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Author(s): Nascimento A.V.
Singh A.
Bousbaa H.
Ferreira D.
Sarmento B.
Amiji M.M.
Title: Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles
Publisher: Elsevier
Issue Date: 2017
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
Subject: alanine aminotransferase
aspartate aminotransferase
chitosan nanoparticle
epidermal growth factor receptor
protein Mad2
small interfering RNA
epidermal growth factor receptor
MAD2L1 protein, human
protein Mad2
small interfering RNA
A549 cell line
alanine aminotransferase blood level
animal experiment
animal model
animal tissue
aspartate aminotransferase blood level
cancer chemotherapy
cancer gene therapy
cancer inhibition
cancer model
cancer patient
cancer resistance
cell proliferation
controlled study
creatinine blood level
DNA replication
drug cytotoxicity
drug dose reduction
drug dose regimen
drug effect
drug efficacy
drug potentiation
drug safety
drug screening
gene silencing
gene targeting
human cell
in vitro study
in vivo study
lung adenocarcinoma
multimodality cancer therapy
nonviral gene delivery system
nonviral gene therapy
priority journal
single drug dose
tumor growth inhibition rate
tumor volume
tumor xenograft
urea nitrogen blood level
weight change
A-549 cell line
Carcinoma, Non-Small-Cell Lung
drug effects
drug resistance
Lung Neoplasms
A549 Cells
Carcinoma, Non-Small-Cell Lung
Drug Resistance, Neoplasm
Gene Knockdown Techniques
Gene Silencing
Inhibitory Concentration 50
Lung Neoplasms
Mad2 Proteins
Receptor, Epidermal Growth Factor
RNA, Small Interfering
Xenograft Model Antitumor Assays
Source: Acta Biomaterialia, vol. 47, p. 71-80
Document Type: Artigo em Revista Científica Internacional
Rights: restrictedAccess
Appears in Collections:CIIMAR - Artigo em Revista Científica Internacional

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