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A review on RNAi therapy for NSCLC: Opportunities and challenges

Advanced Review

Vignesh Kumar, Sairam Yadavilli, Raghuraman Kannan

Published Online: Nov 10 2020

DOI: 10.1002/wnan.1677

Full article on Wiley Online Library: HTML PDF

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Abstract 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

General classification for Type I and Type II nanosystems for siRNA delivery

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Schematic illustration of synthesis of mesoporous silica nanoparticles (MSN) for an efficient targeted co‐delivery of siRNA and anticancer drugs. (a) Modification of MSN with MPTS; (b) Activation of thiol groups on the MSN surface with Aldrithiol‐2 to produced pyridyldithiol reactive groups; (c) Encapsulation of DOX inside modified MSN; (d) Encapsulation of CIS inside modified MSN; (e) Modification of surface of CIS‐loaded MSN with siRNA and PEG‐LHRH; (f) Modification of surface of DOX‐loaded MSN with siRNA and PEG‐LHRH. (Reprinted with permission from Taratula et al., 2011, Copyright 2020 with permission from Taylor & Francis)

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Optimizing hyaluronic acid (HA)/cisplatin nanoparticles and identifying the resistant genes in drug‐resistant cells. To determine the cisplatin resistance in resistant NSCLC cells, cisplatin drug was incubated with both sensitive and resistant cells (A549/A549^DDP) at various concentrations for 2 days. (a) Cell viability was assessed to determine the IC₅₀ (half maximal inhibitory concentration). (b) To improve the delivery, cisplatin was encapsulated in 1,8‐diaminooctane (ODA)‐modified HA nanosystems with and without poly(ethylene glycol) (PEG) and characterized. (c) The cytotoxicity of HA‐ODA and HA‐ODA/PEG nanoparticles were measured with and without cisplatin along with cisplatin alone as a control in resistant A549^DDP cells. In order to identify the resistant genes in NSCLC and SCLC cells, RNA was extracted from both resistant and sensitive cells. (d) With appropriate primers, the reverse transcription‐PCR was run to identify the expression of resistant genes. NSCLC, non‐small cell lung cancer; SCLC, small cell lung cancer. (Reprinted with permission from Ganesh et al., 2013, Copyright 2020 with permission from the American Society of Gene & Cell Therapy)

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Chitosan nanoparticles loaded with Mad2‐siRNA and PEG and evaluation of the nanoparticles in mice bearing A549 WT and A549 DDP xenograft tumors (a) Schematic representation of nanoparticles; (b) and percentage tumor growth inhibition following treatment with single or combination therapy of Mad2 siRNA and cisplatin in sensitive and resistant A549 tumor bearing mice n = 8 mice, **p < .01, *** p < .001 (t‐test comparing to PBS treatment). (Reprinted with permission from Nascimento et al., 2017, Copyright 2020 with permission from Elsevier)

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(a) Schematic illustration of synthesis of targeted [email protected] NPs; (b) Mechanism of intracellular action of [email protected] NPs carrying oncogene siRNA. (Reprinted with permission from Shi et al., 2017, Copyright 2020 with permission from American Society of Gene and Cell Therapy)

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Evaluation of stability of nanoconstructs and transfection ability in cells. Change in hydrodynamic size of nanoconstructs in (a) water; (b) 10% serum containing RPMI media; (c) 1× PBS; and (d) change in Zeta potential for constructs in water for a duration for 120 hr. siRNA stability. (e) Stability of free‐siRNA (left) and GAbsiAXL (right) in serum was analyzed using PAGE for a duration of 48 hr. GAbsiAXL exhibits high serum stability for 48 hr while free siRNA degrades within 4 hr. No presence of unbound siRNA was detected for GAbsiAXL suggesting strong particle attachment. Gene knockdown efficacy. Change in AXL expression levels in H820 cells after 72 hr of treatment with (f) transfected siRNA; (g) nanoconstructs (with and without TKI); and (h) Downregulation efficiency of siRNA and nanoconstructs calculated by band densitometry. 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)

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(a) Schematic representation of tri‐block nanoparticle (TBN) consisting of gelatin nanoparticle encapsulated with gefitinib and surface functionalized with cetuximab conjugated siRNA; (b) TEM image of Gelatin Nanoparticles; and (c) TEM image of TBN. (Reprinted with permission from Srikar et al., 2016, Copyright 2020 with permission from Nature)

