The suppression of lung tumorigenesis by aerosol-delivered folate–chitosan-graft-polyethylenimine/Akt1 shRNA complexes through the Akt signaling pathway

Jiang, Hu‐Lin; Xu, Cheng-Xiong; Kim, You-Kyoung; Arote, Rohidas; Jere, Dhananjay; Lim, Hyung-Taek; Cho, Myung‐Haing; Cho, Chong‐Su

doi:10.1016/j.biomaterials.2009.07.017

Cited by 116 publications

(81 citation statements)

References 38 publications

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“…29 Furthermore, a previous study has shown that aerosol delivery of shAkt1 with polymer carrier can suppress the tumorigenesis. 3 In this regard, we delivered GT-SPE/ shAkt1 complexes to the lung of the K-ras LA1 lung cancer mouse model. Akt pathway regulates Bcl-2 family members and apoptotic activity, 30 thus, inhibition of Akt1 with GT-SPE by repeated aerosol shAkt1 deliveries may facilitate apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Based on previously used methods, mice were placed in a nose-only exposure chamber and exposed to the aerosol for gene delivery. 3 Twelve BALB/c mice were randomly divided into three groups (four mice/group). To check the efficiency of GT-SPE as a gene carrier, treatment groups were exposed to aerosol containing green fluorescent protein (GFP) expression plasmid DNA with and without a carrier, and the remaining group was used as an untreated control.…”

Section: In Vivo Aerosol Delivery Studymentioning

confidence: 99%

“…At the end of the experiment, the mice were sacrificed. 3 During necropsy, neoplastic lesions of the lung surfaces were carefully counted under a microscope, following the method described previously. 14 At the same time, the lungs were perfused with PBS, and a lobe of the left lung was collected and fixed in 10% neutral buffered formalin for histopathological examination.…”

Section: In Vivo Aerosol Delivery Studymentioning

confidence: 99%

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Suppression of lung cancer progression by biocompatible glycerol triacrylate– spermine-mediated delivery of shAkt1

Hong

Kim²,

Kim³

et al. 2012

IJN

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Background: Polyethylenimine (PEI)-based nonviral gene-delivery systems are commonly employed because of their high transfection efficiency. However, the toxic nature of PEI is a significant obstacle in clinical gene therapy. In this study, we developed biocompatible glycerol triacrylate-spermine (GT-SPE) polyspermine as a nanosized gene carrier for potential lung cancer gene therapy. Methods: The GT-SPE was synthesized using the Michael addition reaction between GT and SPE. The molecular weight was characterized using gel permeability chromatography multiangle laser light scattering and the composition of the polymer was analyzed using proton nuclear magnetic resonance. Results: The GT-SPE successfully protected the DNA from nucleases. The average particle size of the GT-SPE was 121 nm with a zeta potential of +23.45 mV. The GT-SPE was found to be less toxic than PEI for various cell lines, as well as for a murine model. Finally, our results showed that the GT-SPE/small hairpin Akt1 (shAkt1) complex suppressed lung tumorigenesis in a K-ras LA1 lung cancer mice model by inducing apoptosis through the Akt signaling pathway and cell cycle arrest. Aerosol delivered GT-SPE/shAkt1, which reduced matrix metalloproteinase-9 activity and suppressed the expression levels of proliferating cell nuclear antigen, as well as vascular endothelial growth factors and CD31, which are known proliferation and angiogenesis markers, respectively. Conclusion: Our data suggest that GT-SPE may be a candidate for short hairpin-shaped RNAbased aerosol lung cancer gene therapy. Keywords: lung cancer, gene therapy, aerosol delivery, spermine RNA interference (RNAi) has attracted significant attention in the research of genetic disorders and infectious diseases, including cancer, because of its therapeutic effects. 1,2Transfecting synthetic small interfering RNA (siRNA) or plasmid DNA vectors can directly induce RNA interference by expressing short hairpin-shaped RNA (shRNA). 3Several lines of evidence have demonstrated that shRNA-expressing vectors yielded more durable knockdown effects when compared to siRNA. 4 Naked shRNA has a strong anionic-charged phosphodiester backbone and, as a result, cannot freely cross the cellular membrane. Therefore, viral or nonviral delivery systems that facilitate c ellular transfection of shRNA are required. 5 In terms of gene delivery, viral vectors are very efficient, but they have the potential to cause inadequate DNA-carrying capacity, immunogenicity, and mutations in patients. 6,7 In contrast, nonviral vectors are stable, easy to modify, and have been proven to possess high biocompatibility. 8,9 One of the nonviral vectors, polyethylenimine (PEI), is a very effective polymer that can be used Dovepress submit your manuscript | www.dovepress.com for gene delivery in any pH condition because of the proton sponge effect. Dovepress 2293 O R I G I N A L R E S E A R C H10 However, PEI is toxic in nature and is also known to stimulate apoptotic pathways. 11,12 As an alternative to nonviral polymer, we have dev...

