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Transport systems are developed to improve the solubility of the transported drug, increase its stability, enhance its pharmacological activity and target cancer while minimising side effects. In this work, nanoporous silica particles that can be functionalized and loaded with a large number of hydrophobic molecules are proposed. The designed system was modified with folic acid to target the folic acid receptors of cancer cells. This modification enabled a higher uptake of the drug by the cells. Hypericin was selected as a hydrophobic molecule/drug with photodynamic properties suitable for diagnosis and therapy. Fluorescence microscopy and flow cytometry were used to detect the targeting and distribution of hypericin in the cancer cells. Furthermore, the combination of folic acid and hypericin has been shown to form singlet oxygen and to have a synergistic effect in improving the efficacy of photodynamic therapy. The functionalisation of the particles proposed in this work holds great potential for the delivery of hydrophobic drugs to other types of cancer cells with increased expression of the folic acid receptor to which the particles can be attached., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Folic acid receptor-targeted drug delivery system is a promising candidate for tumor-targeted delivery because its elevated expression specifically on tumor cells enables the selective delivery of cytotoxic cargo to cancerous tissue, thereby minimizing toxic side effects and increasing the therapeutic index. Pyridine bisfolate-chitosan (PyBFA@CS NPs) and folate-chitosan nanocomposite (FA@CS NPs) were synthesized with suitable particle size (256.0 ± 15.0 and 161.0 ± 5.0 nm), high stability (ζ = -27.0 ± 0.1 and -30.0 ± 0.2 mV), respectively, and satisfactory biocompatibility to target cells expressing folate receptors and try to answer the question: Is the metal center always important for activity? Since almost all pharmaceuticals work by binding to specific proteins or DNA, the in vitro binding of human serum albumin (HSA) to PyBFA@CS NPs and FA@CS NPs has been investigated and compared with PyBFA. Strong affinity to HSA is shown by quenching and binding constants in the range of 10 5 and 10 4  M -1 , respectively with PyBFA@CS NPs showing the strongest. The compounds-HSA kinetic stability, affinity, and association constants were investigated using a stopped-flow method. The findings showed that all formulations bind by a static quenching mechanism that consists of two reversible steps: rapid second-order binding and a more slowly first-order isomerization reaction. The overall coordination affinity of HSA to PyBFA@CS NPs (6.6 × 10 6  M -1 ), PyBFA (4.4 × 10 6  M -1 ), and FA@CS NPs (1.3 × 10 6  M -1 ) was measured and The relative reactivity is roughly (PyBFA@CS NPs)/(PyBFA)/(FA@CS NPs) = 5/3/1. Additionally, in vitro cytotoxicity revealed that, consistent with the binding constants and coordination affinity, active-targeting formulations greatly inhibited FR-positive MCF-7 cells in compared to FRs-negative A549 cells in the following trend: PyBFA@CS NPs > PyBFA > FA@CS NPs. Furthermore, in vitro drug release of PyBFA@CS NPs was found to be stable in PBS at pH 7.4, however, the in pH 5.4 and in pH 5.4 containing 10 mM glutathione (GSH) (mimicking the tumor microenvironment) reached 43 % and 73 %, respectively indicating that the PyBFA@CS NPs system is sensitive to GSH. Folate-modified nanoparticles, PyBFA@CS NPs, are a promising therapeutic for MCF-7 therapy because they not only showed a greater affinity for HSA, but also showed higher cleavage efficiency toward the minor groove of pBR322 DNA via the hydrolytic way, as well as effective antibacterial activity that avoids the usage of extra antibiotics.‬‬‬‬‬‬‬‬‬‬‬‬ ‬‬‬‬‬‬‬‬‬‬‬‬‬‬., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Breast cancer presents a significant global health challenge, ranking highest incidence rate among all types of cancers. Functionalised nanocarriers offer a promising solution for precise drug delivery by actively targeting cancer cells through specific receptors, notably folate receptors. By overcoming the limitations of passive targeting in conventional therapies, this approach holds the potential for enhanced treatment efficacy through combination therapy. Encouraging outcomes from studies like in vitro and in vivo , underscore the promise of this innovative approach. This review explores the therapeutic potential of FA (Folic acid) functionalised nanocarriers tailored for breast cancer management, discussing various chemical modification techniques for functionalization. It examines FA-conjugated nanocarriers containing chemotherapeutics to enhance treatment efficacy and addresses the pharmacokinetic aspect of these functionalised nanocarriers. Additionally, the review integrates active targeting via folic acid with theranostics, photothermal therapy, and photodynamic therapy, offering a comprehensive management strategy. Emphasising rigorous experimental validation for practical utility, the review underscores the need to bridge laboratory research to clinical application. While these functionalised nanocarriers show promise, their credibility and applicability in real-world settings necessitate thorough validation for effective clinical use.

