Folate Receptor Saturation, Recycling, and Release Kinetics in Activated Macrophages

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4655-4655
Author(s):  
Bindu Varghese ◽  
Erina Vlashi ◽  
Philip S. Low
Keyword(s):  
Folic Acid ◽  
Folate Receptor ◽  
Release Kinetics ◽  
Water Soluble ◽  
Imaging Agents ◽  
Activated Macrophages ◽  
Binding Characteristics ◽  
Folate Conjugate ◽  
Made In

Abstract Activated macrophages over-express a receptor for the vitamin, folic acid. Conjugation of folic acid to low molecular weight drugs, genes, liposomes, nanoparticles, and imaging agents does not significantly compromise the vitamin’s affinity for its receptor, thus facilitating both therapeutic and imaging agents to be targeted as folate conjugates to activated macrophages. In these studies the in vivo kinetics and binding characteristics of the folate receptor on macrophages has been characterized with the objective of optimizing targeted drug delivery. Our results show that saturation of the receptor in inflamed tissues can be reached at a dose of 100 nmol/kg. Furthermore, the rapid recycling characteristics of the receptor (every 10–20 minutes) suggests that frequent dosing will allow for maximal uptake of folate conjugates by activated macrophages accumulated in inflamed tissues. Finally, the short circulation half-life (30 minutes) of the water-soluble folate conjugate used in this study minimizes the possibility of nonspecific uptake by receptor-negative tissues. The kinetic observations made in this study can be utilized to optimize the therapeutic efficacy and imaging agent delivery of folate conjugates to activated macrophages in vivo.

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 Synthesis and evaluation of radiolabeled, folic acid-PEG conjugated, amino silane coated magnetic nanoparticles in tumor bearing Balb/C mice

Nukleonika ◽  
2015 ◽  
Vol 60 (3) ◽  
pp. 497-502 ◽  
Author(s):  
Javad Razjouyan ◽  
Hamidreza Zolata ◽  
Omid Khayat ◽  
Fereidoun Nowshiravan ◽  
Nami Shadanpour ◽  
...  
Keyword(s):  
Folic Acid ◽  
Folate Receptor ◽  
Superparamagnetic Iron Oxide ◽  
Fibroblast Cell ◽  
Mouse Fibroblast ◽  
Tumor Uptake ◽  
Mri Imaging ◽  
Tumor Bearing ◽  
Biodistribution Studies

Abstract To design a potent agent for positron emission tomography/magnetic resonance imaging (PET/MRI) imaging and targeted magnetic hyperthermia-radioisotope cancer therapy radiolabeled surface modified superparamagnetic iron oxide nanoparticles (SPIONs) were used as nanocarriers. Folic acid was conjugated for increasing selective cellular binding and internalization through receptor-mediated endocytosis. SPIONs were synthesized by the thermal decomposition of tris (acetylacetonato) iron (III) to achieve narrow and uniform nanoparticles. To increase the biocompatibility of SPIONs, they were coated with (3-aminopropyl) triethoxysilane (APTES), and then conjugated with synthesized folic acid-polyethylene glycol (FA-PEG) through amine group of (3-aminopropyl) triethoxysilane. Finally, the particles were labeled with 64Cu (t1/2 = 12.7 h) using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxy succinimide ester) DOTA-NHS chelator. After the characterization of SPIONs, their cellular internalization was evaluated in folate receptor (FR) overexpressing KB (established from a HeLa cell contamination) and mouse fibroblast cell (MFB) lines. Eventually, active and passive targeting effects of complex were assessed in KB tumor-bearing Balb/C mice through biodistribution studies. Synthesized bare SPIONs had low toxicity effect on healthy cells, but surface modification increased their biocompatibility. Moreover, KB cells viability was reduced when using folate conjugated SPIONs due to FR-mediated endocytosis, while having little effect on healthy cells (MFB). Moreover, this radiotracer had tolerable in vivo characteristics and tumor uptake. In the receptor blocked case, tumor uptake was decreased, indicating FR-specific uptake in tumor tissue while enhanced permeability and retention effect was major mechanism for tumor uptake.

scholarly journals In silico virtual screening-based study of nutraceuticals predicts the therapeutic potentials of folic acid and its derivatives against COVID-19

