scholarly journals Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small-molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids

2020 ◽  
Author(s):  
Ezgi Oner ◽  
Mustafa Kotmakci ◽  
Anne-Marie Baird ◽  
Steven G. Gray ◽  
Bilge Debelec Butuner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cellular Uptake ◽  
Transfection Efficiency ◽  
Cationic Lipid ◽  
Lipid Nanoparticles ◽  
In Vivo Studies ◽  
Great Promise ◽  
Tumor Spheroids

Abstract Background: siRNAs hold a great potential for cancer therapy, however, poor stability in body fluids and low cellular uptake limit their use in the clinic. To enhance the bioavailability of siRNAs in tumors, novel, safe, and effective carriers are needed. Results: Here, we developed cationic solid lipid nanoparticles (cSLNs) to carry siRNAs targeting EphA2 receptor tyrosine kinase (siEphA2), which is overexpressed in many solid tumors including prostate cancer (PCa). Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in PCa cells. DDAB-cSLN showed better cellular uptake efficiency with similar silencing compared to commercial transfection reagent Dharmafect-2. After verifying the efficacy of siEphA2-loaded nanoparticles, we further evaluated a potential combination with a histone lysine demethylase inhibitor, JIB-04. Silencing EphA2 by siEphA2-loaded DDAB-cSLN did not affect the viability (2D and 3D), migration, and clonogenicity of PC-3 cells alone. However, upon co-administration, there was a decrease in the aforementioned cellular responses due to JIB-04. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing efficiency of siEphA2-loaded nanoparticles was further increased with co-treatment. Conclusions: We have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, detailed preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on PCa cells and tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows a great promise for targeting other genes and cancer types in further in vitro and in vivo studies.

scholarly journals Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small-molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids

2020 ◽  
Author(s):  
Ezgi Oner ◽  
Mustafa Kotmakci ◽  
Anne-Marie Baird ◽  
Steven G. Gray ◽  
Bilge Debelec Butuner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cellular Uptake ◽  
Transfection Efficiency ◽  
Cationic Lipid ◽  
Lipid Nanoparticles ◽  
Great Promise ◽  
Tumor Spheroids ◽  
Lysine Demethylase

AbstractsiRNAs hold a great potential for cancer therapy, however, poor stability in body fluids and low cellular uptake limit their use in the clinic. To enhance the bioavailability of siRNAs in tumors, novel, safe, and effective carriers are needed. Here, we developed cationic solid lipid nanoparticles (cSLNs) to carry siRNAs targeting EphA2 receptor tyrosine kinase (siEphA2), which is overexpressed in many solid tumors including prostate cancer (PCa). Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in PCa cells. After verifying the efficacy of siEphA2-loaded nanoparticles, we further evaluated a potential combination with a histone lysine demethylase inhibitor, JIB-04. Silencing EphA2 by siEphA2-loaded DDAB-cSLN did not affect the viability (2D and 3D), migration, and clonogenicity of PC-3 cells alone. However, upon co-administration, there was a decrease in the aforementioned cellular responses due to JIB-04. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing efficiency of siEphA2-loaded nanoparticles was further increased with co-treatment. In conclusion, we have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, detailed preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on PCa cells and tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows a great promise for targeting other genes and cancer types in further in vitro and in vivo studies.

scholarly journals Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small‐molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ezgi Oner ◽  
Mustafa Kotmakci ◽  
Anne-Marie Baird ◽  
Steven G. Gray ◽  
Bilge Debelec Butuner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cellular Uptake ◽  
Transfection Efficiency ◽  
3D Culture ◽  
Lipid Nanoparticles ◽  
In Vivo Studies ◽  
Great Promise ◽  
Prostate Cancer Cells ◽  
Tumor Spheroids

Abstract Background siRNAs hold a great potential for cancer therapy, however, poor stability in body fluids and low cellular uptake limit their use in the clinic. To enhance the bioavailability of siRNAs in tumors, novel, safe, and effective carriers are needed. Results Here, we developed cationic solid lipid nanoparticles (cSLNs) to carry siRNAs targeting EphA2 receptor tyrosine kinase (siEphA2), which is overexpressed in many solid tumors including prostate cancer. Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in prostate cancer cells. DDAB-cSLN showed better cellular uptake efficiency with similar silencing compared to commercial transfection reagent (Dharmafect 2). After verifying the efficacy of siEphA2-loaded nanoparticles, we further evaluated a potential combination with a histone lysine demethylase inhibitor, JIB-04. Silencing EphA2 by siEphA2-loaded DDAB-cSLN did not affect the viability (2D or 3D culture), migration, nor clonogenicity of PC-3 cells alone. However, upon co-administration with JIB-04, there was a decrease in cellular responses. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing by siEphA2-loaded nanoparticles was further increased with co-treatment. Conclusions We have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on prostate cancer cells and prostate cancer tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows great promise for targeting other genes and cancer types in further in vitro and in vivo studies.

