Aptamer-Functionalized DNA Origami for Targeted Codelivery of Antisense Oligonucleotides and Doxorubicin to Enhance Therapy in Drug-Resistant Cancer Cells
| Autor: | Mengyun He, Qingshan Pan, Xia Chu, Juan Zhang, Cunpeng Nie, Yanlei Hu, Manman He, Chang Liu, Ting-Ting Chen, Jintao Yi |
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| Rok vydání: | 2019 |
| Předmět: |
Materials science
Cell Survival Aptamer Antineoplastic Agents 02 engineering and technology Microscopy Atomic Force HeLa 03 medical and health sciences medicine Humans DNA origami Gene silencing General Materials Science Doxorubicin 030304 developmental biology 0303 health sciences biology DNA Oligonucleotides Antisense Flow Cytometry 021001 nanoscience & nanotechnology biology.organism_classification Drug Resistance Multiple In vitro Drug Resistance Neoplasm Cancer cell MCF-7 Cells Cancer research Nanocarriers 0210 nano-technology HeLa Cells medicine.drug |
| Zdroj: | ACS Applied Materials & Interfaces. 12:400-409 |
| ISSN: | 1944-8252 1944-8244 |
| Popis: | Drug resistance is a major obstacle to the efficient therapy of drug-resistant cancer. To overcome this problem, we constructed a multifunctional DNA origami-based nanocarrier for codelivery of a chemotherapeutic drug (doxorubicin, Dox) and two different antisense oligonucleotides (ASOs; B-cell lymphoma 2 (Bcl2) and P-glycoprotein (P-gp)) into drug-resistant cancer cells for enhanced therapy. To increase the targeting ability of origami, staple strands with 5'-end extended MUC1 sequences were used in the preparation of aptamer-functionalized origami carrying ASOs (Apt-origami-ASO). Dox-loaded Apt-origami-ASO (Apt-Dox-origami-ASO) was prepared by electrostatic adsorption of Dox in origami. Atomic force microscopy (AFM) images demonstrated the successful preparation of Apt-origami-ASO. In vitro studies showed that the Apt-Dox-origami-ASO (Apt-DOA) could controllably release Dox in pH 5.0 phosphate-buffered saline (PBS) buffer and release ASOs in response to glutathione. Further experiments revealed that the origami could protect ASOs against nuclease degradation in 10% FBS. Confocal imaging showed that the Apt-DOA nanocarrier could efficiently enter the Hela/adriamycin (ADR) cells and escape from lysosomes for codelivery of Dox and ASOs into the cytoplasm. The quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot assays testified the efficient silencing of Bcl2 and P-gp mRNA and downregulation of the corresponding protein expressions by Apt-DOA in Hela/ADR cells. Moreover, with the synergetic effect by codelivery of multi-ASOs and Dox, the anticancer assay showed that Apt-DOA could circumvent multidrug resistance and significantly enhance cancer therapy in Hela/ADR and MCF-7/ADR cells. Hence, this multifunctional origami-based codelivery nanocarrier presents a new strategy for efficient therapy of drug-resistant cancer. |
| Databáze: | OpenAIRE |
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