scholarly journals Folate-Targeted mRNA Delivery Using Chitosan-Functionalized Selenium Nanoparticles: Potential in Cancer Immunotherapy

2019 ◽  
Vol 12 (4) ◽  
pp. 164 ◽  
Author(s):  
Maiyo ◽  
Singh
Keyword(s):  
Messenger Rna ◽  
Folate Receptor ◽  
Selenium Nanoparticles ◽  
Breast Adenocarcinoma ◽  
Kb Cells ◽  
Selenium Uptake ◽  
Ethidium Bromide Staining ◽  
Low Cytotoxicity ◽  
Uptake Studies

Systemic messenger RNA (mRNA) delivery, although still in its infancy, holds immense potential for application in cancer vaccination and immunotherapy. Its advantages over DNA transfection make it attractive in applications where transient expression is desired. However, this has proved challenging due to mRNA’s instability and susceptibility to degradation. Selenium is important for immune function and modulation, with selenium nanoparticles (SeNPs) finding a niche in biomedicine as drug delivery vehicles, owing to their biocompatibility, low toxicity, and biodegradability. In this investigation, we synthesized chitosan-coated SeNPs with a folic acid targeting moiety for Fluc mRNA delivery to cancer cells in vitro. Synthesized SeNPs were stable and well dispersed, and ranged from 59 to 102 nm in size. Nanoparticles bound and protected mRNA from RNase degradation, while exhibiting low cytotoxicity in the human embryonic kidney (HEK293), breast adenocarcinoma (MCF-7), and nasopharyngeal (KB) cells in culture. Moderate cytotoxicity evidenced in the colorectal carcinoma (Caco-2) and colon carcinoma (HT-29) cells was attributed to apoptosis induction by selenium, as confirmed by acridine orange/ethidium bromide staining. Selenium uptake studies corroborated the transfection results, where significant transgene expression was evident for the overexpressed folate receptor-positive KB cells when compared to the other cells with less or no folate receptors.

scholarly journals Folate (pteroylglutamate) uptake in human red blood cells, erythroid precursors and KB cells at high extracellular folate concentrations. Evidence against a role for specific folate-binding and transport proteins

1989 ◽  
Vol 260 (2) ◽  
pp. 401-411 ◽  
Author(s):  
A C Antony ◽  
M A Kane ◽  
S R Krishnan ◽  
R S Kincade ◽  
R S Verma
Keyword(s):  
Folate Receptor ◽  
Transport Proteins ◽  
Human Cells ◽  
Kb Cells ◽  
Uptake Mechanism ◽  
Human Red Blood Cells ◽  
Physiological Relevance ◽  
Cell Accumulation ◽  
Normal Human

Membrane-associated folate (pteroylglutamate, PteGlu)-binding proteins (FBPs) play an important role as PteGlu-transport proteins in malignant and normal human cells. Since high extracellular folate (PteGlu) concentrations (EFC) profoundly influenced uptake and toxicity of the anti-PteGlu methotrexate in malignant KB cells, we studied human cells to determine additional mechanisms for PteGlu uptake when the EFC was varied. At low EFC (less than 10 nM), the predominant mechanism for folate uptake in mature erythrocytes was through binding to externally oriented FBPs which were quantitatively insignificant (4-6 orders of magnitude lower) and of no apparent physiological relevance when compared with KB cells. However, the predominant mechanism of PteGlu accumulation at high EFC [10-250 nM] in intact erythrocytes and sealed right-side-out (RSO) ghosts was not FBP-mediated and non-specific. This conclusion was based on the findings that radiolabelled PteGlu uptake: (i) continued even in the presence of a 1000-fold excess of unlabelled PteGlu and was linear and not saturable up to 250 nM; (ii) was two-fold higher at pH 4.5 than 7.5; (iii) was less than 2-fold increased at 37 degrees C compared with 4 degrees C; and (iv) was unaffected after trypsin-mediated proteolysis of greater than 75% FBPs. The [3H]PteGlu and 125I-PteGlu (histamine derivative) accumulated intracellularly through the non-specific PteGlu-uptake mechanism was unaltered biochemically and in a soluble compartment. Raising the EFC 500-fold higher than controls during erythropoiesis in vitro resulted in reversal of the expected anti-(placental folate-receptor)-antiserum-induced megaloblastic changes in orthochromatic normoblasts derived from burst-forming unit-erythroid colonies. Furthermore, at EFC greater than 0.1 microM, KB-cell accumulation of [3H]PteGlu was also predominantly through a mechanism that did not involve specific FBPs. Thus, at high EFC, a major component of PteGlu transport in human cells is not mediated through FBPs and is likely to be a passive diffusion process.

