Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors.
Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors.
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DOI：
10.3390/ijms21217867
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发表时间：
2020-10-23
影响因子：
5.6
通讯作者：
Hajitou A
中科院分区：
文献类型：
--
作者：
Tsafa E;Bentayebi K;Topanurak S;Yata T;Przystal J;Fongmoon D;Hajji N;Waramit S;Suwan K;Hajitou A
将靶向系统性基因递送和针对癌症的系统性化疗相结合，化学病毒疗法具有改善化疗和基因治疗治疗并克服癌症耐药性的潜力。我们引入了一种名为人腺相关病毒（AAV）/噬菌体或AAVP的噬菌体（噬菌体）载体，用于将治疗基因系统性靶向至癌症。该载体被设计为重组腺相关病毒基因组（rAAV）和丝状噬菌体衣壳之间的杂合体。为了实现肿瘤靶向，我们在噬菌体衣壳上展示了结合α-V/β-3（αvβ3）整联蛋白受体的双环CDCRGDCFC（RGD 4C）配体。在这里，我们研究了阿霉素化疗药物和靶向基因递送的RGD 4C/AAVP载体的组合。首先，我们表明，多柔比星在二维（2D）细胞培养物和由人和鼠癌细胞建立的三维（3D）肿瘤球中增强了RGD 4C/AAVP的转基因表达，同时保留了RGD 4C/AAVP的选择性基因递送。接下来，我们证实了阿霉素既不增加载体与癌细胞的附着，也不增加载体细胞的进入。相比之下，多柔比星可以通过核膜的不稳定促进RGD 4C/AAVP基因组的核积累来改变载体的细胞内运输。最后，多柔比星和RGD 4C/AAVP靶向自杀基因疗法的组合发挥协同作用，以在2D和3D肿瘤球设置中破坏人和鼠肿瘤细胞。
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.
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影响因子：
5.4
作者：
Ferrari, FK;Samulski, T;Samulski, RJ
通讯作者：
Samulski, RJ
影响因子：
11.2
作者：
Krag, David N.;Shukla, Girja S.;Thomas, Christian
通讯作者：
Thomas, Christian
影响因子：
3.7
作者：
Paoloni MC;Tandle A;Mazcko C;Hanna E;Kachala S;Leblanc A;Newman S;Vail D;Henry C;Thamm D;Sorenmo K;Hajitou A;Pasqualini R;Arap W;Khanna C;Libutti SK
通讯作者：
Libutti SK
影响因子：
64.5
作者：
Hajitou, A;Trepel, M;Arap, W
通讯作者：
Arap, W
影响因子：
8.8
作者：
FERGUSON, JE;DODWELL, DJ;HOWELL, A
通讯作者：
HOWELL, A