Active Targeted Nanoformulations via Folate Receptors: State of the Art and Future Perspectives

In normal tissues, the expression of folate receptors is low and limited to cells that are important for embryonic development or for folate reabsorption. However, in several pathological conditions some cells, such as cancer cells and activated macrophages, overexpress folate receptors (FRs). This overexpression makes them a potential therapeutic target in the treatment of cancer and inflammatory diseases to obtain a selective delivery of drugs at altered cells level, and thus to improve the therapeutic efficacy and decrease the systemic toxicity of the pharmacological treatments. Two strategies have been used to achieve this folate receptor targeting: (i) the use of ligands with high affinity to FRs (e.g., folic acid or anti-FRs monoclonal antibodies) linked to the therapeutic agents or (ii) the use of nanocarriers whose surface is decorated with these ligands and in which the drug is encapsulated. This manuscript analyzes the use of FRs as a target to develop new therapeutic tools in the treatment of cancer and inflammatory diseases with an emphasis on the nanoformulations that have been developed for both therapeutic and imaging purposes.

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Folate Receptor β (FRβ) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1

Cells ◽

10.3390/cells9061445 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1445

Author(s):

Rafael Samaniego ◽

Ángeles Domínguez-Soto ◽

Manohar Ratnam ◽

Takami Matsuyama ◽

Paloma Sánchez-Mateos ◽

...

Keyword(s):

Inflammatory Diseases ◽

Folate Receptor ◽

Regulatory Region ◽

Therapeutic Interventions ◽

Gene Profile ◽

Tumor Associated Macrophages ◽

Human Macrophages ◽

Pathological Conditions ◽

Functional Relevance ◽

Macrophage Subset

As macrophages exhibit a huge functional plasticity under homeostasis and pathological conditions, they have become a therapeutic target for chronic inflammatory diseases. Hence, the identification of macrophage subset-specific markers is a requisite for the development of macrophage-directed therapeutic interventions. In this regard, the macrophage-specific Folate Receptor β (FRβ, encoded by the FOLR2 gene) has been already validated as a target for molecular delivery in cancer as well as in macrophage-targeting therapeutic strategies for chronic inflammatory pathologies. We now show that the transcriptome of human macrophages from healthy and inflamed tissues (tumor; rheumatoid arthritis, RA) share a significant over-representation of the “anti-inflammatory gene set”, which defines the gene profile of M-CSF-dependent IL-10-producing human macrophages (M-MØ). More specifically, FOLR2 expression has been found to strongly correlate with the expression of M-MØ-specific genes in tissue-resident macrophages, tumor-associated macrophages (TAM) and macrophages from inflamed synovium, and also correlates with the presence of the PU.1 transcription factor. In fact, PU.1-binding elements are found upstream of the first exon of FOLR2 and most M-MØ-specific- and TAM-specific genes. The functional relevance of PU.1 binding was demonstrated through analysis of the proximal regulatory region of the FOLR2 gene, whose activity was dependent on a cluster of PU.1-binding sequences. Further, siRNA-mediated knockdown established the importance of PU.1 for FOLR2 gene expression in myeloid cells. Therefore, we provide evidence that FRβ marks tissue-resident macrophages as well as macrophages within inflamed tissues, and its expression is dependent on PU.1.

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microRNAs: Emerging players in oral cancers and inflammatory disorders

Tumor Biology ◽

10.1177/1010428317698379 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831769837 ◽

Cited By ~ 12

Author(s):

Varun Kulkarni ◽

Juhi Raju Uttamani ◽

Afsar Raza Naqvi ◽

Salvador Nares

Keyword(s):

Inflammatory Diseases ◽

Oral Diseases ◽

Clinical Value ◽

Oral Cancers ◽

Pathological Conditions ◽

Therapeutic Value ◽

Human Sera ◽

Therapeutic Tools ◽

Microrna Dysregulation ◽

Potential Use

Association of oral diseases and disorders with altered microRNA profiles is firmly recognized. These evidences support the potential use of microRNAs as therapeutic tools for diagnosis, prognosis, and treatment of various diseases. In this review, we highlight the association of altered microRNA signatures in oral cancers and oral inflammatory diseases. Advances in our ability to detect microRNAs in human sera and saliva further highlight their clinical value as potential biomarkers. We have discussed key mechanisms underlying microRNA dysregulation in pathological conditions. The use of microRNAs in diagnostics and their potential therapeutic value in the treatment of oral diseases are reviewed.

