期刊
JOURNAL OF NANOBIOTECHNOLOGY
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12951-022-01530-6
关键词
Macropinocytosis; Cell-cycle; Glucose-regulated protein; Tat/pDNA-Ca2+ nanoparticle; Suicide gene therapy; Ovarian cancer
资金
- National Natural Science Foundation of China [81373318]
- National Translational Science Center for Molecular Medicine Fund [F1034361]
- Chinese Pharmacertical Association-Yiling Pharmacertical Innovation Fund [CPAYLJ202003]
- Key Research Fund of Tianjin Project Team [XB202010]
- Key Research and Development Program of Tianjin [20YFZCSY00450]
- Tianjin sci-tech commissioner Fund [21YDTPJC00220]
This study highlights the use of Tat/pDNA-Ca2+ nanoparticles for tumor-targeted suicide gene therapy. These nanoparticles show improved delivery efficiency and utilize macropinocytosis for intercellular delivery. The mitochondrial chaperone GRP75 plays a dual role in cell-cycle-dependent macropinocytosis of Tat/pDNA-Ca2+ nanoparticles. The targeting of GRP75 combined with cell-cycle or macropinocytosis inhibitors demonstrates distinct suicide gene therapy efficiency.
Practice of tumor-targeted suicide gene therapy is hampered by unsafe and low efficient delivery of plasmid DNA (pDNA). Using HIV-Tat-derived peptide (Tat) to non-covalently form Tat/pDNA complexes advances the delivery performance. However, this innovative approach is still limited by intracellular delivery efficiency and cell-cycle status. In this study, Tat/pDNA complexes were further condensed into smaller, nontoxic nanoparticles by Ca2+ addition. Formulated Tat/pDNA-Ca2+ nanoparticles mainly use macropinocytosis for intercellular delivery, and their macropinocytic uptake was persisted in mitosis (M-) phase and highly activated in DNA synthesis (S-) phase of cell-cycle. Over-expression or phosphorylation of a mitochondrial chaperone, 75-kDa glucose-regulated protein (GRP75), promoted monopolar spindle kinase 1 (MPS1)-controlled centrosome duplication and cell-cycle progress, but also driven cell-cycle-dependent macropinocytosis of Tat/pDNA-Ca2+ nanoparticles. Further in vivo molecular imaging based on DF (Fluc-eGFP)-TF (RFP-Rluc-HSV-ttk) system showed that Tat/pDNA-Ca2+ nanoparticles exhibited highly suicide gene therapy efficiency in mouse model xenografted with human ovarian cancer. Furthermore, arresting cell-cycle at S-phase markedly enhanced delivery performance of Tat/pDNA-Ca2+ nanoparticles, whereas targeting GRP75 reduced their macropinocytic delivery. More importantly, in vivo targeting GRP75 combined with cell-cycle or macropinocytosis inhibitors exhibited distinct suicide gene therapy efficiency. In summary, our data highlight that mitochondrial chaperone GRP75 moonlights as a biphasic driver underlying cell-cycle-dependent macropinocytosis of Tat/pDNA-Ca2+ nanoparticles in ovarian cancer.
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