Temozolomide hexadecyl ester targeted plga nanoparticles for drug-resistant glioblastoma therapy via intranasal administration

Abstract

Introduction: Temozolomide (TMZ) is the first-line drug for glioblastoma (GBM), but it is limited in clinical use due to the drug resistance, poor brain targeting, and side effects. Temozolomide hexadecyl ester (TMZ16e), a TMZ derivative with high lipophilicity, membrane permeability, and high anti-glioma properties, has the potential to reverse drug resistance. In this study, anti-ephrin type-A receptor 3 (EphA3) modified TMZ16e loaded nanoparticles (NPs) were prepared for targeted GBM therapy via intranasal administration to deliver TMZ16e to the brain, treat drug-resistant glioma effectively, and reduce peripheral toxicity.Methods: TMZ16e loaded NPs were prepared by emulsion solvent evaporation method followed by modified with anti-EphA3 (anti-EphA3-TMZ16e-NPs). In vitro evaluations were performed by an MTT assay and flow cytometry analysis. The orthotopic nude mice models were used to evaluate the anti-glioma effect in vivo. Additionally, we investigated the anti-drug resistant mechanism by western blot analysis.Results: The particle size of the prepared NPs was less than 200 nm, and the zeta potential of TMZ16e-NPs and anti-EphA3-TMZ16e-NPs were -23.05 ± 1.48 mV and -28.65 ± 1.20mV, respectively, which is suitable for nasal delivery. In vitro studies have shown that anti-EphA3 modification increased the cellular uptake of nanoparticles in T98G cells. The cytotoxicity in the anti-EphA3-TMZ16e-NPs treated group was significantly higher than that of the TMZ16e-NPs, TMZ16e, and TMZ groups (p < 0.01), and the cell cycle was blocked. Western blotting analysis showed that the TMZ16e-loaded NPs were able to effectively downregulate the expression level of O6-methylguanine-deoxyribonucleic acid-methyltransferase (MGMT) protein in T98G cells and reverse drug resistance. In vivo studies showed that the median survival time of tumor-bearing nude mice in the anti-EphA3-TMZ16e-NPs group was extended to 41 days, which was 1.71-fold higher than that of the saline group and the TUNEL staining results of the brain tissue section indicated that the TMZ16e-loaded NPs could elevate apoptosis in T98G cells.Conclusion: In conclusion, the TMZ16e-loaded NPs can be effectively delivered to the brain and targeted to gliomas, exhibiting better anti-glioma activity, indicating they possess great potential in the treatment of drug-resistant glioma.

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery

“…To confirm the safety of PLGA NPs and SLNs in the brain microenvironment, both particle types have been studied in vitro for compatibility with neurons and other resident brain cells. PLGA NPs did not affect the integrity of human SH-SY5Y neuroblastoma cells, monocytes, and 16 HBE epithelial cells used to model the BBB, rodent PC12 catecholaminergic neurons, brain endothelial cells, primary microglia and primary astrocytes, or murine hippocampal neurons, N2a neuroblastoma cells, and N9 microglia [ 38 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. Notably, prolonged PLGA NP exposure did not alter neuronal morphology or affect the viability of primary rat neuronal-glial mixed cultures up to concentrations of 2.5 mg/mL [ 61 ].…”

“…Robust in vitro models of brain cancers exist, which involve culturing tumour cells and testing drug efficacy by measuring cell death. PLGA NPs loaded with a derivative of the anti-cancer drug temozolomide were non-toxic to 16HBE cells but reduced the viability of T98G GBM cells to 20% of control [ 58 ]. Doxorubicin-entrapped SLNs induced cell death when applied to U87MG GBM cells [ 74 ].…”

“…L-Dopa encapsulation in PLGA NPs and nasal administration also improved motor deficits and prolonged drug action compared to intranasal and oral free drug in the MPTP mouse model of PD [ 174 ]. The anti-glioma effects of anti-vascular endothelial growth factor immunotherapy bevacizumab, temozolomide derivative TMZ16e, and cell-cycle inhibitor paclitaxel-loaded PLGA NPs were apparent after intranasal administration in mouse models of GBM [ 58 , 163 , 181 ]. The AED lamotrigine and anti-depressant agent desvenlafaxine were also found to delay seizure onset and reduce symptoms of depression, respectively, when delivered through the nose in PLGA NPs to rats rather than by nasal or i.v.…”

Development of Berberine-Loaded Nanoparticles for Astrocytoma Cells Administration and Photodynamic Therapy Stimulation

“…Several attempts were made to formulate PGLA-based NPs to effectively deliver drugs to GBM cells, including methotrexate and paclitaxel [26], doxorubicin [27], temozolomide and DNA repair inhibitors [28], metformin/irinotecan [29], and cisplatin [30]. More advanced contributions have reported the development of specifically designed intranasal or intracranial NPs for GBM treatments [31,32]. On the other hand, only a few studies have been reported on NP encapsulation of BBR in cancer [33,34], and in particular, no published contribution has reported the development of PLGA-based NP systems to deliver BBR to glial tumor cells, even if other BBR-NP encapsulation strategies have been proposed for this purpose [24,[35][36][37].…”

Methotrexate-Loaded PLGA Nanoparticle: Extended Survival of GBM-Bearing Rats

“…PLGA is from synthetic ones and PLGA-based nanostr�ct�res are �nder wide st�dies beca�se of their extraordinary feat�res s�ch as s�stained dr�g release, biocompatibility, biodegradability, ease of s�rface modification with hydrophilic agents, and ability to load both hydrophilic and hydrophobic substances [13]. There are various studies that have loaded chemothera-pe�tics in PLGA nanoparticles with the aim of GB� treatments [14][15][16].…”