tumor effects of temozolomide. This review will summarize pharmacogenomic studies of temozolomide in gliomas which can lay the foundation to personalized chemotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with ∼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with ̴ 20% cell viability at 1 mM TMZA after 72 h incubation time. Finally, the fluorescently labelled NPs showed co-localization with the bioluminescent syngeneic BL6 intra-cranial tumour mouse model after intravenous administration., (Copyright © 2021. Published by Elsevier B.V.)

Glioblastoma multiforme (GBM) is the most common primary brain cancer. GBM has aggressive development, and the pharmacological treatment remains a challenge due to GBM anatomical characteristics' (the blood-brain barrier and tumor microenvironment) and the increasing resistance to marketed drugs, such as temozolomide (TMZ), the first-line drug for GBM treatment. Due to physical-chemical properties such as short half-life time and the increasing resistance shown by GBM cells, high doses and repeated administrations are necessary, leading to significant adverse events. This review will discuss the main molecular mechanisms of TMZ resistance and the use of functionalized nanocarriers as an efficient and safe strategy for TMZ delivery. GBM-targeting nanocarriers are an important tool for the treatment of GBM, demonstrating to improve the biopharmaceutical properties of TMZ and repurpose its use in anti-GBM therapy. Technical aspects of nanocarriers will be discussed, and biological models highlighting the advantages and effects of functionalization strategies in TMZ anti-GBM activity. Finally, conclusions regarding the main findings will be made in the context of new perspectives for the treatment of GBM using TMZ as a chemotherapy agent, improving the sensibility and biological anti-tumor effect of TMZ through functionalization strategies., (Copyright © 2021 Elsevier B.V. All rights reserved.)