scholarly journals Polymerized Selenium Nanoparticles for Folate-Receptor-Targeted Delivery of Anti-Luc-siRNA: Potential for Gene Silencing

Biomedicines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 76 ◽  
Author(s):  
Fiona Maiyo ◽  
Moganavelli Singh
Keyword(s):  
Gene Silencing ◽  
Cell Lines ◽  
Targeted Delivery ◽  
Folate Receptor ◽  
Docking Studies ◽  
Selenium Nanoparticles ◽  
Luciferase Gene ◽  
Therapeutic Outcomes ◽  
Transmission Electron

The development of a biocompatible and nontoxic gene delivery vehicle remains a challenging task. Selenium nanoparticles (SeNPs) have the potential to increase delivery efficiency, to reduce side effects, and to improve therapeutic outcomes. In this study, chitosan (Ch) functionalized folate (FA)-targeted SeNPs were synthesized, characterized, and evaluated for their potential to bind, protect, and safely deliver Fluc-siRNA in vitro. SeNPs of less than 100 nm were successfully synthesised and further confirmed using UV-vis and Fourier transform infrared spectroscopy, transmission electron microscopy, and nanoparticle tracking analysis. Cell viability studies were conducted in vitro in selected cancer and non-cancer cell lines. Folate receptor (FOLR1) targeted and nontargeted luciferase gene silencing studies were assessed in the transformed Hela-tat-Luc cell line expressing the luciferase gene. Targeted and nontargeted SeNP nanocomplexes showed minimal toxicity in all cell lines at selected w/w ratios. Maximum gene silencing was achieved at optimum w/w ratios for both nanocomplexes, with Selenium-chitosan-folic acid (SeChFA) nanocomplexes showing slightly better transgene silencing, as supported by results from docking studies showing that SeChFA nanocomplexes interacted strongly with the folate receptor (FOLR1) with high binding energy of −4.4 kcal mol−1.

Differentiation-independent retinoid induction of folate receptor type β, a potential tumor target in myeloid leukemia

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3529-3536 ◽  
Author(s):  
Hui Wang ◽  
Xuan Zheng ◽  
Frederick G. Behm ◽  
Manohar Ratnam
Keyword(s):  
Retinoic Acid ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Transforming Growth Factor ◽  
Retinoic Acid Receptor ◽  
Folate Receptor ◽  
Leukemia Cells ◽  
Luciferase Reporter ◽  
Luciferase Reporter Construct

Abstract Folate receptor (FR) type β is expressed in the myelomonocytic lineage, predominantly during neutrophil maturation and in myeloid leukemias. FR-β expression was elevated up to 20-fold by all-trans retinoic acid (ATRA) in KG-1 myeloid leukemia cells in a dose-dependent and reversible manner in the absence of terminal differentiation or cell growth inhibition. ATRA also increased FR-β expression in vitro in myeloid leukemia cells from patient marrow. FR-β was not up-regulated in KG-1 cells treated with phorbol ester, dexamethasone, 1,25-dihydroxy vitamin D3, or transforming growth factor β. ATRA did not induce FR-β expression in receptor negative cells of diverse origin. The ATRA-induced increase in FR-β expression in KG-1 cells occurred at the level of messenger RNA synthesis, and in 293 cells containing a stably integrated FR-β promoter–luciferase reporter construct, ATRA induced expression of the reporter. From experiments using retinoid agonists and antagonists and from cotransfection studies using the FR-β promoter and expression plasmids for the nuclear receptors retinoic acid receptor (RAR)α, RARβ, or RARγ, it appears that the retinoid effect on FR-β expression could be mediated by ligand binding to RARs α, β, or γ, but not to retinoid X receptors. Furthermore, there was apparent cross-talk between RARα and RARγ selective agonists or antagonists, suggesting a common downstream target for RAR isoforms in inducing FR-β expression. Thus, blocks in the RARα-specific pathway of retinoid-induced differentiation may be bypassed during retinoid induction of FR-β expression. The results suggest that to facilitate FR-targeted therapies, retinoids may be used to modulate FR-β expression in myeloid leukemia cells refractory to retinoid differentiation therapy.