DNA synthesis and methylations are crucial during pre-implantation embryonic development, and are mediated by one-carbon metabolism of folates. Folates, transported into the cells via folate receptors (FOLR1 and FOLR2) and carriers (SLC19A1), are metabolized by various enzymes involved in folate-methionine cycle. However, the variations in temporal expression of folate transporters and folate-methionine cycle enzymes during pre-implantation embryo development is obscure. Thus, the present study aimed to investigate the differential expression of the genes for folate transporters and folate-methionine cycle enzymes. We also examined the expression of folate transport proteins in different pre-implantation development stages. Immature buffalo oocytes were matured in maturation medium followed by in vitro fertilization and culture at standard culture conditions. The temporal pattern of gene expression in buffalo, when compared to previous studies, indicated an inter-specific variation. The transcripts of some enzymes and folate transporters were significantly upregulated after zygotic genome activation. The transcripts as well as proteins for FOLR1, FOLR2 and SLC19A1 were present in oocytes and all the pre-implantation embryo stages. FOLR1 was present in the nuclei of different stages of developing embryos but not in the metaphase (MII) oocytes. As a result, the present study advocates the existence of active folate transport in buffalo oocytes and pre-implantation embryos. The data provided by the analysis of differential gene expression of folate transporters and metabolic enzymes would likely contribute to a better understanding of the role of folates in embryo development as well as advancements in assisted reproductive technologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Targeted nanocarriers could reach new levels of drug delivery, bringing new tools for personalized medicine. It is known that cancer cells overexpress folate receptors on the cell surface compared to healthy cells, which could be used to create new nanocarriers with specific targeting moiety. In addition, magnetic nanoparticles can be guided under the influence of an external magnetic field in different areas of the body, allowing their precise localization. The main purpose of this paper was to decorate the surface of magnetic nanoparticles with poly(2-hydroxyethyl methacrylate) (PHEMA) by surface-initiated atomic transfer radical polymerization (SI-ATRP) followed by covalent bonding of folic acid to side groups of the polymer to create a high specificity magnetic nanocarrier with increased internalization capacity in tumor cells. The biocompatibility of the nanocarriers was demonstrated by testing them on the NHDF cell line and folate-dependent internalization capacity was tested on three tumor cell lines: MCF-7, HeLa and HepG2. It has also been shown that a higher concentration of folic acid covalently bound to the polymer leads to a higher internalization in tumor cells compared to healthy cells. Last but not least, magnetic resonance imaging was used to highlight the magnetic properties of the functionalized nanoparticles obtained.

