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Article

Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors

1
Phage Therapy Group, Department of Brain Sciences, Imperial College London, London W12 0NN, UK
2
Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
3
Department of Medical Services, Lampang Cancer Hospital, Ministry of Public Health, Lampang 52000, Thailand
4
John Fulcher Neuro-Oncology Laboratory, Department of Brain Sciences, Imperial College London, London W12 0NN, UK
*
Authors to whom correspondence should be addressed.
Present address: Biochemistry Unit, Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(21), 7867; https://doi.org/10.3390/ijms21217867
Received: 28 July 2020 / Revised: 18 October 2020 / Accepted: 19 October 2020 / Published: 23 October 2020
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 (αvβ3) 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. View Full-Text
Keywords: doxorubicin; cancer; bacteriophage; targeted gene delivery doxorubicin; cancer; bacteriophage; targeted gene delivery
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MDPI and ACS Style

Tsafa, E.; Bentayebi, K.; Topanurak, S.; Yata, T.; Przystal, J.; Fongmoon, D.; Hajji, N.; Waramit, S.; Suwan, K.; Hajitou, A. Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors. Int. J. Mol. Sci. 2020, 21, 7867. https://doi.org/10.3390/ijms21217867

AMA Style

Tsafa E, Bentayebi K, Topanurak S, Yata T, Przystal J, Fongmoon D, Hajji N, Waramit S, Suwan K, Hajitou A. Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors. International Journal of Molecular Sciences. 2020; 21(21):7867. https://doi.org/10.3390/ijms21217867

Chicago/Turabian Style

Tsafa, Effrosyni, Kaoutar Bentayebi, Supachai Topanurak, Teerapong Yata, Justyna Przystal, Duriya Fongmoon, Nabil Hajji, Sajee Waramit, Keittisak Suwan, and Amin Hajitou. 2020. "Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors" International Journal of Molecular Sciences 21, no. 21: 7867. https://doi.org/10.3390/ijms21217867

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