Differentiation-independent retinoid induction of folate receptor type β, a potential tumor target in myeloid leukemia

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3529-3536 ◽  
Author(s):  
Hui Wang ◽  
Xuan Zheng ◽  
Frederick G. Behm ◽  
Manohar Ratnam
Keyword(s):  
Retinoic Acid ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Transforming Growth Factor ◽  
Retinoic Acid Receptor ◽  
Folate Receptor ◽  
Leukemia Cells ◽  
Luciferase Reporter ◽  
Luciferase Reporter Construct

Folate receptor (FR) type β is expressed in the myelomonocytic lineage, predominantly during neutrophil maturation and in myeloid leukemias. FR-β expression was elevated up to 20-fold by all-trans retinoic acid (ATRA) in KG-1 myeloid leukemia cells in a dose-dependent and reversible manner in the absence of terminal differentiation or cell growth inhibition. ATRA also increased FR-β expression in vitro in myeloid leukemia cells from patient marrow. FR-β was not up-regulated in KG-1 cells treated with phorbol ester, dexamethasone, 1,25-dihydroxy vitamin D3, or transforming growth factor β. ATRA did not induce FR-β expression in receptor negative cells of diverse origin. The ATRA-induced increase in FR-β expression in KG-1 cells occurred at the level of messenger RNA synthesis, and in 293 cells containing a stably integrated FR-β promoter–luciferase reporter construct, ATRA induced expression of the reporter. From experiments using retinoid agonists and antagonists and from cotransfection studies using the FR-β promoter and expression plasmids for the nuclear receptors retinoic acid receptor (RAR)α, RARβ, or RARγ, it appears that the retinoid effect on FR-β expression could be mediated by ligand binding to RARs α, β, or γ, but not to retinoid X receptors. Furthermore, there was apparent cross-talk between RARα and RARγ selective agonists or antagonists, suggesting a common downstream target for RAR isoforms in inducing FR-β expression. Thus, blocks in the RARα-specific pathway of retinoid-induced differentiation may be bypassed during retinoid induction of FR-β expression. The results suggest that to facilitate FR-targeted therapies, retinoids may be used to modulate FR-β expression in myeloid leukemia cells refractory to retinoid differentiation therapy.

Folate receptor-targeted multimodal polymersomes for delivery of quantum dots and doxorubicin to breast adenocarcinoma: In vitro and in vivo evaluation

2016 ◽  
Vol 500 (1-2) ◽  
pp. 162-178 ◽  
Author(s):  
Mona Alibolandi ◽  
Khalil Abnous ◽  
Fatemeh Sadeghi ◽  
Hossein Hosseinkhani ◽  
Mohammad Ramezani ◽  
...  
Keyword(s):  
Quantum Dots ◽  
Folate Receptor ◽  
Breast Adenocarcinoma ◽  
In Vivo Evaluation

Selenium Nanoparticles in Folate-Targeted delivery of the pCMV-Luc DNA Reporter Gene

2020 ◽  
Vol 16 ◽  
Author(s):  
Fiona C Maiyo ◽  
Londiwe S Mbatha ◽  
Moganavelli Singh
Keyword(s):  
Gene Delivery ◽  
Reporter Gene ◽  
Targeted Delivery ◽  
Transgene Expression ◽  
Folate Receptor ◽  
Selenium Nanoparticles ◽  
Hek293 Cells ◽  
Luciferase Reporter ◽  
Breast Adenocarcinoma ◽  
Mcf 7

Background: Selenium, an essential micronutrient, has been studied for decades for its anticancer properties. Selenium nanoparticles (SeNPs) have now emerged as an interesting alternative for drug and gene delivery. Aims: We aimed to demonstrate in proof of principle, the potential use of SeNPs in targeted pCMV-Luc DNA (pDNA) delivery in vitro. Objectives: To chemically synthesize, characterize and evaluate the transgene expression of functionalized SeNPs in five human cell lines. Methods: SeNPs were synthesized via chemical reduction, coated with chitosan (Ch) and a targeting moiety folic acid (FA). All nanoparticles were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), UV-vis and Fourier transform infra-red (FTIR) spectroscopy. Nanoparticle:pDNA interactions were assessed using the electrophoretic mobility shift, dye displacement and nuclease protection assays. The MTT and Luciferase reporter gene assays were used to determine cytotoxicity and transgene expression respectively, in the human colorectal adenocarcinoma (HT-29 and Caco-2), breast adenocarcinoma (MCF-7), oral epidermoid/cervical carcinoma contaminant (KB) and the embryonic kidney (HEK293) cells. Results: Homogenous nanoparticles of 60-70 nm were able to successfully bind, compact and protect the pDNA from enzyme digestion. Low cytotoxicity was observed in all cells, except for the MCF-7 cells, which could be attributed to apoptosis and necrosis. Luciferase gene expression was highest for the targeted nanocomplexes in the folate-receptor rich KB cell line, confirming nanocomplex uptake through folate receptor-mediated endocytosis. Conclusion: This study opens a new avenue for synergistic treatment of cancer, combining selenium’s bioactivity and its carrier potential for therapeutic gene delivery.

