title: Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles.
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.
  
  
  
  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.
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal; Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Portugal; Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, USA; I3S, Instituto de Investigação e Inovação em Saúde and INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Portugal.
authors.forename: Ana Vanessa
authors.initials: AV
authors.lastname: Nascimento
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Singh
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Portugal.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bousbaa
authors.affiliation: Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Portugal.
authors.forename: Domingos
authors.initials: D
authors.lastname: Ferreira
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal; I3S, Instituto de Investigação e Inovação em Saúde and INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sarmento
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, USA. Electronic address: m.amiji@neu.edu.
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048271:Chitosan / Q000737:chemistry; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy; D064246:Mad2 Proteins / Q000378:metabolism*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D034741:RNA, Small Interfering; D048271:Chitosan; D066246:ErbB Receptors; D002945:Cisplatin
keywords: Cisplatin resistance; EGFR-targeted chitosan nanoparticles; Efficacy; Mad2 siRNA delivery; Non-small cell lung cancer models; Safety profile