scholarly journals Investigating the Impact of Delivery System Design on the Efficacy of Self-Amplifying RNA Vaccines

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 212 ◽  
Author(s):  
Giulia Anderluzzi ◽  
Gustavo Lou ◽  
Simona Gallorini ◽  
Michela Brazzoli ◽  
Russell Johnson ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Transfection Efficiency ◽  
Polymeric Nanoparticles ◽  
Cationic Lipid ◽  
Antigen Expression ◽  
In Vivo Studies ◽  
Humoral And Cellular Immunity ◽  
The Impact

messenger RNA (mRNA)-based vaccines combine the positive attributes of both live-attenuated and subunit vaccines. In order for these to be applied for clinical use, they require to be formulated with delivery systems. However, there are limited in vivo studies which compare different delivery platforms. Therefore, we have compared four different cationic platforms: (1) liposomes, (2) solid lipid nanoparticles (SLNs), (3) polymeric nanoparticles (NPs) and (4) emulsions, to deliver a self-amplifying mRNA (SAM) vaccine. All formulations contained either the non-ionizable cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or dimethyldioctadecylammonium bromide (DDA) and they were characterized in terms of physico-chemical attributes, in vitro transfection efficiency and in vivo vaccine potency. Our results showed that SAM encapsulating DOTAP polymeric nanoparticles, DOTAP liposomes and DDA liposomes induced the highest antigen expression in vitro and, from these, DOTAP polymeric nanoparticles were the most potent in triggering humoral and cellular immunity among candidates in vivo.

scholarly journals A Gemini Cationic Lipid with Histidine Residues as a Novel Lipid-Based Gene Nanocarrier: A Biophysical and Biochemical Study

Nanomaterials ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 1061 ◽  
Author(s):  
María Martínez-Negro ◽  
Laura Blanco-Fernández ◽  
Paolo Tentori ◽  
Lourdes Pérez ◽  
Aurora Pinazo ◽  
...  
Keyword(s):  
Biochemical Study ◽  
Cationic Lipid ◽  
Green Fluorescence Protein ◽  
In Vivo Studies ◽  
Interleukin 12 ◽  
Specific Gene ◽  
Gene Therapies ◽  
Biological Studies

This work reports the synthesis of a novel gemini cationic lipid that incorporates two histidine-type head groups (C3(C16His)2). Mixed with a helper lipid 1,2-dioleoyl-sn-glycero-3-phosphatidyl ethanol amine (DOPE), it was used to transfect three different types of plasmid DNA: one encoding the green fluorescence protein (pEGFP-C3), one encoding a luciferase (pCMV-Luc), and a therapeutic anti-tumoral agent encoding interleukin-12 (pCMV-IL12). Complementary biophysical experiments (zeta potential, gel electrophoresis, small-angle X-ray scattering (SAXS), and fluorescence anisotropy) and biological studies (FACS, luminometry, and cytotoxicity) of these C3(C16His)2/DOPE-pDNA lipoplexes provided vast insight into their outcomes as gene carriers. They were found to efficiently compact and protect pDNA against DNase I degradation by forming nanoaggregates of 120–290 nm in size, which were further characterized as very fluidic lamellar structures based in a sandwich-type phase, with alternating layers of mixed lipids and an aqueous monolayer where the pDNA and counterions are located. The optimum formulations of these nanoaggregates were able to transfect the pDNAs into COS-7 and HeLa cells with high cell viability, comparable or superior to that of the standard Lipo2000*. The vast amount of information collected from the in vitro studies points to this histidine-based lipid nanocarrier as a potentially interesting candidate for future in vivo studies investigating specific gene therapies.

scholarly journals Vitamin D and prostate cancer

2013 ◽  
Vol 66 (5-6) ◽  
pp. 259-262
Author(s):  
Goran Marusic ◽  
Dimitrije Jeremic ◽  
Sasa Vojinov ◽  
Natasa Filipovic ◽  
Milan Popov
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Physiological Role ◽  
In Vivo Studies ◽  
Vitamin D Metabolism ◽  
Genetic Changes ◽  
Metabolic Role

In addition to the metabolic role of vitamin D, which is well known and clearly defined, there have been many hypotheses regarding its anti-proliferative and pro-apoptotic role. Epidemiology and Significance of Prostate Cancer. Prostate cancer is the second most common malignancy in men. Long period of cancerogenesis, available tumor markers and high incidence make this cancer ideal for preventive measures. Physiological Role of Vitamin D and its Effect on Prostate Cancer Cells. In vitro and in vivo studies have shown the anti-proliferative and pro-apoptopic role of vitamin D. Disorders of vitamin D metabolism are noted in vitamin D gene level, vitamin D receptor, vitamin D responsive elements and androgen receptors. We present the most important effect of those changes on vitamin D metabolism. Conclusion. Available studies on vitamin D level in serum, prostate tissue, observed activity of vitamin D enzymes and genetic changes give us only a slight insight into the basic mechanisms of vitamin D action in the development of prostate cancer; therefore, further investigations are needed.

