作者
Mahmoud S Alghamri,Kaushik Banerjee,Anzar Mujeeb,Ava Mauser,Ayman Taher,Rohit Thalla,Brandon L. McClellan,Maria L. Varela,Svetlana M. Stamatovic,Gabriela Martínez-Revollar,Anuska V. Andjelkovic,Jeffrey A. Gregory,Padma Kadiyala,Anda-Alexandra Calinescu,Jennifer A. Jiménez,April A. Apfelbaum,Elizabeth R. Lawlor,Stephen V. Carney,Andrea Comba,Syed M. Faisal,Marcus Barissi,Marta Edwards,Henry D. Appelman,Yilun Sun,Jingyao Gan,Rose Ackermann,Anna Schwendeman,Marianela Candolfi,Michael R. Olin,Joerg Lahann,Pedro R. Löwenstein,María G. Castro
摘要
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.