scholarly journals Dendrimer-Coated Gold Nanoparticles for Efficient Folate-Targeted mRNA Delivery In Vitro

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 900
Author(s):  
Londiwe Simphiwe Mbatha ◽  
Fiona Maiyo ◽  
Aliscia Daniels ◽  
Moganavelli Singh
Keyword(s):  
Gold Nanoparticles ◽  
Messenger Rna ◽  
Transgene Expression ◽  
Vaccine Development ◽  
Luciferase Reporter ◽  
Kb Cells ◽  
Luciferase Reporter Gene ◽  
Attractive Candidate ◽  
Mcf 7

Messenger RNA (mRNA) is not an attractive candidate for gene therapy due to its instability and has therefore received little attention. Recent studies show the advantage of mRNA over DNA, especially in cancer immunotherapy and vaccine development. This study aimed to formulate folic-acid-(FA)-modified, poly-amidoamine-generation-5 (PAMAM G5D)-grafted gold nanoparticles (AuNPs) and to evaluate their cytotoxicity and transgene expression using the luciferase reporter gene (FLuc-mRNA) in vitro. Nanocomplexes were spherical and of favorable size. Nanocomplexes at optimum nanoparticle:mRNA (w/w) binding ratios showed good protection of the bound mRNA against nucleases and were well tolerated in all cell lines. Transgene expression was significantly (p < 0.0001) higher with FA-targeted, dendrimer-grafted AuNPs (Au:G5D:FA) in FA receptors overexpressing MCF-7 and KB cells compared to the G5D and G5D:FA NPs, decreasing significantly (p < 0.01) in the presence of excess competing FA ligand, which confirmed nanocomplex uptake via receptor mediation. Overall, transgene expression of the Au:G5D and Au:G5D:FA nanocomplexes exceeded that of G5D and G5D:FA nanocomplexes, indicating the pivotal role played by the inclusion of the AuNP delivery system. The favorable properties imparted by the AuNPs potentiated an increased level of luciferase gene expression.

scholarly journals Development of Folate-Functionalized PEGylated Zein Nanoparticles for Ligand-Directed Delivery of Paclitaxel

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 562 ◽  
Author(s):  
Zar Chi Soe ◽  
Wenquan Ou ◽  
Milan Gautam ◽  
Kishwor Poudel ◽  
Bo Kyun Kim ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Targeted Delivery ◽  
Folate Receptor ◽  
A549 Cells ◽  
Kb Cells ◽  
Cell Cycle Profile ◽  
Folate Receptors ◽  
Targeted Nanoparticles ◽  
Nanoparticle System

In this study, we investigated the active targeted delivery of a hydrophobic drug, paclitaxel (PTX), via receptor-mediated endocytosis by folate receptors expressed on cancer cells using a protein-based nanoparticle system. PTX was loaded on zein nanoparticles and conjugated with folate (PTX/Zein-FA) to estimate its chemotherapeutic efficacy in folate receptor-expressing KB cancer cells. PTX/Zein-FA nanoparticles were successfully developed, with a nanoparticle size of ~180 nm and narrow polydispersity index (~0.22). Accelerated release of PTX in an acidic environment was observed for PTX/Zein-FA. An in vitro cellular study of PTX/Zein-FAs in KB cells suggested that PTX/Zein-FA improved the cytotoxic activity of PTX on folate receptors overexpressed in cancer cells by inducing proapoptotic proteins and inhibiting anti-apoptotic proteins. In addition, PTX/Zein-FA exhibited anti-migratory properties and could alter the cell cycle profile of KB cells. A549 cells, which are folate receptor-negative cancer cells, showed no significant enhancement in the in vitro cellular activities of PTX/Zein-FA. We describe the antitumor efficacy of PTX/Zein-FA in KB tumor-bearing mice with minimum toxicity in healthy organs, and the results were confirmed in comparison with free drug and non-targeted nanoparticles.