scholarly journals A Review of the Potential of Phytochemicals from Prunus africana (Hook f.) Kalkman Stem Bark for Chemoprevention and Chemotherapy of Prostate Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Richard Komakech ◽  
Youngmin Kang ◽  
Jun-Hwan Lee ◽  
Francis Omujal
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Treatment Options ◽  
Chemotherapeutic Agents ◽  
Sub Saharan Africa ◽  
In Vivo Studies ◽  
Prostate Cancer Cells ◽  
Prunus Africana

Prostate cancer remains one of the major causes of death worldwide. In view of the limited treatment options for patients with prostate cancer, preventive and treatment approaches based on natural compounds can play an integral role in tackling this disease. Recent evidence supports the beneficial effects of plant-derived phytochemicals as chemopreventive and chemotherapeutic agents for various cancers, including prostate cancer. Prunus africana has been used for generations in African traditional medicine to treat prostate cancer. This review examined the potential roles of the phytochemicals from P. africana, an endangered, sub-Saharan Africa plant in the chemoprevention and chemotherapy of prostate cancer. In vitro and in vivo studies have provided strong pharmacological evidence for antiprostate cancer activities of P. africana-derived phytochemicals. Through synergistic interactions between different effective phytochemicals, P. africana extracts have been shown to exhibit very strong antiandrogenic and antiangiogenic activities and have the ability to kill tumor cells via apoptotic pathways, prevent the proliferation of prostate cancer cells, and alter the signaling pathways required for the maintenance of prostate cancer cells. However, further preclinical and clinical studies ought to be done to advance and eventually use these promising phytochemicals for the prevention and chemotherapy of human prostate cancer.

Effect of cabazitaxel on the growth of human castration-refractory prostate cancer cells in vitro compared to docetaxel and on the anti-tumor properties of the angio-inhibitor PEDF in vivo.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 205-205
Author(s):  
Thomas Nelius ◽  
Courtney Jarvis ◽  
Dalia Martinez-Marin ◽  
Stephanie Filleur
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Lines ◽  
In Vitro Cytotoxicity ◽  
In Vivo Studies ◽  
Raw264.7 Macrophages

205 Background: Docetaxel/DTX and cabazitaxel/CBZ have shown promise in the treatment of metastatic Castration-Refractory Prostate Cancer/mCPRC however, comparative studies are missing. Toxicities of these drugs are significant, urging the need to modify taxane regimens. Recently, low-dose metronomic/LDM treatments using conventional chemotherapeutic drugs have shown benefits in CPRC in improving the effect of anti-angiogenic agents. Previously, we have demonstrated that LDM-DTX in combination with PEDF curbs significantly CRPC growth, limits metastases formation and prolongs survival in vivo. In this study, we intended to compare the cytotoxic effect of CBZ and DTX on CRPC cells in vitro and CL1 tumors in vivo. Methods: PC3, DU145 cell lines were from ATCC.CL1 cells were obtained from androgen-deprived LNCaP cells. Cell proliferation was assessed by crystal violet staining and cell cycle analyses. In vitro cytotoxicity assays were performed on CL1 cells/RAW264.7 macrophages co-cultures treated with PEDF and increasing doses of taxanes. For the in vivo studies, CL1 cells were engineered to stably express the DsRed Express protein +/- PEDF. PEDF anti-tumor effects were assessed on s.c. xenografts treated with DTX (5mg/kg ip ev. 4 day) as reference, CBZ (5mg/kg ip ev. 4 days, 1mg/kg for 10 days, 0.5mg/kg q.a.d. and 0.1mg/kg daily) or placebo. Results: CBZ limits cell proliferation with a greater efficacy than DTX in all CRPC cell lines tested. DU145 presented the largest difference. High doses of taxane blocked tumor cells in mitosis, whereas LDM increased the SubG1 population. This effect was significantly higher in DU145 cells treated with CBZ. In vivo, 5mg/kg CBZ delayed tumor growth more efficiently than 5mg/kg DTX. PEDF/5mg/kg CBZ markedly delayed tumor growth compared to all treatments. Finally, engulfment of tumor cells by macrophages was higher in combined treatments suggesting an inflammation-related process. Conclusions: CBZ is more efficient than DTX both in vitro and in vivo.The data also reinforce PEDF as a promising anti-neoplasic agent in combination with LDM taxane chemotherapies.

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