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Intratumor injection of CCL21-coupled vault nanoparticles is associated with reduction in tumor volume in an in vivo model of glioma

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Abstract

Purpose

Glioblastoma (GBM) is the most common and malignant primary adult brain tumor. Current care includes surgical resection, radiation, and chemotherapy. Recent clinical trials for GBM have demonstrated extended survival using interventions such as tumor vaccines or tumor-treating fields. However, prognosis generally remains poor, with expected survival of 20 months after randomization. Chemokine-based immunotherapy utilizing CCL21 locally recruits lymphocytes and dendritic cells to enhance host antitumor response. Here, we report a preliminary study utilizing CPZ-vault nanoparticles as a vehicle to package, protect, and steadily deliver therapy to optimize CCL21 therapy in a murine flank model of GBM.

Methods

GL261 cells were subcutaneously injected into the left flank of eight-week-old female C57BL/6 mice. Mice were treated with intratumoral injections of either: (1) CCL21-packaged vault nanoparticles (CPZ-CCL21), (2) free recombinant CCL21 chemokine empty vault nanoparticles, (3) empty vault nanoparticles, or 4) PBS.

Results

The results of this study showed that CCL21-packaged vault nanoparticle injections can decrease the tumor volume in vivo. Additionally, this study showed mice injected with CCL21-packaged vault nanoparticle had the smallest average tumor volume and remained the only treatment group with a negative percent change in tumor volume.

Conclusions

This preliminary study establishes vault nanoparticles as a feasible vehicle to increase drug delivery and immune response in a flank murine model of GBM. Future animal studies involving an intracranial orthotopic tumor model are required to fully evaluate the potential for CCL21-packaged vault nanoparticles as a strategy to bypass the blood brain barrier, enhance intracranial immune activity, and improve intracranial tumor control and survival.

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Authors and Affiliations

  1. Departments of Neurosurgery, University of California, Los Angeles, CA, USA

    Brittany L. Voth, Panayiotis E. Pelargos, Natalie E. Barnette, Nikhilesh S. Bhatt, Cheng Hao Jacky Chen, Carlito Lagman, Lawrance K. Chung, Thien Nguyen, John P. Sheppard, Prasanth Romiyo, Leonard H. Rome & Isaac Yang

  2. Departments of Radiation Oncology, University of California, Los Angeles, CA, USA

    Isaac Yang

  3. Departments of Biological Chemistry, Jonsson Comprehensive Cancer Center, University of California, 300 Stein Plaza, Suite 562, 5th Floor Wasserman Building, Los Angeles, CA, 90095-6901, USA

    Sergey Mareninov, Valerie A. Kickhoefer & Isaac Yang

  4. Departments of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    William H. Yong

Authors
  1. Brittany L. Voth
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  2. Panayiotis E. Pelargos
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  3. Natalie E. Barnette
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  4. Nikhilesh S. Bhatt
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  13. William H. Yong
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  14. Leonard H. Rome
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  15. Isaac Yang
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Corresponding author

Correspondence to Isaac Yang.

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Conflicts of interest

Carlito Lagman was partially supported by a Gurtin Skull Base Research Fellowship. Lawrance K. Chung was partially supported by an AMA Foundation Seed Grant and an AΩA Carolyn L. Kuckein Student Research Fellowship. Isaac Yang (senior author) was partially supported by a Visionary Fund Grant, an Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research UCLA Scholars in Translational Medicine Program Award, the Jason Dessel Memorial Seed Grant, the UCLA Honberger Endowment Brain Tumor Research Seed Grant, and the STOP CANCER Research Career Development Award. Isaac Yang is a consultant for Brainlab. The remaining authors report no conflict-of-interests concerning the materials or methods used or the findings specified in this study.

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Voth, B.L., Pelargos, P.E., Barnette, N.E. et al. Intratumor injection of CCL21-coupled vault nanoparticles is associated with reduction in tumor volume in an in vivo model of glioma. J Neurooncol 147, 599–605 (2020). https://doi.org/10.1007/s11060-020-03479-8

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