Transmorphic phage-guided systemic delivery of TNFα gene for the treatment of human pediatric medulloblastoma
File(s)
Published version
Author(s)
Al-Bahrani, Mariam
Asavarut, Paladd
Waramit, Sajee
Suwan, Keittisak
Hajitou, Amin
Type
Journal Article
Abstract
Medulloblastoma is the most common childhood brain tumor with an unfavorable prognosis and limited options of harmful treatments that are associated with devastating long-term side effects. Therefore, the development of safe, noninvasive, and effective therapeutic approaches is required to save the quality of life of young medulloblastoma survivors. We postulated that therapeutic targeting is a solution. Thus, we used a recently designed tumor-targeted bacteriophage (phage)-derived particle, named transmorphic phage/AAV, TPA, to deliver a transgene expressing the tumor necrosis factor-alpha (TNFα) for targeted systemic therapy of medulloblastoma. This vector was engineered to display the double-cyclic RGD4C ligand to selectively target tumors after intravenous administration. Furthermore, the lack of native phage tropism in mammalian cells warrants safe and selective systemic delivery to the tumor microenvironment. In vitro RGD4C.TPA.TNFα treatment of human medulloblastoma cells generated efficient and selective TNFα expression, subsequently triggering cell death. Combination with the chemotherapeutic drug cisplatin used clinically against medulloblastoma resulted in augmented effect through the enhancement of TNFα gene expression. Systemic administration of RGD4C.TPA.TNFα to mice-bearing subcutaneous medulloblastoma xenografts resulted in selective tumor homing of these particles and consequently, targeted tumor expression of TNFα, apoptosis, and destruction of the tumor vasculature. Thus, our RGD4C.TPA.TNFα particle provides selective and efficient systemic delivery of TNFα to medulloblastoma, yielding a potential TNFα anti-medulloblastoma therapy while sparing healthy tissues from the systemic toxicity of this cytokine.
Date Issued
2023-07
Date Acceptance
2023-06-05
Citation
The FASEB Journal, 2023, 37 (7), pp.1-16
ISSN
0892-6638
Publisher
Wiley
Start Page
1
End Page
16
Journal / Book Title
The FASEB Journal
Volume
37
Issue
7
Copyright Statement
© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/37331004
Subjects
Animals
Bacteriophages
Brain Neoplasms
Cell Line, Tumor
Child
Genetic Therapy
Humans
Mammals
Mice
Quality of Life
Tumor Microenvironment
Tumor Necrosis Factor-alpha
bacteriophage-guided delivery
immunotherapy
medulloblastoma
targeted systemic therapy
tumor necrosis factor-alpha (TNFα)
Publication Status
Published
Coverage Spatial
United States
Article Number
e23038
Date Publish Online
2023-06-18