Combined treatments which use nanoparticles and drugs could be a synergistic strategy for the treatment of a variety of cancers to overcome drug resistance, low efficacy, and high-dose-induced systemic toxicity. In this study, the effects on human colon adenocarcinoma cells of surface modified Fe 3 O 4 magnetic nanoparticles (MNPs) in combination with sodium butyrate (NaBu), added as a free formulation, were examined demonstrating that the co-delivery produced a cytotoxic effect on malignant cells. Two different MNP coatings were investigated: a simple polyethylene glycol (PEG) layer and a mixed folic acid (FA) and PEG layer. Our results demonstrated that MNPs with FA (FA-PEG@MNPs) have a better cellular uptake than the ones without FA (PEG@MNPs), probably due to the presence of folate that acts as an activator of folate receptors (FRs) expression. However, in the presence of NaBu, the difference between the two types of MNPs was reduced. These similar behaviors for both MNPs likely occurred because of the differentiation induced by butyrate that increases the uptake of ferromagnetic nanoparticles. Moreover, we observed a strong decrease of cell viability in a NaBu dose-dependent manner. Taking into account these results, the cooperation of multifunctional MNPs with NaBu, taking into consideration the particular cancer-cell properties, can be a valuable tool for future cancer treatment.

Objectives: Proper metabolism of the folate is crucial for maintaining DNA integrity, chromosome structure, methylation, as well as gene expression, and thus, folate is speculated to contribute to the etiology of different disorders. Since the etiology of autism spectrum disorder (ASD) is believed to be influenced by both genetic and environmental factors, we hypothesized that functional single nucleotide polymorphisms (SNPs) affecting folate metabolic pathway may have a causal role in the etiology of ASD. Methods: We analyzed three SNPs, rs2071010, rs2298444 and rs1801198 (in the folate receptor 1, folate receptor 2 and transcobalamin 2, respectively), in 867 ethnically matched subjects including 206 ASD probands and 286 controls. Plasma vitamin B 6 and folate were measured in age-matched probands and controls. Results: ASD probands showed a higher frequency of rs2298444 'A' allele ( P  = 0.01) and genotypes with 'A' allele ( P  = 0.03) when compared with the controls. rs1801198 'C' allele and 'CG' genotype also showed higher occurrence in the probands ( P  = 0.009 and 0.005, respectively). Gender-based stratified analysis revealed a significant higher frequency of rs2298444 'A' allele ( P  = 0.003), genotypes with rs2298444 'A' allele ( P  = 0.003) and rs1801198 CG ( P  = 0.001) in the male probands. Studied variants also showed statistically significant associations with ASD-associated traits measured by the Childhood Autism Rating Scale. ASD subjects exhibited gross deficiency in vitamin B 6 level when compared with age-matched controls ( P  < 0.001), which correlated with risk genetic variants. Discussion: We infer from this pioneering study on eastern Indian subjects that vitamin B 6 deficiency, along with risk gene variants, may affect ASD-associated symptoms, warranting further investigation in large cohorts.

Background: Photodynamic therapy (PDT), a clinical anticancer therapeutic modality, has a long history in clinical cancer treatments since the 1970s. However, PDT has not been widely used largely because of metabolic problems and off-target phototoxicities of the current clinical photosensitizers., Purpose: The objective of the study is to develop a high-efficiency and high-specificity carrier to precisely deliver photosensitizers to tumor sites, aiming at addressing metabolic problems, as well as the systemic damages current clinical photosensitizers are known to cause., Methods: We synthesized a polydopamine (PDA)-based carrier with the modification of folic acid (FA), which is to target the overexpressed folate receptors on tumor surfaces. We used this carrier to load a cationic phthalocyanine-type photosensitizer (Pc) and generated a PDA-FA-Pc nanomedicine. We determined the antitumor effects and the specificity to tumor cell lines in vitro. In addition, we established human cancer-xenografted mice models to evaluate the tumor-targeting property and anticancer efficacies in vivo., Results: Our PDA-FA-Pc nanomedicine demonstrated a high stability in normal physiological conditions, however, could specifically release photosensitizers in acidic conditions, eg, tumor microenvironment and lysosomes in cancer cells. Additionally, PDA-FA-Pc nanomedicine demonstrated a much higher cellular uptake and phototoxicity in cancer cell lines than in healthy cell lines. Moreover, the in vivo imaging data indicated excellent tumor-targeting properties of PDA-FA-Pc nanomedicine in human cancer-xenografted mice. Lastly, PDA-FA-Pc nanomedicine was found to significantly suppress tumor growth within two human cancer-xenografted mice models., Conclusion: Our current study not only demonstrates PDA-FA-Pc nanomedicine as a highly potent and specific anticancer agent, but also suggests a strategy to address the metabolic and specificity problems of clinical photosensitizers., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Yan et al.)