2020 ◽  
Author(s):  
Vipul Kumar ◽  
Manoj Jena
Keyword(s):  
Folic Acid ◽  
Virtual Screening ◽  
Water Soluble ◽  
Water Soluble Vitamin ◽  
Starting Point ◽  
Cheap Alternative ◽  
Tetrahydrofolic Acid ◽  
Novel Coronavirus

Abstract The recent outbreak of the novel coronavirus (SARS-CoV-2) in the Wuhan province of China has taken millions of lives worldwide. In this pandemic situation and absence of known drugs and vaccines against novel coronavirus disease (COVID-19), there is an urgent need for the repurposing of the existing drugs against it. So, here we have examined a safe and cheap alternative against this virus by screening hundreds of nutraceuticals compounds against known therapeutic targets of SARS-COV-2 by molecular docking .The virtual screening results were then analyzed for binding energy and interactive residues in the best binding pose. All these analyses of this study strongly predicted the potential of Folic acid and its derivates like Tetrahydrofolic acid and 5-methyl tetrahydrofolic acid against SARS-COV-2. The strong and stable binding affinity of this water-soluble vitamin and its derivatives against the SARS-COV-2, indicating that they could be valuable drugs against the management of this COVID-19 pandemic. This study could serve as the starting point for further investigation of these molecules through in-vitro and in-vivo assays.

scholarly journals Targeting CD146 using folic acid–conjugated nanoparticles and suppression of tumor growth in a mouse glioma model

2020 ◽  
pp. 1-11
Author(s):  
Naoki Fukui ◽  
Toshio Yawata ◽  
Takahito Nakajo ◽  
Yu Kawanishi ◽  
Youichirou Higashi ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Folic Acid ◽  
Tumor Growth ◽  
In Vivo Imaging ◽  
Water Soluble ◽  
Therapeutic Effects ◽  
Glioma Model ◽  
Mouse Glioma

OBJECTIVEGlioma stem cells (GSCs) are responsible for tumor initiation, therapeutic resistance, and recurrence. CD146 is mainly expressed in dividing GSCs and regulates cell cycle progression. However, the evaluation of the efficacy of targeted therapy against CD146 in vivo remains to be investigated. In this study, the authors aimed to develop gene therapy targeting GSCs using chitosan oligosaccharide lactate (COL) nanoparticles (NPs) conjugated with folic acid–polyethylene glycol (FA-PEG-COL NPs) for in vitro and in vivo delivery of CD146 small-interfering RNA (siCD146) and to determine the effect of CD146 knockdown on tumor growth.METHODSTo examine the uptake of NPs by tumor cells, immunofluorescence staining, flow cytometry, and in vivo imaging were performed. The knockdown effect of siCD146 was measured by western blot and water-soluble tetrazolium salt–8 assay in mouse glioma cells. The efficacy of siRNA therapy–targeted GSCs was evaluated by monitoring tumor growth through in vivo imaging and histological analysis.RESULTSIn vivo accumulation of the FA-PEG-COL NPs in subcutaneous and intracranial gliomas following NP administration via a mouse tail vein was observed. Additionally, in vitro delivery of siCD146 ionically cross-linked NPs, reduced CD146 levels, and suppressed growth in the glioma tumor sphere. Evaluation of the in vivo therapeutic effects of siCD146–cross-linked NPs in a mouse glioma model revealed significant suppression of intracranial tumor growth, with complete removal of the tumor observed in some mice on histological examination. Furthermore, delivery of siCD146 significantly reduced the Ki-67 index in residual tumor tissues relative to that in control mice.CONCLUSIONSCD146 is a potential therapeutic target, and folic acid–conjugated NPs delivering siRNA may facilitate gene therapy in malignant gliomas.

scholarly journals Folate Receptor-Targeting and Reactive Oxygen Species-Responsive Liposomal Formulation of Methotrexate for Treatment of Rheumatoid Arthritis

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 582 ◽  
Author(s):  
Chen ◽  
Amerigos J.C. ◽  
Su ◽  
Guissi ◽  
Xiao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Reactive Oxygen Species ◽  
Hydrogen Peroxide ◽  
Drug Release ◽  
Cellular Uptake ◽  
Folate Receptor ◽  
Oxygen Species ◽  
Activated Macrophages

