Silencing AXL by covalent siRNA-gelatin-antibody nanoconjugate inactivates mTOR/EMT pathway and stimulates p53 for TKI sensitization in NSCLC

Suresh, Dhananjay; Zambre, Ajit; Mukherjee, S.; Ghoshdastidar, Shreya; Jiang, Yuyong; Joshi, Trupti; Upendran, Anandhi; Kannan, Raghuraman

doi:10.1016/j.nano.2019.04.010

Cited by 24 publications

(26 citation statements)

References 53 publications

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“…For these reasons, AXL kinase represents a valid therapeutic target to counteract cancer. In this sense, Suresh et al developed antibody functionalized gelatin nanoparticles (GAb) for effective cytoplasmatic delivery of anti-AXL siRNA in lung cancer cells [94]. These nanostructures repressed EMT by downregulating MMPs production and key EMT-related proteins, such as N-cadherin and vimentin, sensitizing H820 and H1975 cell lines to tyrosine kinase inhibitors [94].…”

Section: Axl Kinasementioning

confidence: 99%

Nanomaterials as Inhibitors of Epithelial Mesenchymal Transition in Cancer Treatment

Cordani

Strippoli

Somoza

2019

Cancers

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Epithelial-mesenchymal transition (EMT) has emerged as a key regulator of cell invasion and metastasis in cancers. Besides the acquisition of migratory/invasive abilities, the EMT process is tightly connected with the generation of cancer stem cells (CSCs), thus contributing to chemoresistance. However, although EMT represents a relevant therapeutic target for cancer treatment, its application in the clinic is still limited due to various reasons, including tumor-stage heterogeneity, molecular-cellular target specificity, and appropriate drug delivery. Concerning this last point, different nanomaterials may be used to counteract EMT induction, providing novel therapeutic tools against many different cancers. In this review, (1) we discuss the application of various nanomaterials for EMT-based therapies in cancer, (2) we summarize the therapeutic relevance of some of the proposed EMT targets, and (3) we review the potential benefits and weaknesses of each approach.

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Section: Axl Kinasementioning

confidence: 99%

Nanomaterials as Inhibitors of Epithelial Mesenchymal Transition in Cancer Treatment

Cordani

Strippoli

Somoza

2019

Cancers

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“…Like with liposomes, the majority of these utilize APIs loaded into a lipophilic core, including pirfenidone (a drug used to treat pulmonary fibrosis) ( Singh et al, 2019 ), MDB5 (a novel form of Hedgehog (Hh) inhibitor GDC-0449) ( Kumar et al, 2019 ), salinomycin (an antibiotic with anti-cancer properties) ( Sousa et al, 2019 ), and doxorubicin (an anthracycline chemotherapeutic) ( Fang et al, 2014 ; Seifi-Najmi et al, 2016 ). Multiple formulations also make use of siRNA targeting genes along the EMT pathway ( Fang et al, 2014 ; Seifi-Najmi et al, 2016 ; Li et al, 2019 ; Suresh et al, 2019 ), including one directly conjugated to PEI to form a polyplex ( Ding et al, 2018 ; Wang Y. et al, 2019 ), as well as an inhibitor of CXCR4 ( Suresh et al, 2019 ), a chemokine receptor involved in the promotion of tumor migration and EMT ( Lin et al, 2018 ). These all resulted in the inhibition of key EMT-biomarkers, including PAI-1, TGF-β, VEGF, Hh, Vimentin, and N-Cadherin.…”

Section: Nanomedicinementioning

confidence: 99%

“…These all resulted in the inhibition of key EMT-biomarkers, including PAI-1, TGF-β, VEGF, Hh, Vimentin, and N-Cadherin. This led to decreased collagen deposition ( Wang Y. et al, 2019 ; Kumar et al, 2019 ; Li et al, 2019 ), cell migration and metastasis ( Fang et al, 2014 ; Seifi-Najmi et al, 2016 ; Sousa et al, 2019 ), and tumor growth ( Suresh et al, 2019 ). Polymeric NPs increased lung penetration and retention, provided stability by a polymer-siRNA conjugate, and facilitated codelivery further enhanced API efficacies.…”

