Publication: Doxorubicin improves cancer cell targeting by filamentous phage gene delivery vectors
Issued Date
2020-11-01
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ISSN
14220067
16616596
16616596
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2-s2.0-85093871726
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Mahidol University
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SCOPUS
Bibliographic Citation
International Journal of Molecular Sciences. Vol.21, No.21 (2020), 1-18
Suggested Citation
Effrosyni Tsafa, Kaoutar Bentayebi, Supachai Topanurak, Teerapong Yata, Justyna Przystal, Duriya Fongmoon, Nabil Hajji, Sajee Waramit, Keittisak Suwan, Amin Hajitou Doxorubicin improves cancer cell targeting by filamentous phage gene delivery vectors. International Journal of Molecular Sciences. Vol.21, No.21 (2020), 1-18. doi:10.3390/ijms21217867 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/59860
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Title
Doxorubicin improves cancer cell targeting by filamentous phage gene delivery vectors
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Abstract
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Merging targeted systemic gene delivery and systemic chemotherapy against cancer, chemovirotherapy, has the potential to improve chemotherapy and gene therapy treatments and overcome cancer resistance. We introduced a bacteriophage (phage) vector, named human adeno-associated virus (AAV)/phage or AAVP, for the systemic targeting of therapeutic genes to cancer. The vector was designed as a hybrid between a recombinant adeno-associated virus genome (rAAV) and a filamentous phage capsid. To achieve tumor targeting, we displayed on the phage capsid the double-cyclic CDCRGDCFC (RGD4C) ligand that binds the alpha-V/beta-3 (αv β3) integrin receptor. Here, we investigated a combination of doxorubicin chemotherapeutic drug and targeted gene delivery by the RGD4C/AAVP vector. Firstly, we showed that doxorubicin boosts transgene expression from the RGD4C/AAVP in two-dimensional (2D) cell cultures and three-dimensional (3D) tumor spheres established from human and murine cancer cells, while preserving selective gene delivery by RGD4C/AAVP. Next, we confirmed that doxorubicin does not increase vector attachment to cancer cells nor vector cell entry. In contrast, doxorubicin may alter the intracellular trafficking of the vector by facilitating nuclear accumulation of the RGD4C/AAVP genome through destabilization of the nuclear membrane. Finally, a combination of doxorubicin and RGD4C/AAVP-targeted suicide gene therapy exerts a synergistic effect to destroy human and murine tumor cells in 2D and 3D tumor sphere settings.