Multifunctional nanomedicines with active targeting and stimuli-responsive drug release function utilizing pathophysiological features of the disease are regarded as an effective strategy for treatment of rheumatoid arthritis (RA). Under the inflammatory environment of RA, activated macrophages revealed increased expression of folate receptor and elevated intracellular reactive oxygen species (ROS) level. In this study, we successfully conjugated folate to polyethylene glycol 100 monostearate as film-forming material and further prepared methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes, herein, shortened to FOL-MTX&CAT-L, that could actively target to activated macrophages. Thereafter, elevated intracellular hydrogen peroxide, the main source of ROS, diffused into liposomes and encapsulated CAT catalyzed the decomposition of hydrogen peroxide into oxygen and water. Continuous oxygen-generation inside liposomes would eventually disorganize its structure and release the encapsulated MTX. We characterized the in vitro drug release, cellular uptake and cytotoxicity studies as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety studies of FOL-MTX&CAT-L. In vitro results revealed that FOL-MTX&CAT-L possessed sufficient ROS-sensitive drug release, displayed an improved cellular uptake through folate-mediated endocytosis and exhibited a higher cytotoxic effect on activated RAW264.7 cells. Moreover, in vivo results showed prolonged blood circulation time of PEGylated liposomes, enhanced accumulation of MTX in inflamed joints of collagen-induced arthritis (CIA) mice, reinforced therapeutic efficacy and minimal toxicity toward major organs. These results imply that FOL-MTX&CAT-L may be used as an effective nanomedicine system for RA treatment.

scholarly journals Enhanced Anticancer Efficacy of Dual Drug-Loaded Self-Assembled Nanostructured Lipid Carriers Mediated by pH-Responsive Folic Acid and Human-Derived Cell Penetrating Peptide dNP2

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 600
Author(s):  
Zhe Ma ◽  
Jiaxin Pi ◽  
Ying Zhang ◽  
Huan Qin ◽  
Bing Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Folic Acid ◽  
Cancer Treatment ◽  
Folate Receptor ◽  
Chemotherapeutic Agents ◽  
Cell Penetrating Peptide ◽  
Nanostructured Lipid Carrier ◽  
The Poor ◽  
Cell Penetrating

The poor ability of recognition and penetration of chemotherapeutic agents to tumor cells are still great challenges for targeted breast cancer treatment. Herein, we established a tumor-targeted nanostructured lipid carrier encapsulating gambogic acid (GA) and paclitaxel (PTX), which was co-modified with acid-cleavable folic acid (cFA) and a human-derived cell penetrating peptide dNP2 (CKIKKVKKKGRKKIKKVKKKGRK). The multi-functional nano-platform exhibited an enhanced targeting and penetrability to tumor tissues, which was accomplished by the combined action of cFA and dNP2. After intravenous injection, firstly, cFA could actively target the breast cancer tissues by the selective recognition of folate receptor (FR); then, upon arrival at the tumor microenvironment, the acid-cleavable FA and dNP2 dual modified nanostructured lipid carrier (cFA/dNP2-GA/PTX-NLC) exhibited sensitive cleavage of folic acid (FA), which could reduce the hindrance effect of FA to maximize the dNP2 cell-penetrating properties. The effect of different modification on cellular uptake, in vivo bio-distribution, and anticancer activity of NLCs proved our hypothesis that compared with NLCs modified by non-cleavable FA or a single ligand, cFA/dNP2-GA/PTX-NLC displayed more efficient intracellular delivery, stronger targeting ability in vivo, improved cytotoxicity on 4T1 cells, and produced the better therapeutic efficacy of GA and PTX. The strategy affords a feasible way to overcome the poor recognition and permeability of medicines in cancer treatment.