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Preparation and Evaluation of Novel Folate Isonitrile 99mTc Complexes as Potential Tumor Imaging Agents to Target Folate Receptors

Molecules ◽

10.3390/molecules26154552 ◽

2021 ◽

Vol 26 (15) ◽

pp. 4552

Author(s):

Junhong Feng ◽

Xuran Zhang ◽

Qing Ruan ◽

Yuhao Jiang ◽

Junbo Zhang

Keyword(s):

Radiochemical Purity ◽

Tumor Imaging ◽

Folate Receptor ◽

Imaging Agents ◽

Folate Receptors ◽

Biodistribution Studies ◽

Specific Tumor ◽

Folate Receptor Targeting ◽

Preparation And Evaluation

In order to seek novel technetium-99m folate receptor-targeting agents, two folate derivatives (CN5FA and CNPFA) were synthesized and radiolabeled to obtain [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA complexes, which exhibited high radiochemical purity (>95%) without purification, hydrophilicity, and good stability in vitro. The KB cell competitive binding experiments indicated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specificity to folate receptor. Biodistribution studies in KB tumor-bearing mice illustrated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specific tumor uptake. Compared with [99mTc]Tc-CN5FA, the tumor/muscle ratios of [99mTc]Tc-CNPFA were higher, resulting in a better SPECT/CT imaging background. According to the results, the two 99mTc complexes have potential as tumor imaging agents to target folate receptors.

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Surface Ultrastructure of Human Ectocervix in Certain Pathological Conditions

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100119636 ◽

1985 ◽

Vol 43 ◽

pp. 570-571

Author(s):

S. Mukherjee ◽

T. Guha ◽

B. Chakrabarti ◽

P. Chakrabarti

Keyword(s):

Epithelial Cells ◽

Marked Reduction ◽

Squamous Epithelium ◽

Malignant Tumour ◽

Surface Ultrastructure ◽

Normal Tissues ◽

Pathological Conditions ◽

Hexagonal Shape ◽

Columnar Cells ◽

Scanning Electron

The cervix is an important organ in reproduction. Its malfunction is frequently a factor for infertility. Ectocervix region does not appear to have received much attention although many studies have been reported on the endocervix. We report here our SEM observations on ectocervix in certain pathological conditions compared to normal ectocervix.Ectocervix specimens from human females with specific pathological disorders were processed for Scanning Electron Microscopy by conventional method and they were examined in a Philips SEM.The normal ectocervix is lined by flat layer of squamous epithelial cells with microridges (Fig. 1). These cells are known to be formed from columnar cells through metaplastic transformation. The cells of carcinoma-bearing ectocervix show a disorganised appearance (Fig. 2). In non-malignant tumour surface some cuboidal and few columnar cells were seen (Fig. 3). A cyst appears like an overgrowth on the surface of the squamous epithelium (Fig. 4). In ulcerated ectocervix a marked reduction of epithelial cells are observed (Fig. 5); the cells are devoid of microridges and, the large polygonal cells, as observed in normal tissues, have somehow acquired comparatively small hexagonal shape

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Smart Human-Serum-Albumin-As2O3Nanodrug with Self-Amplified Folate Receptor-Targeting Ability for Chronic Myeloid Leukemia Treatment

Angewandte Chemie ◽

10.1002/ange.201701366 ◽

2017 ◽

Vol 129 (36) ◽

pp. 10985-10989 ◽

Cited By ~ 4

Author(s):

