Chemosensitization of Temozolomide-Resistant Pediatric Diffuse Midline Glioma Using Potent Nanoencapsulated Forms of a N(3)-Propargyl Analogue

Abstract

The lack of clinical response to the alkylating agent temozolomide (TMZ) in pediatric diffuse midline/intrinsic pontine glioma (DIPG) has been associated with O 6 -methylguanine-DNA-methyltransferase (MGMT) expression and mismatch repair deficiency. Hence, a potent N(3)propargyl analogue (N3P) was derived, which not only evades MGMT but also remains effective in mismatch repair deficient cells. Due to the poor pharmacokinetic profile of N3P (t 1/2 < 1 h) and to bypass the blood−brain barrier, we proposed convection enhanced delivery (CED) as a method of administration to decrease dose and systemic toxicity. Moreover, to enhance N3P solubility, stability, and sustained distribution in vivo, either it was incorporated into an apoferritin (AFt) nanocage or its sulfobutyl ether β-cyclodextrin complex was loaded into nanoliposomes (Lip). The resultant AFt-N3P and Lip-N3P nanoparticles (NPs) had hydrodynamic diameters of 14 vs 93 nm, icosahedral vs spherical morphology, negative surface charge (−17 vs −34 mV), and encapsulating ∼630 vs ∼21000 N3P molecules per NP, respectively. Both NPs showed a sustained release profile and instant uptake within 1 h incubation in vitro. In comparison to the naked drug, N3P NPs demonstrated stronger anticancer efficacy against 2D TMZ-resistant DIPG cell cultures [IC 50 = 14.6 (Lip-N3P) vs 32.8 μM (N3P); DIPG-IV) and (IC 50 = 101.8 (AFt-N3P) vs 111.9 μM (N3P); DIPG-VI)]. Likewise, both N3P-NPs significantly (P < 0.01) inhibited 3D spheroid growth compared to the native N3P in MGMT + DIPG-VI (100 μM) and mismatch repair deficient DIPG-XIX (50 μM) cultures. Interestingly, the potency of TMZ was remarkably enhanced when encapsulated in AFt NPs against DIPG-IV, -VI, and -XIX spheroid cultures. Dynamic PET scans of CED-administered zirconium-89 ( 89 Zr)-labeled AFt-NPs in rats also demonstrated substantial enhancement over free 89 Zr radionuclide in terms of localized distribution kinetics and retention within the brain parenchyma. Overall, both NP formulations of N3P represent promising approaches for treatment of TMZ-resistant DIPG and merit the next phase of preclinical evaluation.

A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes

“…Moreover, the risk signature was closely related to genomic alterations, which reinforces the notion that abnormally activated target genes do not act alone but crosstalk with other important factors affecting survival outcomes, including the TERTp mutation, MGMTp methylation, and chr 7+/10- status. Previous studies have reported a link between these genomic alterations and survival outcomes, but the present results facilitate further investigation of the mechanisms underlying tumor progression ( Brat et al, 2018 ; Galbraith et al, 2020 ; Heravi Shargh et al, 2021 ). Furthermore, we found that radiotherapy failed to promote survival outcomes in grade II patients, likely increasing only their financial and social burden.…”

Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives

“…Shargh et al developed three nanodelivery systems of TMZ analogue (N3Propargyl) including an apoferritin (AFt) nanocage, a sulfobutyl ether β-cyclodextrin (SBE-β-CD) nanocomplex, and SBE-β-CD in nanoliposomes and tested on 2D-spheroids and 3D obtained from DIPG cell lines resistant to TMZ. The formulations were efficacious in reducing the tumor sphere size [ 79 ].…”

Radiotherapy and radio‐sensitization in H3K27M‐mutated diffuse midline gliomas

“…13,14,[236][237][238][239][240][241][242] Recently, the development of nanotechnologies allows to reformulate TMZ to enhance therapeutic efficiency with the evasion of MGMT enzyme. 243 In addition, pulsed ultrasound and convection-enhanced delivery (CED) have been applied…”

“…However, the clinical of outcomes are not satisfied due to the unmethylation of the O 6 ‐methylguanine‐DNA methyltransferase (MGMT) associated facilitation of DNA damage repair, and relatively intact blood–brain barrier (BBB) 13,14,236–242 . Recently, the development of nanotechnologies allows to reformulate TMZ to enhance therapeutic efficiency with the evasion of MGMT enzyme 243 . In addition, pulsed ultrasound and convection‐enhanced delivery (CED) have been applied to temporally disrupt the BBB and increase the concentration of drug delivery in tumor area, as a result, to enhance the sensitivity of chemotherapies and radiotherapy 244,245 …”