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Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles
| Summary: | Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emergence of inherent and acquired drug resistance in cancer cells. As a common strategy to overcome drug resistance, higher doses of chemo-agents are administered. However, adverse side effects are usually increased as a consequence. A potentially effective approach is to combine chemotherapy with other therapeutic strategies such as small interfering RNAs (siRNAs) that allow the use of lower yet efficient doses of the anticancer drugs. We previously developed epidermal growth factor receptor (EGFR)-targeted chitosan (CS) nanoparticles as a versatile delivery system for silencing the essential mitotic checkpoint gene Mad2, and induce cell death. Here, we tested this system as a single therapy and in combination with cisplatin in cisplatin sensitive and resistant lung cancer models, and characterized its in vivo efficacy and safety. Combination treatment resulted in significant improvement in tumor inhibition that was strikingly more effective in cisplatin-resistant tumors. Importantly, effective cisplatin dosage was dramatically reduced in the co-therapy regimen resulting in negligible toxic effects from the drug as confirmed by parameters such as body weight gain, biochemical markers of hepatic and renal function, and histopathology of liver/kidney/spleen tissues. Overall, we demonstrate that the combination of Mad2 siRNA-loaded CS nanoparticles strategy with chemotherapeutic agents such as cisplatin constitutes an efficient and safe approach for the treatment of drug resistant tumors. Statement of Significance Lung cancer remains one of the leading killers in the United States and around the world. Platinum agents, including cisplatin, are the first line treatment in lung cancer, including non-small cell lung cancer (NSCLC), which is the predominant form of lung cancer. In this study, we have evaluated Mad2 cell-cycle checkpoint gene silencing using small interfering RNA (siRNA) delivered systemically using epidermal growth factor receptor-targeted chitosan nanoparticles in drug sensitive and resistant models of NSCLC. Our results show that Mad2 gene silencing using targeted chitosan nanoparticles has tremendous potential in overcoming platinum resistance in NSCLC. © 2016 Acta Materialia |
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| Subject: | small interfering RNA Mad2 Proteins drug dose regimen animal mouse single drug dose drug potentiation drug cytotoxicity Carcinoma, Non-Small-Cell Lung metabolism drug effects nonviral gene delivery system Inhibitory Concentration 50 creatinine cancer chemotherapy Chitosan Humans protein Mad2 drug safety nonhuman aspartate aminotransferase blood level histopathology drug effect human pathology drug dose reduction nanomedicine cisplatin Nanoparticles Article gene targeting cell proliferation epidermal growth factor receptor nanoencapsulation lung adenocarcinoma monotherapy controlled study aspartate aminotransferase Lung Neoplasms drug efficacy female alanine aminotransferase drug resistance Drug Resistance, Neoplasm Animals cancer model animal model DNA replication human cell priority journal animal tissue drug screening gene silencing animal experiment MAD2L1 protein, human A549 Cells cancer resistance nanoparticle urea nitrogen blood level in vitro study RNA, Small Interfering Mice multimodality cancer therapy Receptor, Epidermal Growth Factor cancer gene therapy DNA tumor volume urea chemistry creatinine blood level weight change Cisplatin A-549 cell line cancer inhibition alanine aminotransferase blood level Gene Knockdown Techniques IC50 in vivo study A549 cell line nitrogen cancer patient chitosan nanoparticle Xenograft Model Antitumor Assays chitosan nonviral gene therapy tumor xenograft Gene Silencing tumor growth inhibition rate |
| Country: | Portugal |
| Document type: | journal article |
| Access type: | Restricted |
| Associated institution: | Repositório Aberto da Universidade do Porto |
| Language: | English |
| Origin: | Repositório Aberto da Universidade do Porto |
| _version_ | 1850560640878379008 |
|---|---|
| conditionsOfAccess_str | restricted access |
| country_str | PT |