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Evaluation of concurrent delivery of miR‐34a and siRNA‐Kras combination in mouse models improves therapeutic response. (a) KP cell number following incubation with 7C1‐siRNA combinations. Each siRNA dose is 30 nM. Error bars are SD (n = 3 wells per group); (b) Normalized lung tumor volume in KP mice following treatment with 7C1‐siRNA combinations. Ten weeks after tumor initiation, mice were dosed with 2 mg/kg of 7C1‐siLuc or 7C1‐miR‐34a/siKras every other day for four doses. Error bars are SD (n = 8 mice per group, n = 1 tumor per mouse). **p < .01 for 7C1‐miR‐34a/siKras compared with single treatment; (c) Quantification of apoptotic cells marked by CC3 in treated tumors (n = 27, 29, 36, and 46 tumors per time point, respectively); (d) Kaplan–Meier survival curve of KP mice treated with cisplatin and 7C1 nanoparticle formulated with miR34a/siKras combination (siCombo) therapies (n = 8, 8, 8, and 10 mice per group). Day 0 refers to tumor initiation. Arrows or arrowheads indicate time points of cisplatin or nanoparticle administration, respectively. *p < .05; **p < .01. (Reprinted with permission from Xue et al., 2014, Copyright 2020 with permission from PNAS)

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Results obtained using the nanoparticles in mice with human non‐small cell lung carcinoma. (a) Suppression of targeted EGFR1‐TK mRNA by siRNA delivered by non‐targeted and targeted NLC; (b) Suppression of four EGFR‐TKs by the selected pool of siRNAs delivered by targeted LHRH‐NLC‐siRNAs‐TAX system; (c) Apoptosis induction in the lung tumor; (d) Changes in lung tumor volume after beginning of treatment (mice were treated on days 0, 3, 7, 11, 14, 17, 21, and 24). The progression of tumor growth was monitored using bioluminescent and magnetic resonance imaging and tumor volume was calculated using software supplied with IVIS and magnetic resonance imaging systems. [1—Control (untreated tumor); 2—Free non‐bound TAX (I.V. administration); 3—Non‐targeted NLC‐siRNAs (inhalation); 4—Non‐targeted NLC‐TAX (inhalation); 5—Non‐targeted NLC‐siRNAs‐TAX (inhalation); 6—tumor targeted LHRH‐NLC‐siRNAs‐TAX (inhalation). Means ± SD are shown. *p < .05 when compared with control; †p < .05 when compared with free TAX; ‡p < .05 when compare with NLC‐siRNAs; +p < .05 when compared with NLC‐TAX; ×p < .05 when compared with NLC‐siRNA‐TAX]. (Reprinted with permission from Garbuzenko et al., 2019, Copyright 2020 with permission from Ivyspring)

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Schematic illustration of (a) the in vivo codelivery mechanism and (b) the preparation procedure of GMP‐ and/or VEGF siRNA‐loaded LCP formulations. AA, anisamide; EPR, enhanced permeability and retention; GMP, gemcitabine monophosphate; LCP, lipid/calcium/phosphate. (Reprinted with permission from Zhang, Peng, et al., 2013, Copyright 2020 with permission from American Society of Gene and Cell Therapy)

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(a) Schematic illustration of nanoparticles containing VEGF siRNA, and etoposide for NSCLC; Evaluation of tumor growth inhibition of the nanoparticle and compared with controls in orthotopic A549 tumor models. (b) Bioluminescence images of different formulations listed in the graph at different time points—presented as days; (c) Bioluminescence image intensity of nanoparticles and combinations at predesigned time points; (d) Change in body weight of mice during treatment at different type points; (e) Representative H&E images of orthotopic A549 lung tumors after different formulations treatment. Different formulations represented (i) Saline, (ii) ETO injection, (iii) P‐Lip/ETO‐siVEGF, (iv) PHCL‐Lip/siVEGF, (v) PHCL‐Lip/ETO, (vi) PHCL‐Lip/ETO‐siVEGF. Data was represented as mean ± SD (n = 5). (Reprinted with permission from Li et al., 2019, Copyright 2020 with permission from Ivyspring)

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Further Reading

Peng,, Y., Yang,, J., Zhang,, E., Sun,, H., Wang,, Q., Wang,, T., … Shi,, C. (2012). Human positive coactivator 4 is a potential novel therapeutic target in non‐small cell lung cancer. Cancer Gene Therapy, 19(10), 690–696. https://doi.org/10.1038/cgt.2012.52
Wang,, S., Pan,, H., Liu,, D., Mao,, N., Zuo,, C., Li,, L., … Wu,, J. (2015). Excision repair cross complementation group 1 is a chemotherapy‐tolerating gene in cisplatin‐based treatment for non‐small cell lung cancer. International Journal of Oncology, 46(2), 809–817. https://doi.org/10.3892/ijo.2014.2784

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