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

Vahid Heravi Shargh, Jeni Luckett, Kaouthar Bouzinab, Stephen Paisey, Lyudmila Turyanska, William G B Singleton, Stephen Lowis, Pavel Gershkovich, Tracey D Bradshaw, Malcolm F G Stevens, Alison Bienemann, Beth Coyle*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

The lack of clinical response to the alkylating agent temozolomide (TMZ) in pediatric diffuse midline/intrinsic pontine glioma (DIPG) has been associated with O6-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 (t1/2 < 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 [IC50 = 14.6 (Lip-N3P) vs 32.8 μM (N3P); DIPG-IV) and (IC50 = 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 (89Zr)-labeled AFt-NPs in rats also demonstrated substantial enhancement over free 89Zr 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.

Original languageEnglish
Pages (from-to)35266-35280
Number of pages15
JournalACS Applied Materials and Interfaces
Volume13
Issue number30
DOIs
Publication statusPublished - 26 Jul 2021

Bibliographical note

Funding Information:
This work was supported by grant 16-228 from the Children with Cancer UK (awarded to B.C.) and the EPSRC grant EP/L01646X/1 (awarded to K.B.).

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

Keywords

  • Diffuse intrinsic pontine glioma
  • DIPG
  • Temozolomide
  • TMZ
  • N(3)-propargyl
  • N3P
  • drug delivery
  • apoferritin
  • AFt
  • nanoliposome

Fingerprint

Dive into the research topics of 'Chemosensitization of Temozolomide-Resistant Pediatric Diffuse Midline Glioma Using Potent Nanoencapsulated Forms of a N(3)-Propargyl Analogue'. Together they form a unique fingerprint.

Cite this