Folic acid (FA), also termed folate, is an essential vitamin for health at all ages since it participates in the biosynthesis of nucleotides, amino acids, neurotransmitters, and certain vitamins. It is therefore crucial for rapidly growing tissues such as those of the fetus. It is becoming clear that FA deficiency and impaired folate pathways are implicated in many diseases of both early life and old age. FA can be transported into the cell by the folate receptor, the reduced folate transporter, and proton-coupled folate transporter. Folate transport proteins are present in certain eye tissues, which explains why FA plays an important role in eye development. The purpose of this literature review is to investigate the evidence relating FA deficiency to eye diseases.

A tumor-targeted, folic acid (FA) conjugated-Auricularia auricular polysaccharide (AAP) -cis-diaminedichloroplatinum (CDDP) complex (FA-AAP-CDDP) was used for cervical carcinoma chemotherapy. The drug delivery system was able to enhance the antitumor potency of CDDP, and to reduce the toxic side effects of CDDP. The kidney of mice treated by FA-AAP-CDDP complex had higher superoxide dismutase, catalase, and glutathione peroxidase activities, and lower malondialdehyde. FA-AAP-CDDP complex could induce more interleukin-2, interleukin-4, and interferon-γ in mice. In addition, the FA-AAP-CDDP complex significantly promoted the expression of Bax and caspase-3 protein, but inhibited the expression of Bcl-2 protein, which activated the mitochondrial apoptotic pathway of tumor cells in nude mice. Moreover, the FA-AAP-CDDP complex had a higher intratumoral accumulation, was lower in the kidneys. This study may provide a new direction for folate receptor targeted polymers to improve anti-tumor activity, but reduce side effects of CDDP., (Copyright © 2017. Published by Elsevier B.V.)

