Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy

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

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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 languageEnglish (US)
Pages (from-to)8729-8750
Number of pages22
JournalACS nano
Issue number6
StatePublished - Jun 28 2022

Bibliographical note

Funding 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.

Publisher Copyright:
© 2022 American Chemical Society.


  • CXCL12/CXCR4
  • glioma
  • immunogenic cell death
  • immunotherapy
  • nanoparticles
  • synthetic protein
  • systemic delivery
  • tumor microenvironment


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