Section: Nanomedicinementioning

confidence: 99%

Nanoapproaches to Modifying Epigenetics of Epithelial Mesenchymal Transition for Treatment of Pulmonary Fibrosis

et al. 2020

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Idiopathic Pulmonary Fibrosis (IPF) is a chronically progressive interstitial lung that affects over 3 M people worldwide and rising in incidence. With a median survival of 2–3 years, IPF is consequently associated with high morbidity, mortality, and healthcare burden. Although two antifibrotic therapies, pirfenidone and nintedanib, are approved for human use, these agents reduce the rate of decline of pulmonary function but are not curative and do not reverse established fibrosis. In this review, we discuss the prevailing epithelial injury hypothesis, wherein pathogenic airway epithelial cell-state changes known as Epithelial Mesenchymal Transition (EMT) promotes the expansion of myofibroblast populations. Myofibroblasts are principal components of extracellular matrix production that result in airspace loss and mortality. We review the epigenetic transition driving EMT, a process produced by changes in histone acetylation regulating mesenchymal gene expression programs. This mechanistic work has focused on the central role of bromodomain-containing protein 4 in mediating EMT and myofibroblast transition and initial preclinical work has provided evidence of efficacy. As nanomedicine presents a promising approach to enhancing the efficacy of such anti-IPF agents, we then focus on the state of nanomedicine formulations for inhalable delivery in the treatment of pulmonary diseases, including liposomes, polymeric nanoparticles (NPs), inorganic NPs, and exosomes. These nanoscale agents potentially provide unique properties to existing pulmonary therapeutics, including controlled release, reduced systemic toxicity, and combination delivery. NP-based approaches for pulmonary delivery thus offer substantial promise to modify epigenetic regulators of EMT and advance treatments for IPF.

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“…Among all, anexelekto (AXL) kinase has emerged as a dominant oncoprotein that promotes cancer progression in TKI‐resistant NSCLC patients (Suresh et al, 2019; Zhang, Wang, Zhao, & Cui, 2018). This strong correlation is explained by the ability of AXL to mediate epithelial‐to‐mesenchymal transition (EMT) and activate similar downstream signaling nodes as EGFR, including the PI3K/AKT and JAK/STAT pathways that promote cell growth and proliferation (Gay, Balaji, & Byers, 2017; Suresh et al, 2019; Zhang et al, 2018). Researchers attempted to address this challenge through co‐administration of EGFR inhibitors with AXL inhibitors such as R428, DS‐1205b, ONO‐7475, BGB324, or XL880 (Jimbo et al, 2019; Okura et al, 2020; Zhang et al, 2018).…”

Section: Silencing Axlmentioning

confidence: 99%

“…GAbsiAXL downregulated AXL expression successfully by over 70% ( p ≤ .001; from three independent experiments). (Reprinted with permission from Suresh et al, 2019, Copyright 2020 with permission from Elsevier)…”

Section: Silencing Axlmentioning

confidence: 99%

A review on RNAi therapy for NSCLC: Opportunities and challenges

Kumar

Yadavilli

Kannan

2020

WIREs Nanomed Nanobiotechnol

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Non‐small cell lung cancer (NSCLC) is the primary cause of cancer death worldwide. Despite developments in chemotherapy and targeted therapies, the 5‐year survival rate has remained at approximately 16% for the last four decades. NSCLC is a heterogeneous group of tumors that, through mutations and drivers, also demonstrate intra‐tumor heterogeneity. Thus, current treatment approaches revolve around targeting these oncogenes, often using small molecule inhibitors and chemotherapeutics. However, the efficacy of these therapies has been crippled by acquired and inherent drug‐resistance in the tumor, accompanied by increased therapeutic dosages and subsequent devastating off‐target effects for patients. Evidently, there is a critical need for developing treatment methodologies more effective than the current standard of care. Fortunately, RNA interference, particularly small interfering RNA (siRNA), presents an alternative of silencing specific oncogenes to control tumor growth. Although siRNA therapy is subject to rapid degradation and poor internalization in vivo, nanoparticles can serve as nontoxic and efficient delivery vehicles, even introducing combinational delivery of multiple therapeutic agents. Indeed, siRNA‐nanoconstructs possess extraordinary potential as an innovative modality to address clinical needs. This state‐of‐the‐art review summarizes the recent advancements in the development of novel nanosystems for delivering siRNA to NSCLC tumors and analyzes the efficacy of representative examples. By illuminating the most promising biomarkers for silencing, we hope to streamline current therapeutic efforts and highlight powerful translational opportunities to combat NSCLC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Lipid‐Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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Silencing AXL by covalent siRNA-gelatin-antibody nanoconjugate inactivates mTOR/EMT pathway and stimulates p53 for TKI sensitization in NSCLC

Cited by 24 publications

References 53 publications

Nanomaterials as Inhibitors of Epithelial Mesenchymal Transition in Cancer Treatment

Nanomaterials as Inhibitors of Epithelial Mesenchymal Transition in Cancer Treatment

Nanoapproaches to Modifying Epigenetics of Epithelial Mesenchymal Transition for Treatment of Pulmonary Fibrosis

A review on RNAi therapy for NSCLC: Opportunities and challenges

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