Folate receptors (FR) are over-expressed on a wide variety of tumor cells and are a potential molecular target for radiolabeled folates. In this respect, several SPECT and PET based radiofolates have been evaluated in the past albeit with their high renal uptake posing limitation towards their clinical use. To overcome this, a new 99m Tc labeled folic acid was synthesized via the use of [ 99m TcN(PNP)] 2+ metal fragment, where the presence of the latter pharmacophore redirects in vivo clearance via the hepatobiliary pathway. In this respect, folic acid was derivatized at the γ-acid group with a cysteine BFCA (bifunctional chelating agent) and subsequently reacted with the preformed [ 99m TcN] 2+ intermediate in presence of PNP2 (bisphosphine) ligand, to yield the final complex. While preliminary, in vivo distribution of the complex exhibited high association of activity with liver and intestines and provided support to the rationality of the present design as clearance of labeled folic acid could be effected via the hepatic route, the in vitro studies of the folic acid-cysteine conjugate carried out in KB-31 cells, did not show much promise with reduction in receptor affinity in comparison with the native folic acid. The route followed herein to prepare a folic-acid based radiotracer constitutes the first report of radiolabeling folic acid using the [ 99m TcN(PNP)] 2+ as a radiosynthon. Modification in the structure of conjugate by linking the BFCA through a long-chain linker can be envisaged to improve the affinity of [ 99m TcN(PNP)]-folic acid complex towards FRs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Present work evaluates the potential of a newly synthesized (68)Ga-NOTA-folic acid conjugate for PET imaging of tumors over-expressing folate receptors (FRs). NOTA-folic acid conjugate was synthesized and characterized. It was radiolabeled with (68)Ga in ≥ 95% radiolabeling yields. In vitro cell binding studies showed a maximum cell uptake of 1.7±0.4% per million KB cells which was completely blocked on addition of cold folic acid showing specificity towards the FRs. However, further studies in tumor xenografts are warranted in order to assess the potential of (68)Ga-folic acid complex for imaging tumors over-expressing FRs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In this work, based on terminal protection of folate-linked ssDNA (FA-ssDNA) and the SYBR Gold fluorescent dye, we describe the development of a label-free fluorescent strategy for the detection of folate receptors (FRs). The binding between the target FR and the FA moiety of the FA-ssDNA protects the FR bound FA-ssDNA from digesting by Exo I. The binding of SYBR Gold to the terminal protected, un-digested FA-ssDNA leads to enhanced fluorescent emission for the monitoring of FR with a detection limit of 30 pM. Besides, the developed method also shows high selectivity toward FR against other control proteins. Moreover, our approach avoids the labeling of the probes with fluorescent tags and achieves label-free detection of FR. With these advantages, the proposed method thus holds promising potential for the development of simple and convenient strategies for the detection of other proteins by using different small molecule receptor/protein ligand pairs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aim: Development and evaluation of a new targeted gene delivery system by first preforming self-assembled nanocomplexes from a polycationic amphiphilic cyclodextrin (paCD) and pDNA and then decorating the surface of the nanoparticles with folic acid (FA)., Experimental Section: The cyclodextrin derivative (T2) is a tetradecacationic structure incorporating 14 primary amino groups and 7 thioureido groups at the primary face of a cyclomaltoheptaose (β-CD) core and 14 hexanoyl chains at the secondary face., Results and Conclusions: T2 complexed and protected pDNA (luciferase-encoding plasmid DNA, pCMVLuc) and efficiently mediated transfection in vitro and in vivo with no associated toxicity. The combination of folic acid with CDplexes afforded ternary nanocomplexes (Fol-CDplexes) that enhanced significantly the transfection activity of pCMVLuc in human cervix adenocarcinoma HeLa cells, especially when formulated with 1 μg FA/μg DNA. The observed transfection enhancement was associated to specific folate receptor (FR)-mediated internalization of Fol-CDplexes, as corroborated by employing a receptor-deficient cell line (HepG2) and an excess of free folic acid. The in vivo studies, including luciferase reporter gene expression and biodistribution, indicated that 24h after intravenous administration of the T2-pDNA nanocomplexes, transfection takes part mainly in the liver and partially in the lung. Interestingly, the corresponding Fol-CDplexes lead to an increase in the transfection activity in the lung and the liver compared to non-targeted CDplexes. Folate-CDplexes developed in this study have improved transfection efficiency and although various methods have been used for the preparation of ligand-DNA-complexes, covalent binding is usually needed and insoluble aggregates are formed unless the concentration of the components is minimized. However, the complexes developed by first time in this work were prepared by simple mixing. The synthetic nature of this formulation provides the potential of flexibility in terms of composition and the capability of inexpensive and large-scale production of the complexes. These nanovectors may be an adequate alternative to viral vectors for gene therapy in the future., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Folate therapy reduces, but does not normalize homocysteine (Hcy) levels, frequently elevated in chronic kidney disease (CKD). The mechanisms of this folate resistance are unknown. Cellular acquisition of folate is mediated by folate receptors (FRs), whose expression is also modulated by folate status, through an Hcy-dependent regulation mechanism involving heterogeneous nuclear ribonucleoprotein-E1 (hnRNP-E1). Our objective was to evaluate whether an alteration of the FR2 (the form present in nucleated blood cells) expression is present in CKD patients on haemodialysis (HD), and its susceptibility to folate treatment., Methods: A population of chronic uraemic patients on HD was enrolled, along with a control group, and studies on FR2 receptor expression and related items were performed in plasma and mononuclear cells from peripheral blood. A subgroup of patients was treated with methyltetrahydrofolate for 1 month., Results: In HD, there was a significant reduction in FR2 protein expression compared with controls, not correlated with Hcy concentrations, while its mRNA levels were significantly increased. After folate treatment, there was a significant mRNA decrease, in the absence of significant changes in receptor protein expression. hnRNP-E1 gene and protein expression levels increased pre-treatment, while decreased post-treatment., Conclusions: In HD, FR2 expression is altered in peripheral mononuclear cells, since its levels are decreased and are not responsive to variations in Hcy concentration, while the intracellular machinery (receptor mRNA and hnRNP-E1), possibly triggering its regulation, is conserved. These findings provide insight into the mechanisms of folate resistance in uraemia.

