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https://hdl.handle.net/10216/120399
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DC Field | Value | Language |
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dc.creator | Nascimento A.V. | |
dc.creator | Singh A. | |
dc.creator | Bousbaa H. | |
dc.creator | Ferreira D. | |
dc.creator | Sarmento B. | |
dc.creator | Amiji M.M. | |
dc.date.accessioned | 2019-05-31T16:15:25Z | - |
dc.date.available | 2019-05-31T16:15:25Z | - |
dc.date.issued | 2017 | |
dc.identifier.issn | 17427061 | |
dc.identifier.uri | https://hdl.handle.net/10216/120399 | - |
dc.description.abstract | 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 | |
dc.description.sponsorship | This study was supported by a grant from the National Cancer Institute ( NCI ), US Alliance for Nanotechnology in Cancer Platform Technology ( CNPP ) grant U01-CA15552 and by NCI R21 grant CA179652-01A1 . This work was partially supported by CESPU under the project 02-CQF-CICS-776 2011N. Ana Vanessa Nascimento thanks the Fundação Ciência e Tecnologia (FCT), Portugal, for her Ph.D. grant no. SFRH/BD/69271/2010. Appendix A | |
dc.language.iso | eng | |
dc.publisher | Elsevier | |
dc.relation.ispartof | Acta Biomaterialia, vol. 47, p. 71-80 | |
dc.rights | restrictedAccess | |
dc.subject | alanine aminotransferase | |
dc.subject | aspartate aminotransferase | |
dc.subject | chitosan nanoparticle | |
dc.subject | cisplatin | |
dc.subject | creatinine | |
dc.subject | DNA | |
dc.subject | epidermal growth factor receptor | |
dc.subject | nitrogen | |
dc.subject | protein Mad2 | |
dc.subject | small interfering RNA | |
dc.subject | urea | |
dc.subject | chitosan | |
dc.subject | cisplatin | |
dc.subject | epidermal growth factor receptor | |
dc.subject | MAD2L1 protein, human | |
dc.subject | nanoparticle | |
dc.subject | protein Mad2 | |
dc.subject | small interfering RNA | |
dc.subject | A549 cell line | |
dc.subject | alanine aminotransferase blood level | |
dc.subject | animal experiment | |
dc.subject | animal model | |
dc.subject | animal tissue | |
dc.subject | Article | |
dc.subject | aspartate aminotransferase blood level | |
dc.subject | cancer chemotherapy | |
dc.subject | cancer gene therapy | |
dc.subject | cancer inhibition | |
dc.subject | cancer model | |
dc.subject | cancer patient | |
dc.subject | cancer resistance | |
dc.subject | cell proliferation | |
dc.subject | controlled study | |
dc.subject | creatinine blood level | |
dc.subject | DNA replication | |
dc.subject | drug cytotoxicity | |
dc.subject | drug dose reduction | |
dc.subject | drug dose regimen | |
dc.subject | drug effect | |
dc.subject | drug efficacy | |
dc.subject | drug potentiation | |
dc.subject | drug safety | |
dc.subject | drug screening | |
dc.subject | female | |
dc.subject | gene silencing | |
dc.subject | gene targeting | |
dc.subject | histopathology | |
dc.subject | human | |
dc.subject | human cell | |
dc.subject | IC50 | |
dc.subject | in vitro study | |
dc.subject | in vivo study | |
dc.subject | lung adenocarcinoma | |
dc.subject | monotherapy | |
dc.subject | mouse | |
dc.subject | multimodality cancer therapy | |
dc.subject | nanoencapsulation | |
dc.subject | nanomedicine | |
dc.subject | nonhuman | |
dc.subject | nonviral gene delivery system | |
dc.subject | nonviral gene therapy | |
dc.subject | priority journal | |
dc.subject | single drug dose | |
dc.subject | tumor growth inhibition rate | |
dc.subject | tumor volume | |
dc.subject | tumor xenograft | |
dc.subject | urea nitrogen blood level | |
dc.subject | weight change | |
dc.subject | A-549 cell line | |
dc.subject | animal | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | chemistry | |
dc.subject | drug effects | |
dc.subject | drug resistance | |
dc.subject | Lung Neoplasms | |
dc.subject | metabolism | |
dc.subject | pathology | |
dc.subject | A549 Cells | |
dc.subject | Animals | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | Chitosan | |
dc.subject | Cisplatin | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Gene Knockdown Techniques | |
dc.subject | Gene Silencing | |
dc.subject | Humans | |
dc.subject | Inhibitory Concentration 50 | |
dc.subject | Lung Neoplasms | |
dc.subject | Mad2 Proteins | |
dc.subject | Mice | |
dc.subject | Nanoparticles | |
dc.subject | Receptor, Epidermal Growth Factor | |
dc.subject | RNA, Small Interfering | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.title | Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles | |
dc.type | Artigo em Revista Científica Internacional | |
dc.contributor.uporto | CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental | |
dc.identifier.doi | 10.1016/j.actbio.2016.09.045 | |
dc.relation.publisherversion | http://dx.doi.org/10.1016/j.actbio.2016.09.045 | |
Appears in Collections: | CIIMAR - Artigo em Revista Científica Internacional |
Files in This Item:
File | Description | Size | Format | |
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Nascimento AV_2017.pdf Restricted Access | 2.77 MB | Adobe PDF | Request a copy |
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