scholarly journals The Antagonism of Folate Receptor by the Integrase Inhibitor Dolutegravir: Developmental Toxicity Reduction by Supplemental Folic Acid

2019 ◽  
Author(s):  
Robert M. Cabrera ◽  
Jaclyn P. Souder ◽  
John W. Steele ◽  
Lythou Yeo ◽  
Gabriel Tukeman ◽  
...  
Keyword(s):  
Folic Acid ◽  
Folate Receptor ◽  
Developmental Toxicity ◽  
Fold Increase ◽  
Integrase Inhibitor ◽  
Hiv Integrase ◽  
Binding Studies ◽  
Childbearing Age ◽  
Vitamin B9

ABSTRACTHuman immunodeficiency virus (HIV) integrase inhibitors are increasingly being used for antiretroviral therapy (ART), and dolutegravir (DTG/Tivicay) has emerged as a leading core agent. In 2018, the Tsepamo study reported a 6- to 9-fold increase for neural tube defect (NTD) risk among the offspring of mothers receiving DTG during early gestation. Maternal folate (vitamin B9) status is the largest known modifier of NTD risk, so we evaluated folate-related mechanisms of action and the critical period for DTG developmental toxicity. Folate receptor (FOLR1) binding studies indicate DTG is a non-competitive FOLR1 antagonist at therapeutic concentrations.In vitrotesting indicates calcium (2mM) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase (DHFR). Early embryonic exposure to DTG is developmentally toxic in zebrafish, and supplemental folic acid can mitigate DTG developmental toxicity. The results from these studies are expected to inform and guide future animal models and clinical studies of DTG-based ART in women of childbearing age.

scholarly journals Effect of The Ethylene Inhibitor “Agno3”, Vitamin B9 “Folic Acid” And Thiol Compound “GSH” On in Vitro Propagation of Sideritis Syriaca L. Subsp. Syriaca (Hellenic Mountain Tea of The Crete Island)

2019 ◽  
Vol 8 ◽  
pp. 1086-1103
Author(s):  
Virginia Sarropoulou ◽  
Eleni Maloupa
Keyword(s):  
Folic Acid ◽  
Shoot Multiplication ◽  
Fold Increase ◽  
Simultaneous Application ◽  
Thiol Compound ◽  
Vitamin B9 ◽  
Crete Island ◽  
Ethylene Inhibitor ◽  
Final Survival

The aim of this research was to study the effect of the ethylene inhibitor “silver nitrate (AgNO3)” and vitamin B9 "folic acid" in different concentrations combined with cytokinin BA as well as the antioxidant thiol compound “L-glutathione reduced (GSH)” in different concentrations simultaneously with auxins (IBA+NAA) on micropropagation efficiency of the endemic Sideritis syriaca L. subsp. syriaca (Hellenic mountain tea of Crete/ Malotira) using shoot tip explants. The culture medium used was the MS supplemented with 30 g/l sucrose. The simultaneous application 5 ?M AgNO3 + 2.2 ?M BA promoted best the initial shoot induction stage exhibiting 4.5 shoots/ explant and 100% shoot multiplication (5 weeks). Folic acid applied at 0.25 mg/l in combination with 0.5 mg/l BA exhibited the highest shoot multiplication percentage (90%) (4 weeks). GSH at 10 ?M with 10.7 ?M NAA + 4.92 ?M IBA gave the greatest root length (13.68 mm), at 25 ?M caused a 3-fold increase in rooting (90%) and 250 ?M GSH raised by 20% shoot multiplication (80%). An 89% final survival rate of rooted microplants to ex vitro unheated greenhouse conditions was recorded within 8 weeks period during mid-late spring. Thus, the acclimatization and hardening process was successfully completed.

scholarly journals Evaluating biological activity of folic acid-modified and 10-hydroxycamptothecin-loaded mesoporous silica nanoparticles

2021 ◽  
Author(s):  
Mei-Xia Zhao ◽  
Di-Feng Chen ◽  
Xue-Jie Zhao ◽  
Lin-Song Li ◽  
Yong-Fang Liu
Keyword(s):  
Folic Acid ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Folate Receptor ◽  
Mesoporous Silica Nanoparticles ◽  
Drug Carriers ◽  
Transmission Electron ◽  
Before And After ◽  
Drug Efficiency