The sensitive determination of folate receptors (FRs) in the early stages of cancer is of great significance for controlling the progression of cancerous cells. Many folic acid (FA)-based electrochemical biosensors have been utilized to detect FRs with promising performances, but most were complicated, non-reproducible, non-biocompatible, and time and cost consuming. Here, we developed an environmentally friendly and sensitive biosensor for FR detection. We proposed an electrochemical impedimetric biosensor formed by nanofibers (NFs) of bio-copolymers prepared by electrospinning. The biosensor combines the advantages of bio-friendly polymers, such as sodium alginate (SA) and polyethylene oxide (PEO) as an antifouling polymer, with FA as a biorecognition element. The NF nanocomposites were characterized using various techniques, including SEM, FTIR, zeta potential (ZP), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). We evaluated the performance of the NF biosensor using EIS and demonstrated FR detection in plasma with a limit of detection of 3 pM. Furthermore, the biosensor showed high selectivity, reliability, and good stability when stored for two months. This biosensor was constructed from 'green credentials' holding polymers that are highly needed in the new paradigm shift in the medical industry. [ABSTRACT FROM AUTHOR]

Targeting folate receptors is a potential solution to low tumor selectivity concerning conventional chemotherapeutics. Apart from antibody–drug conjugates, folate-functionalized nanoparticle drug delivery systems are interesting to be explored due to many advantages, yet currently, none seems to enter the clinical trials. Multiple in vitro evidence is available to support its efficacy compared to the non-targeting carrier and free drug formulation. Additionally, several studies pointed out factors affecting its effectiveness, including surface properties and endosomal trapping. However, in vivo biodistribution studies revealed issues that may arise from folate receptor targeting, including rapid liver uptake, subsequently reducing the nanoparticles' tumor uptake. This issue may be due to the folate receptor β expressed by the activated macrophages in the liver; route of administration and tumor location might also influence the targeting effectiveness. Moreover, it is perplexing to generalize nanoparticles reported from various publications, primarily due to the different formulations, lack of characterization, and experimental settings, making it harder to determine the accurate factor influencing targeting effectiveness. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the fourth most common cancer worldwide and the third most frequently diagnosed form of cancer associated with high mortality rates. Recently, targeted drug delivery systems have been under increasing attention owing to advantages such as high therapeutic effectiveness with a significant depletion in adverse events. In this report, we describe the biocompatible and thermoresponsive FA-conjugated PHEA-b-PNIPAAm copolymers as nanocarriers for the delivery of 5-FU. The block copolymers were obtained using RAFT (Reversible Addition–Fragmentation chain Transfer) polymerization and were characterized by methods such as SEC (Size Exclusion Chromatography), NMR (Nuclear Magnetic Resonance), UV–Vis (Ultraviolet–Visible), FT-IR (Fourier Transform Infrared) spectroscopy, and TGA (Thermogravimetric Analysis). Nanoparticles were formed from polymers with and without the drug-5-fluorouracil, which was confirmed using DLS (Dynamic Light Scattering), zeta potential measurements, and TEM (Transmission Electron Microscopy) imaging. The cloud points of the polymers were found to be close to the temperature of the human body. Eventually, polymeric carriers were tested as drug delivery systems for the safety, compatibility, and targeting of colorectal cancer cells (CRC). The biological evaluation indicated high compatibility with the representative host cells. Furthermore, it showed that proposed nanosystems might have therapeutic potential as mitigators for 5-FU-induced monocytopenia, cardiotoxicity, and other chemotherapy-associated disorders. Moreover, results show increased cytotoxicity against cancer cells compared to the drug, including a line with a drug resistance phenotype. Additionally, the ability of synthesized carriers to induce apoptosis and necrosis in treated CRC cells has been confirmed. Undoubtedly, the presented aspects of colorectal cancer therapy promise future solutions to overcome the conventional limitations of current treatment regimens for this type of cancer and to improve the quality of life of the patients. [ABSTRACT FROM AUTHOR]