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Section: Discussionmentioning

confidence: 99%

Section: In Vivo Aerosol Delivery Studymentioning

confidence: 99%

Section: In Vivo Aerosol Delivery Studymentioning

confidence: 99%

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Suppression of lung cancer progression by biocompatible glycerol triacrylate– spermine-mediated delivery of shAkt1

Hong

Kim²,

Kim³

et al. 2012

IJN

Self Cite

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“…Furthermore, the use of these derivatives is expected to potentiate in vivo transfection kinetics with respect to both efficiency and sustained gene silencing. To this end, structural modifications of chitosan have been explored, such as quaternization of the amine group [27,91] and the introduction of functional groups [82,91] as well as conjugation with other polymers [78] or ligands [78,106]. In this regard, chitosan derivatization has been shown to create safer and more efficient gene vectors [78].…”

Section: Nanocarrier-based Sirna Delivery Using Chitosan Derivativesmentioning

confidence: 99%

Chitosan and its derivatives as nanocarriers for siRNA delivery

Al‐Qadi

Grenha

Remuñán‐López

2012

Journal of Drug Delivery Science and Technology

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“…70 Similarly, aerosol delivery of folate-chitosan (FC)-graft-PEI/Akt1 shRNA complexes suppressed lung tumorigenesis through Akt1 signaling pathway. 71 The suppression of lung cancer progression by biocompatible glycerol triacrylate-spermine (GT-SPE)-mediated delivery of shAkt1 was also revealed by Hong et al 72 A synthetic analog of luteinizing hormone-releasing hormone (LHRH) peptide was conjugated to the distal end of polyethylene glycol (PEG) polymer to direct the siRNA nanoparticles specifically to the cancer cells. Results demonstrated that this layer-by-layer modification and targeting approach confers the siRNA nanoparticles' stability in plasma and intracellular bioavailability and provides for their specific uptake by lung cancer cells, accumulation of siRNA in the cytoplasm and efficient gene silencing.…”

Section: Systemic Ncrna Delivery Strategies In Lung Cancer Treatmentmentioning

confidence: 99%

Long and short noncoding RNAs in lung cancer precision medicine: Opportunities and challenges

et al. 2017

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The long and short noncoding RNAs have been involved in the molecular diagnosis, targeted therapy, and predicting prognosis of lung cancer. Utilizing noncoding RNAs as biomarkers and systemic RNA interference as an innovative therapeutic strategy has an immense likelihood to generate novel concepts in precision oncology. Targeting of RNA interference payloads such as small interfering RNAs, microRNA mimetic, or anti-microRNA (antagomirs) into specific cell types has achieved initial success. The clinical trials of noncoding RNA-based therapies are on the way with some positive results. Many attempts are done for developing novel noncoding RNA delivery strategies that could overcome systemic or local barriers. Furthermore, it precipitates concerted efforts to define the molecular subtypes of lung cancer, characterize the genomic landscape of lung cancer subtypes, identify novel therapeutic targets, and reveal mechanisms of sensitivity and resistance to targeted therapies. These efforts contribute a visible effect now in lung cancer precision medicine: patients receive molecular testing to determine whether their tumor harbors an actionable come resistance to the first-generation drugs are in clinical trials, and drugs targeting the immune system are showing activity in patients. This extraordinary promise is tempered by the sobering fact that even the newest treatments for metastatic disease are rarely curative and are effective only in a small fraction of all patients. Thus, ongoing and future efforts to find new vulnerabilities of lung cancers unravel the complexity of drug resistance, increase the efficacy of immunotherapies, and perform biomarker-driven clinical trials are necessary to improve the outcome of lung cancer patients.

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The suppression of lung tumorigenesis by aerosol-delivered folate–chitosan-graft-polyethylenimine/Akt1 shRNA complexes through the Akt signaling pathway

Cited by 116 publications

References 38 publications

Suppression of lung cancer progression by biocompatible glycerol triacrylate– spermine-mediated delivery of shAkt1

Suppression of lung cancer progression by biocompatible glycerol triacrylate– spermine-mediated delivery of shAkt1

Chitosan and its derivatives as nanocarriers for siRNA delivery

Long and short noncoding RNAs in lung cancer precision medicine: Opportunities and challenges

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The suppression of lung tumorigenesis by aerosol-delivered folate–chitosan-graft-polyethylenimine/Akt1 shRNA complexes through the Akt signaling pathway

Cited by 116 publications

References 38 publications

Suppression of lung cancer progression by biocompatible glycerol triacrylate&ndash; spermine-mediated delivery of shAkt1

Suppression of lung cancer progression by biocompatible glycerol triacrylate&ndash; spermine-mediated delivery of shAkt1

Chitosan and its derivatives as nanocarriers for siRNA delivery

Long and short noncoding RNAs in lung cancer precision medicine: Opportunities and challenges

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Product

Resources

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Suppression of lung cancer progression by biocompatible glycerol triacrylate– spermine-mediated delivery of shAkt1

Suppression of lung cancer progression by biocompatible glycerol triacrylate– spermine-mediated delivery of shAkt1