Targeted nanocarrier can selectively deliver anti-tumor drugs to cancer sites improving drug efficiency. Accordingly, a targeted nanocarrier (MSN-FA) was synthesized based on folic acid (FA) modified mesoporous silica nanoparticles (MSNs). These loaded with 10-hydroxycamptothecin (HCPT) to obtain the nano-drug MSN-FA@HCPT. These nanocarriers were characterized by transmission electron microscopy (TEM), zeta potential, ultraviolet-visible spectroscopy (UV-Vis), fourier transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). Notably, the nanocarriers were nearly spherical before and after loading HCPT and exhibited good dispersibility. Also, folate receptor (FR) over-expressing HeLa cells and FR deficient HepG2 cells were used to evaluate in vitro cellular uptake and cytotoxicity of MSN-FA@HCPT and MSN@HCPT. Interestingly, FA-modified nanocarriers enhanced the cytotoxicity of HCPT by improving drug targeting to tumor cells. Also, apoptotic and mitochondrial membrane potential (MMP) reducing effects of MSN-FA@HCPT were more prominent than the MSNs without FA modification. MSN-FA@HCPT can be excellent drug carriers with profound biomedical applications.

scholarly journals Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

2019 ◽  
Vol 75 (3) ◽  
pp. 648-655 ◽  
Author(s):  
Scott L Letendre ◽  
Anthony Mills ◽  
Debbie Hagins ◽  
Susan Swindells ◽  
Franco Felizarta ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Antiviral Activity ◽  
Plasma Concentrations ◽  
Integrase Inhibitor ◽  
Virological Suppression ◽  
Hiv Integrase ◽  
Long Acting ◽  
Hiv 1

Abstract Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays. Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF. Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

scholarly journals Optimisation of Folate-Mediated Liposomal Encapsulated Arsenic Trioxide for Treating HPV-Positive Cervical Cancer Cells In Vitro

2019 ◽  
Vol 20 (9) ◽  
pp. 2156 ◽  
Author(s):  
Akhtar ◽  
Ghali ◽  
Wang ◽  
Bell ◽  
Li ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Folic Acid ◽  
Cancer Cells ◽  
Arsenic Trioxide ◽  
Folate Receptor ◽  
Hpv Infection ◽  
Cytotoxicity Studies ◽  
Cervical Cancer Cells ◽  
Infected Cells

High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO’s therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers.

scholarly journals Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Said A. Hassounah ◽  
Ahmad Alikhani ◽  
Maureen Oliveira ◽  
Simrat Bharaj ◽  
Ruxandra-Ilinca Ibanescu ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Fold Increase ◽  
Integrase Inhibitor ◽  
Antiretroviral Drugs ◽  
Strand Transfer ◽  
Single Cycle ◽  
Genetic Barrier ◽  
Hiv 1

ABSTRACT Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, while a fourth compound, termed cabotegravir (CAB), is currently in late phases of clinical development. Here we report the susceptibilities of simian immunodeficiency virus (SIV) and HIV-1 integrase (IN) mutants containing various RAMs to BIC, CAB, and DTG. BIC potently inhibited SIV and HIV-1 in single cycle infection with 50% effective concentrations (EC50s) in the low nM range. In single cycle SIV infections, none of the E92Q, T97A, Y143R, or N155H substitutions had a significant effect on susceptibility to BIC (≤4-fold increase in EC50), whereas G118R and R263K conferred ∼14-fold and ∼6-fold increases in EC50, respectively. In both single and multiple rounds of HIV-1 infections, BIC remained active against the Y143R, N155H, R263K, R263K/M50I, and R263K/E138K mutants (≤4-fold increase in EC50). In multiple rounds of infection, the G140S/Q148H combination of substitutions decreased HIV-1 susceptibility to BIC 4.8-fold compared to 16.8- and 7.4-fold for CAB and DTG, respectively. BIC possesses an excellent resistance profile in regard to HIV and SIV and could be useful in nonhuman primate models of HIV infection.

scholarly journals Assessment of Intracellular Delivery Potential of Novel Sustainable Poly(δ-decalactone)-Based Micelles

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 726
Author(s):  
Kuldeep Kumar Bansal ◽  
Ezgi Özliseli ◽  
Gaurav Kumar Saraogi ◽  
Jessica M. Rosenholm
Keyword(s):  
Drug Delivery ◽  
Folic Acid ◽  
Folate Receptor ◽  
In Vitro Cytotoxicity ◽  
Uptake Efficiency ◽  
Drug Delivery Carrier ◽  
Intracellular Drug Delivery ◽  
Copolymer Micelles ◽  
Model Drug