scholarly journals Effect of Cationic Lipid Type in Folate-PEG-Modified Cationic Liposomes on Folate Receptor-Mediated siRNA Transfection in Tumor Cells

Pharmaceutics ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 181 ◽  
Author(s):  
Yoshiyuki Hattori ◽  
Satono Shimizu ◽  
Kei-ichi Ozaki ◽  
Hiraku Onishi
Keyword(s):  
Gene Silencing ◽  
Tumor Cells ◽  
Folate Receptor ◽  
Cationic Lipid ◽  
Intratumoral Injection ◽  
Cationic Liposomes ◽  
Kb Cells ◽  
In Vitro Transfection

In this study, we examined the effect of cationic lipid type in folate (FA)-polyethylene glycol (PEG)-modified cationic liposomes on gene-silencing effects in tumor cells using cationic liposomes/siRNA complexes (siRNA lipoplexes). We used three types of cationic cholesterol derivatives, cholesteryl (3-((2-hydroxyethyl)amino)propyl)carbamate hydroiodide (HAPC-Chol), N-(2-(2-hydroxyethylamino)ethyl)cholesteryl-3-carboxamide (OH-Chol), and cholesteryl (2-((2-hydroxyethyl)amino)ethyl)carbamate (OH-C-Chol), and we prepared three types of FA-PEG-modified siRNA lipoplexes. The modification of cationic liposomes with 1–2 mol % PEG-lipid abolished the gene-silencing effect in human nasopharyngeal tumor KB cells, which overexpress the FA receptor (FR). In contrast, FA-PEG-modification of cationic liposomes restored gene-silencing activity regardless of the cationic lipid type in cationic liposomes. However, the optimal amount of PEG-lipid and FA-PEG-lipid in cationic liposomes for selective gene silencing and cellular uptake were different among the three types of cationic liposomes. Furthermore, in vitro transfection of polo-like kinase 1 (PLK1) siRNA by FA-PEG-modified liposomes exhibited strong cytotoxicity in KB cells, compared with PEG-modified liposomes; however, in in vivo therapy, intratumoral injection of PEG-modified PLK1 siRNA lipoplexes inhibited tumor growth of KB xenografts, as well as that of FA-PEG-modified PLK1 siRNA lipoplexes. From these results, the optimal formulation of PEG- and FA-PEG-modified liposomes for FR-selective gene silencing might be different between in vitro and in vivo transfection.

Polymeric Silver Nanoparticles: Potential for Folate-Targeted Delivery of Cisplatin In Vitro

2021 ◽  
Author(s):  
Radhini Veerappan ◽  
Aliscia Daniels ◽  
Moganavelli Singh
Keyword(s):  
Silver Nanoparticles ◽  
Side Effects ◽  
Cancer Therapy ◽  
Hela Cells ◽  
Targeted Delivery ◽  
Folate Receptor ◽  
Breast Adenocarcinoma ◽  
Anticancer Activities

Nanotechnology is a favorable avenue for improving therapeutic strategies, especially in cancer therapy. The harmful side effects of traditional cancer therapy impact dramatically on the patient’s quality of life. Cisplatin, a commonly used anticancer drug, is implicated in side effects such as neurotoxicity, nephrotoxicity and reduced blood cell count. Silver nanoparticles (AgNPs) have been investigated for their antibacterial effects and their anticancer activities to a lesser extent. Their capability as drug delivery vehicles has not been fully exploited, primarily due to their inconclusive cytotoxicity observed in healthy tissues. This study aimed to synthesize and characterize nanoparticles (NPs), consisting of Ag, chitosan (Cs) and folic acid (FA) (CsAg and FACsAg), loading them with cisplatin (C) (C-CsAg and C-FACsAg) and comparing their anticancer activities in the human embryonic kidney (HEK293), breast adenocarcinoma (MCF-7) and cervical carcinoma (HeLa) cells. All NPs and drug nanocomplexes were morphologically and physicochemically characterized, revealing NPs and nanocomplexes of favorable sizes ([Formula: see text][Formula: see text]nm), polydispersity and stability. The drug encapsulation efficiencies for C-CsAg and C-FACsAg were 50% and 72%, respectively, while drug release studies indicated that cisplatin release was pH dependent. The C-FACsAg nanocomplexes produced greater anticancer activity than C-CsAg. Folate receptor-mediated uptake was confirmed for the C-FACsAg nanocomplexes in the receptor-rich HeLa cells boding well for future in vivo research.

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