Low-dose temozolomide selectively increases glioblastoma's vascular permeability, tumor microenvironment penetration and the killing potential of systemic actinium-225 α-particle dendrimer-radioconjugates improving treatment efficacy

Abstract

Purpose: The poor prognosis of glioblastoma is mostly due to the relatively low tumor vascular permeability to therapeutics, the tumor's vicinity to the brain, that limits treatment aggressiveness, and/or drug resistance.

Methods: In this study, the efficacy of systemically injected actinium-225 dendrimer-radioconjugates was evaluated in an immune-competent orthotopic GL261-C57BL/6 mouse model after administration of low-dose, standard-of-care temozolomide, that selectively increased the tumor vascular permeability to dendrimer-radioconjugates. Alpha-particles' short range in tissue combined with the dendrimers' selective uptake by glioblastomas, could limit the irradiation of the neighboring brain, while the complex double-strand DNA breaks caused by α-particles were expected to be largely impervious to resistance by cancer cells.

Results: On mice bearing 9.7 ± 5.7mm³ brain tumors, at activities that did not cause long-term (11-months) toxicities, dendrimer-radioconjugates, that were systemically-administered 24-hours after injection of temozolomide, significantly improved survival compared to dendrimer-radioconjugates alone (44 vs. 39 days mean survival, p = 0.0017) and/or compared to temozolomide alone and/or to non-treated animals (31 and 30 days, p < 0.001). This was attributed to: (1) the noteworthy increase (by 33%) in tumor absorbed doses delivered by dendrimer-radioconjugates when injected after chemotherapy, without altering normal organ (including the brain's) dosimetry; (2) the potentially deeper tumor penetration of dendrimer-radioconjugates, suggested by the enhanced dendrimer penetration within GL261-spheroids, employed as model tumor-avascular regions; and/or (3) the formation of a more lethal cocktail when both modalities acted on same cancer cells.

Conclusions: This study demonstrates the potential and safety of actinium-225 dendrimer-radioconjugates as a systemic α-particle radiotherapy for glioblastoma enhanced by low-dose temozolomide.

Keywords: Actinium-225 alpha-particle radionuclide therapy; Dendrimer-radioconjugates; Glioblastoma; Spheroids; Temozolomide; Tumor-associated macrophages.