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

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. 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. 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. 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.