| description | Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emergence of inherent and acquired drug resistance in cancer cells. As a common strategy to overcome drug resistance, higher doses of chemo-agents are administered. However, adverse side effects are usually increased as a consequence. A potentially effective approach is to combine chemotherapy with other therapeutic strategies such as small interfering RNAs (siRNAs) that allow the use of lower yet efficient doses of the anticancer drugs. We previously developed epidermal growth factor receptor (EGFR)-targeted chitosan (CS) nanoparticles as a versatile delivery system for silencing the essential mitotic checkpoint gene Mad2, and induce cell death. Here, we tested this system as a single therapy and in combination with cisplatin in cisplatin sensitive and resistant lung cancer models, and characterized its in vivo efficacy and safety. Combination treatment resulted in significant improvement in tumor inhibition that was strikingly more effective in cisplatin-resistant tumors. Importantly, effective cisplatin dosage was dramatically reduced in the co-therapy regimen resulting in negligible toxic effects from the drug as confirmed by parameters such as body weight gain, biochemical markers of hepatic and renal function, and histopathology of liver/kidney/spleen tissues. Overall, we demonstrate that the combination of Mad2 siRNA-loaded CS nanoparticles strategy with chemotherapeutic agents such as cisplatin constitutes an efficient and safe approach for the treatment of drug resistant tumors. Statement of Significance Lung cancer remains one of the leading killers in the United States and around the world. Platinum agents, including cisplatin, are the first line treatment in lung cancer, including non-small cell lung cancer (NSCLC), which is the predominant form of lung cancer. In this study, we have evaluated Mad2 cell-cycle checkpoint gene silencing using small interfering RNA (siRNA) delivered systemically using epidermal growth factor receptor-targeted chitosan nanoparticles in drug sensitive and resistant models of NSCLC. Our results show that Mad2 gene silencing using targeted chitosan nanoparticles has tremendous potential in overcoming platinum resistance in NSCLC. © 2016 Acta Materialia |
| documentTypeURL_str | http://purl.org/coar/resource_type/c_6501 |
| documentType_str | journal article |
| id | 45eb0867-1b1b-40c1-93f1-ec621423d3fb |
| identifierHandle_str | https://hdl.handle.net/10216/120399 |
| language | eng |
| relatedInstitutions_str_mv | Repositório Aberto da Universidade do Porto |
| resourceName_str | Repositório Aberto da Universidade do Porto |
| spellingShingle | Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles small interfering RNA Mad2 Proteins drug dose regimen animal mouse single drug dose drug potentiation drug cytotoxicity Carcinoma, Non-Small-Cell Lung metabolism drug effects nonviral gene delivery system Inhibitory Concentration 50 creatinine cancer chemotherapy Chitosan Humans protein Mad2 drug safety nonhuman aspartate aminotransferase blood level histopathology drug effect human pathology drug dose reduction nanomedicine cisplatin Nanoparticles Article gene targeting cell proliferation epidermal growth factor receptor nanoencapsulation lung adenocarcinoma monotherapy controlled study aspartate aminotransferase Lung Neoplasms drug efficacy female alanine aminotransferase drug resistance Drug Resistance, Neoplasm Animals cancer model animal model DNA replication human cell priority journal animal tissue drug screening gene silencing animal experiment MAD2L1 protein, human A549 Cells cancer resistance nanoparticle urea nitrogen blood level in vitro study RNA, Small Interfering Mice multimodality cancer therapy Receptor, Epidermal Growth Factor cancer gene therapy DNA tumor volume urea chemistry creatinine blood level weight change Cisplatin A-549 cell line cancer inhibition alanine aminotransferase blood level Gene Knockdown Techniques IC50 in vivo study A549 cell line nitrogen cancer patient chitosan nanoparticle Xenograft Model Antitumor Assays chitosan nonviral gene therapy tumor xenograft Gene Silencing tumor growth inhibition rate |
| title | Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles |
| topic | small interfering RNA Mad2 Proteins drug dose regimen animal mouse single drug dose drug potentiation drug cytotoxicity Carcinoma, Non-Small-Cell Lung metabolism drug effects nonviral gene delivery system Inhibitory Concentration 50 creatinine cancer chemotherapy Chitosan Humans protein Mad2 drug safety nonhuman aspartate aminotransferase blood level histopathology drug effect human pathology drug dose reduction nanomedicine cisplatin Nanoparticles Article gene targeting cell proliferation epidermal growth factor receptor nanoencapsulation lung adenocarcinoma monotherapy controlled study aspartate aminotransferase Lung Neoplasms drug efficacy female alanine aminotransferase drug resistance Drug Resistance, Neoplasm Animals cancer model animal model DNA replication human cell priority journal animal tissue drug screening gene silencing animal experiment MAD2L1 protein, human A549 Cells cancer resistance nanoparticle urea nitrogen blood level in vitro study RNA, Small Interfering Mice multimodality cancer therapy Receptor, Epidermal Growth Factor cancer gene therapy DNA tumor volume urea chemistry creatinine blood level weight change Cisplatin A-549 cell line cancer inhibition alanine aminotransferase blood level Gene Knockdown Techniques IC50 in vivo study A549 cell line nitrogen cancer patient chitosan nanoparticle Xenograft Model Antitumor Assays chitosan nonviral gene therapy tumor xenograft Gene Silencing tumor growth inhibition rate |