Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells
| Autor: | Yunfeng Yan, Kenneth E. Huffman, Sussana Elkassih, Kejin Zhou, John D. Minna, Hu Xiong, Ryan Carstens, John W. Norman, Li Liu, James Kim, Jason B. Miller, Petra Kos, Daniel J. Siegwart |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Materials science Polyesters Apoptosis 02 engineering and technology Endocytosis Mice 03 medical and health sciences Cell Line Tumor medicine Animals Combinatorial Chemistry Techniques Humans Gene silencing Gene Silencing RNA Small Interfering Lung cancer Cell Proliferation Multidisciplinary Ubiquitin Gene Transfer Techniques Cancer Transfection Carbocyanines 021001 nanoscience & nanotechnology medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology PNAS Plus Cancer cell Drug delivery Cancer research Nanoparticles 0210 nano-technology Drug carrier Biomedical engineering |
| Zdroj: | Proceedings of the National Academy of Sciences. 113 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1606886113 |
| Popis: | Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies. |
| Databáze: | OpenAIRE |
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