Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.
|Original language||English (US)|
|Number of pages||22|
|State||Published - Jun 28 2022|
Bibliographical noteFunding Information:
This work was supported by “National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) Grants R37-NS094804, R01-NS105556, R01-NS122536, R01-NS124167, R21- NS123879-01 and Rogel Cancer Center Scholar Award to M.G.C.; NIH/NINDS Grants R01-NS076991, R01-NS082311, R01-NS096756, R01NS122234; and NIH/NCI R01-CA243916 to P.R.L.; the Department of Neurosurgery; the Pediatric Brain Tumor Foundation, Leah’s Happy Hearts Foundation, Ian’s Friends Foundation (IFF), Chad Tough Foundation, and Smiles for Sophie Forever Foundation to [M.G.C. and P.R.L]. NIH/NCI T32- CA009676 Post-Doctoral Fellowship to M.S.A. NIH/NCI F31CA247104 to AAA, and NIH/NCI F31CA247104 to JAJ. Agencia Nacional de Promoción Científica y Tecnológica, Argentina, PICT-2018-3088 and PICT-2019-00117 and Instituto Nacional del Cancer Argentina, Asistencia Financiera IV to M.C.
© 2022 American Chemical Society.
- immunogenic cell death
- synthetic protein
- systemic delivery
- tumor microenvironment
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't