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Zongchao Han, Ruijuan Gao, Rajendra Mitra, Min Zheng; Developing pH-dependent cancer-directed synergetic treatment for retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1632.
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Cerium oxide nanoparticle (nanoceria) has unique redox activity in that it possesses antioxidant activity at physiological pH, but has an intrinsic oxidase activity at acidic pH. Therefore, using nanoceria as a base vector for anti-tumor therapy would be a preferred option since it can inhibit cancer cells without damaging fellow normal tissues. We have begun to design a novel antitumor delivery system using a chemotherapy drug and tumor target molecules covalently linked to nanoceria. The goal of this project was to develop nanoceria-assisted combination therapies for tumor-directed treatment of retinoblastoma.
We constructed a compound (GCCNP-DOX-AMD070), which contains a chemotherapeutic drug (Doxorubincin, DOX) and a tumor selective targeting reagent (AMD070, CXCE4 antagonist) via surface chemistry of our developed water-soluble nanoceria (GCCNP). Dynamic light scattering (DLS) measurements were performed to confirm the successful construction of the compound. Quantitative assessment of in vitro intracellular reactive oxygen species (ROS) production, cell viability, and CXCR4 (a cancer progression marker) expression were performed by DCF, MTT, and Western blot assays at different pH levels in human tumor cell lines (WERI-Bb-1, Y79, A549, and B16F10) and normal human ARPE-19 cells.
We observed strong CXCR4 expressions in all the tumor cell lines but barely in normal ARPE-19 cells. We detected that the GCCNPs increase the production of ROS and reduce cell viability at pH6.5 but not at pH7.4 in all the cell lines that we tested. We found that our combo system markedly suppressed Y79 CXCR4 expression at PH6.5 compared with that treated with DOX only. Interestingly, we did not find the same changes when pH was 7.4, indicating the pH-dependent antitumor behavior of GCCNP-DOX-AMD070.
We have built a novel antitumor delivery system using a chemotherapy drug and tumor target molecules covalently linked to nanoceria. This system is capable of specifically and selectively targeting tumor cells under tumor microenvironment (acidic conditions) but remain stable under normal physiological pH conditions, thus reducing the problems of off-target. The design of nanoceria combo in this application can be custom-built and functionalized to target different diseases by binding the surface of nanoparticles with a cell-specific targeting molecule and therapeutic specificity.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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