Biodegradable polymers from renewable resources have attracted much attention in recent years within the biomedical field. Lately, poly(δ-decalactone) based copolymer micelles have emerged as a potential drug delivery carrier material as a sustainable alternative to fossil-based polymers. However, their intracellular drug delivery potential is not yet investigated and therefore, in this work, we report on the synthesis and cellular uptake efficiency of poly(δ-decalactone) based micelles with or without a targeting ligand. Folic acid was chosen as a model targeting ligand and Rhodamine B as a fluorescent tracer to demonstrate the straightforward functionalisation aspect of copolymers. The synthesis of block copolymers was accomplished by a combination of facile ring-opening polymerisation and click chemistry to retain the structure uniformity. The presence of folic acid on the surface of micelles with diameter ~150 nm upsurge the uptake efficiency by 1.6 fold on folate receptor overexpressing MDA-MB-231 cells indicating the attainment of targeting using ligand functionality. The drug delivery capability of these carriers was ascertained by using docetaxel as a model drug, whereby the in vitro cytotoxicity of the drug was significantly increased after incorporation in micelles 48 h post incubation. We have also investigated the possible endocytosis route of non-targeted micelles and found that caveolae-mediated endocytosis was the preferred route of uptake. This work strengthens the prospect of using novel bio-based poly(δ-decalactone) micelles as efficient multifunctional drug delivery nanocarriers towards medical applications.

Adriamycin Loaded and Folic Acid Coated Zn-MOF for Tumor-Targeted Chemotherapy of Cervical Cancer

2019 ◽  
Vol 9 (11) ◽  
pp. 1535-1541
Author(s):  
Jing Sun ◽  
Xiang-E Long ◽  
Rong Li ◽  
Chao-Feng Hu ◽  
Xiao-Hong Ge
Keyword(s):  
Folic Acid ◽  
Drug Targeting ◽  
Folate Receptor ◽  
Metal Organic Framework ◽  
Drug Carriers ◽  
Spherical Particles ◽  
Metal Organic ◽  
Cervical Tumors

The drug delivery systems (DDSs) introduced in recent years have been wide recognized to greatly evaluate the efficacy of drugs. With the aim to increase drug targeting to tumors as well as decrease the side effect of both drug and drug carriers, this study has developed a hybrid DDS by incorporation zinc based metal-organic framework (Zn-MOF) and folic acid (FA). Moreover, adriamycin (Adr) as a model anticancer drug was loaded into the FA/Zn-MOF nanoparticle. The as-prepared FA/ZnMOF/Adr was expected to serve as a tumor targeting DDS that capable of effectively delivering Adr to cervical tumors. Characterization revealed that FA/Zn-MOF/Adr was nanosized spherical particles with high stability and biocompatibility. Most importantly, the FA/Zn-MOF/Adr could realize positive targeting to FA overexpressed HeLa cells through folate receptor (FR). Therefore, FA/Zn-MOF/Adr resulted enhanced in vitro and in vivo anticancer benefits than than free Adr or FA unmodified Zn-MOF/Adr.

scholarly journals Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

2014 ◽  
Vol 59 (1) ◽  
pp. 397-406 ◽  
Author(s):  
Tomokazu Yoshinaga ◽  
Masanori Kobayashi ◽  
Takahiro Seki ◽  
Shigeru Miki ◽  
Chiaki Wakasa-Morimoto ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Integrase Inhibitor ◽  
Culture Conditions ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Hiv Replication ◽  
Data Set ◽  
Long Acting ◽  
Anti Hiv

ABSTRACTGSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. Thein vitroantiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

Folate Receptor-Mediated Cancer Cell Specific Gene Delivery Using Folic Acid-Conjugated Oligochitosans

2006 ◽  
Vol 6 (9) ◽  
pp. 2860-2866 ◽  
Author(s):  
Dongwon Lee ◽  
Richard Lockey ◽  
Shyam Mohapatra
Keyword(s):  
Folic Acid ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Cancer Cells ◽  
Transfection Efficiency ◽  
Folate Receptor ◽  
Weight Ratio ◽  
Specific Gene ◽  
Transfer Potential

Chitosan-mediated gene delivery has gained an increasing interest due to its ability to treat cancers and genetic diseases. However, low transfection efficiency and lack of target specificity limit its application for gene and drug delivery. In the present work, folic acid was covalently conjugated to chitosan as a targeting ligand in an attempt to specifically deliver DNA to folate receptor-overexpressing cancer cells. Folic acid-conjugated chitosan (FACN) was successfully synthesized and characterized by 1H-NMR and is biocompatible. In vitro gene transfer potential of FACN was evaluated in human epithelial ovarian cancer OV2008 cells and human breast cancer MCF-7 cells. FACN at a weight ratio of 10 : 1 exhibited significantly (< 0.01) enhanced gene transfer potential in folate receptor-overexpressing cancer cells as compared to unmodified chitosan. Transfection of FACN/pDNA nanocomplexes is competitively inhibited by free folic acid, suggesting the specific gene delivery of FACN/pDNA nanocomplexes is achieved through folate receptor-mediated endocytosis. Taken together, these results demonstrate that FACN provides a promising carrier for cancer gene therapy.

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