Abstract 302: Passive and active nucleic acid delivery against colon cancer cells using a novel nanocarrier aimed for oral administration
| Autor: | George Mattheolabakis, Sagun Poudel |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Cancer Research. 81:302-302 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2021-302 |
| Popis: | Oral delivery of nucleic acids has been challenging, due to unfavorable physiological factors that do not comply with the nucleic acids' properties. Firstly, nucleic acids break down in the harsh acidic gastric environment. Secondly, they are hydrophilic, negatively charged, large-molecular-weight molecules, unable to efficiently penetrate through the mucus membrane and enter the epithelial intestinal wall. We developed a novel nano delivery system of nucleic acids complexed with mannosylated PEI encapsulated in PEG-PCL matrix. We will use this carrier to overcome the above-mentioned limitations of oral nucleic acid delivery aiming for colon cancer treatment. We synthesized the mannosylated PEI with the objective to target colon cancer cells. We will use active targeting as these cells overexpress mannose receptors. We complexed a model nucleic acid, the PGL-3 luciferase expressing plasmid, with mannosylated PEI at the optimal N/P ratio of 20:1. We transfected cancer cells in vitro and analyzed the luciferase expression. Furthermore, we analyzed the cytotoxicity of PCL-PEG nanoparticles containing mannosylated PEI/PGL-3 complexes, as well as the nanoparticles capacity to protect nucleic acids and release their load. Mannosylated PEI successfully complexed with the nucleic acids, protecting from degradation against nucleases. Mannosylated PEI/PGL-3 complexes transfected colon cancer cells and the luciferase expression was significantly higher when compared to PEI alone, at 24 and 48 h. The complexes were successfully up taken by cell lines in a time dependent manner. Competitive transfection assay with free mannose demonstrated the active targeting effect caused due to the mannose receptors. Similarly, the PCL-PEG nanoparticles with mannose PEI/PGL-3 complexes had a limited cytotoxicity. Most importantly, the carrier successfully protected the mannose PEI/PGL-3 complexes in a simulated gastric fluid environment and released them in a simulated intestinal fluid environment. This indicates that the nanocarriers can potentially protect the nucleic acids in an acidic environment, such as the stomach, and release their mannosylated PEI/PGL-3 in a neutral environment, such as in the intestines. Such a behavior would indicate a passive targeting to the small and large intestines. We can conclude that the formulated polymeric nanoparticles were successful in protecting the nucleic acids. The mannosylated PEI was able to completely complex with nucleic acids and actively target colon cancer. This promising nanocarrier and our approach merits further evaluation for the oral administration of nucleic acids in therapeutic applications of passive and active targeting against colon cancer. Citation Format: Sagun Poudel, George Mattheolabakis. Passive and active nucleic acid delivery against colon cancer cells using a novel nanocarrier aimed for oral administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 302. |
| Databáze: | OpenAIRE |
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