In Vitro and In Vivo Evaluation of Novel DTX-Loaded Multifunctional Heparin-Based Polymeric Micelles Targeting Folate Receptors and Endosomes

2020 ◽  
Vol 15 (4) ◽  
pp. 341-359
Author(s):  
Moloud Kazemi ◽  
Jaber Emami ◽  
Farshid Hasanzadeh ◽  
Mohsen Minaiyan ◽  
Mina Mirian ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Antitumor Activity ◽  
Cellular Uptake ◽  
Folate Receptor ◽  
Chemotherapeutic Agents ◽  
Water Soluble ◽  
Growth Monitoring ◽  
Tumor Bearing

Background: The development of biocompatible tumor-targeting delivery systems for anticancer agents is essential for efficacious cancer chemotherapy. Nanoparticles, as drug delivery cargoes for cancer therapy, are rapidly improving to overcome the limitations of conventional chemotherapeutic agents. Heparin–modified nanoparticles are currently being considered as one of the favorable carriers for the delivery of chemotherapeutics to cancer tissues. Objective: This study was aimed at evaluating the in vitro and in vivo antitumor activity of a novel targeted, pH-sensitive, heparin-based polymeric micelle loaded with the poorly water-soluble anticancer drug, docetaxel (DTX). The micelles could overcome the limited water solubility, non-specific distribution, and insufficient drug concentration in tumor tissues. Methods: DTX-loaded folate targeted micelles were prepared and evaluated for physicochemical properties, drug release, in vitro cellular uptake and cytotoxicity in folate receptor-positive and folate receptor-negative cells. Furthermore, the antitumor activity of DTX-loaded micelles was evaluated in the tumor-bearing mice. Some related patents were also studied in this research. Results: The heparin-based targeted micelles exhibited higher in vitro cellular uptake and cytotoxicity against folate receptor over-expressed cells due to the specific receptor-mediated endocytosis. DTX-loaded micelles displayed greater antitumor activity, higher anti-angiogenesis effects, and lower systemic toxicity compared with free DTX in a tumor-induced mice model as confirmed by tumor growth monitoring, immunohistochemical evaluation, and body weight shift. DTX-loaded targeting micelles demonstrated no considerable toxicity on major organs of tumor-bearing mice compared with free DTX. Conclusion: Our results indicated that DTX-loaded multifunctional heparin-based micelles with desirable antitumor activity and low toxicity possess great potential as a targeted drug delivery system in the treatment of cancer.

Design, In Silico Modelling, and Functionality Theory of Novel Folate Receptor Targeted Rutin Encapsulated Folic Acid Conjugated Keratin Nanoparticles for Effective Cancer Treatment

2020 ◽  
Vol 19 (16) ◽  
pp. 1966-1982 ◽  
Author(s):  
Selvaraj Kunjiappan ◽  
Theivendren Panneerselvam ◽  
Saravanan Govindaraj ◽  
Pavadai Parasuraman ◽  
Suraj Baskararaj ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Cell Death ◽  
Folic Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Folate Receptor ◽  
Release Kinetics ◽  
Covalent Binding ◽  
Mcf 7

Objective: Site-specific and toxic-free drug delivery, is an interesting area of research. Nanoengineered drug delivery systems possess a remarkable potential for effective treatment of various types of cancers. Methods: In this study, novel Folic Acid (FA) conjugated keratin nanoparticles (NPs) were assembled with encapsulation and delivery of Rutin (Rt) into breast cancer cells through the overexpressed folate receptor. The biocompatible, Rt encapsulated FA conjugated keratin NPs (FA@Ker NPs) were successfully formulated by a modified precipitation technique. Their morphological shape and size, size distribution, stability, and physical nature were characterized and confirmed. The drug (Rt) encapsulation efficiency, loading capacity and release kinetics were also studied. Results: The observed results of molecular docking and density functionality theory of active drug (Rt) showed a strong interaction and non-covalent binding of the folate receptor and facilitation of endocytosis in breast cancer cells. Further, in vitro cytotoxic effect of FA@Ker NPs was screened against MCF-7 cancer cells, at 55.2 µg/mL of NPs and found to display 50% of cell death at 24h. Moreover, the NPs enhanced the uptake of Rt in MCF-7 cells, and the apoptotic effect of condensed nuclei and distorted membrane bodies was observed. Also, NPs entered into the mitochondria of MCF-7 cells and significantly increased the level of ROS which led to cell death. Conclusion: The developed FA@Ker NPs might be a promising way to enhance anti-cancer activity without disturbing normal healthy cells.

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