Yongbo Peng ◽

Zilong Zhao ◽

Teng Liu ◽

Xiong Li ◽

Xiaoxiao Hu ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Human Serum Albumin ◽

Serum Albumin ◽

Human Serum ◽

Myeloid Leukemia ◽

Folate Receptor ◽

Receptor Targeting ◽

Leukemia Treatment ◽

Targeting Ability ◽

Folate Receptor Targeting

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Folate receptor: a potential target in ovarian cancer

Pteridines ◽

10.1515/pterid-2014-0013 ◽

2015 ◽

Vol 26 (1) ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Marie Bartouskova ◽

Bohuslav Melichar ◽

Beatrice Mohelnikova-Duchonova

Keyword(s):

Ovarian Cancer ◽

Anticancer Agents ◽

Poor Prognosis ◽

Current Knowledge ◽

Folate Receptor ◽

Gynecological Cancer ◽

Predictive Biomarkers ◽

Receptor Expression ◽

Advanced Stage ◽

Potential Therapeutic Target

AbstractOvarian cancer is the most frequent cause of gynecological cancer-related death. Unfortunately, many patients are diagnosed at an advanced stage and have a poor prognosis. The standard treatment for advanced disease involves maximal cytoreductive surgery and chemotherapy based on platinum compounds and taxanes. Patients presenting at an advanced stage have a higher risk of recurrence. The development of drug resistance currently represents a major obstacle in the systematic treatment and, therefore, the discovery of new anticancer agents and approaches should improve the poor prognosis of these patients. Folate receptor α is overexpressed in epithelial ovarian cancer (EOC), but has limited expression in nonmalignant human tissues. The degree of folate receptor expression corresponds with the stage and grade of the disease. Because of this, folate receptor α seems to be a potential therapeutic target for the treatment of ovarian cancer. Currently, several approaches have been studied to target this protein in ovarian cancer treatment. This review summarizes current knowledge about the potential usage of folate receptors as prognostic and predictive biomarkers as well as their role in the management and targeted therapy of ovarian cancer.

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Multifunctional folate receptor-targeting and pH-responsive nanocarriers loaded with methotrexate for treatment of rheumatoid arthritis

International Journal of Nanomedicine ◽

10.2147/ijn.s140992 ◽

2017 ◽

Vol Volume 12 ◽

pp. 6735-6746 ◽

Cited By ~ 31

Author(s):

Jinlong Zhao ◽

Menghui Zhao ◽

Changhui Yu ◽

Xueyan Zhang ◽

Jiaxin Liu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Folate Receptor ◽

Ph Responsive ◽

Receptor Targeting ◽

Folate Receptor Targeting

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The Utility of Iron Chelators in the Management of Inflammatory Disorders

Mediators of Inflammation ◽

10.1155/2015/516740 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 20

Author(s):

C. Lehmann ◽

S. Islam ◽

S. Jarosch ◽

J. Zhou ◽

D. Hoskin ◽

...

Keyword(s):

Inflammatory Diseases ◽

Iron Chelation ◽

Iron Regulation ◽

Human Organism ◽

Iron Availability ◽

Pathological Conditions ◽

Reasonable Approach ◽

Potential Impact ◽

Pharmaceutical Agents

Since iron can contribute to detrimental radical generating processes through the Fenton and Haber-Weiss reactions, it seems to be a reasonable approach to modulate iron-related pathways in inflammation. In the human organism a counterregulatory reduction in iron availability is observed during inflammatory diseases. Under pathological conditions with reduced or increased baseline iron levels different consequences regarding protection or susceptibility to inflammation have to be considered. Given the role of iron in development of inflammatory diseases, pharmaceutical agents targeting this pathway promise to improve the clinical outcome. The objective of this review is to highlight the mechanisms of iron regulation and iron chelation, and to demonstrate the potential impact of this strategy in the management of several acute and chronic inflammatory diseases, including cancer.

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