Targeting folate receptors is a potential solution to low tumor selectivity concerning conventional chemotherapeutics. Apart from antibody–drug conjugates, folate-functionalized nanoparticle drug delivery systems are interesting to be explored due to many advantages, yet currently, none seems to enter the clinical trials. Multiple in vitro evidence is available to support its efficacy compared to the non-targeting carrier and free drug formulation. Additionally, several studies pointed out factors affecting its effectiveness, including surface properties and endosomal trapping. However, in vivo biodistribution studies revealed issues that may arise from folate receptor targeting, including rapid liver uptake, subsequently reducing the nanoparticles’ tumor uptake. This issue may be due to the folate receptor β expressed by the activated macrophages in the liver; route of administration and tumor location might also influence the targeting effectiveness. Moreover, it is perplexing to generalize nanoparticles reported from various publications, primarily due to the different formulations, lack of characterization, and experimental settings, making it harder to determine the accurate factor influencing targeting effectiveness.

The conjugation of chitosan (CS) and folic acid (FA) was prepared and used to coat PLGA nanoparticles (NPs) that are loaded with Docetaxel (DTX) to target cancer cells that have lower pH and overexpression of folate receptors in comparison to normal cells. Three formulations had been prepared to reach the highest loading capacity (LC%) and encapsulation efficiency (EE%) and to study the effect of the amount of FA-CS on the drug release. The sizes, charges, homogeneity, surface morphology, LC% and EE% of the NPs were determined. The NPs were characterized using FTIR and XRD. In vitro release profiles of DTX from PLGA NPs, at pH 5.5 and 7.4 were determined. Finally, in vitro cytotoxicity assay on three cancer cell lines (RPMI 2650, Calu-3, and A549) was studied. The sizes of the three formulations ranged between 250.3±1.7 and 356.3±17.7. All prepared formulations showed acceptable monodispersity with highly positive charges. The EE% was above 85% and the LC% ranged between 6-35%. The in vitro release of DTX show an inverse relation to the amounts of FA-CS used and the pH of the dissolution medium. Coated PLGA NPs showed a significant difference in RPMI 2650, Calu-3, and A549 cell viability in comparison to free DTX. The NPs components were safe and non-toxic to human cells. In conclusion, coating PLGA NPs with FA-CS may be used as a good carrier for chemotherapeutic agents that selectively target carcinogenic tissues. [ABSTRACT FROM AUTHOR]

The quantitative detection of cancer cells and the evaluation of folate receptor (FR) expression on cell membranes are of great significance for tumor‐related research. In this work, a photoelectrochemical (PEC) biosensing interface is proposed for detection of cancer cells based on the construction of nanostructured platforms coupled with surface engineering. A "sphere‐on‐tube" hierarchical nanostructure is fabricated by depositing biomimetic polydopamine nanospheres on TiO2 nanotube arrays. Enhanced PEC responses are achieved with the formation of polyethylene glycol antifouling layers and the immobilization of folic acid as a recognition ligand. Based on the ligand–receptor interaction, the antifouling PEC biosensor exhibits a wide linear range for the detection of the breast cancer cell line MDA‐MB‐231 from 20 to 2.0 × 106 cells mL−1 with a low detection limit of 15 cells mL−1 (S/N = 3). The expressing differentiation of FR on several cancer cells is well discriminated. The proposed PEC cytosensing method shows great potential in detection of cancer cells expressing folate receptors. [ABSTRACT FROM AUTHOR]

Strategic design and synthesis of nanoparticle based preparations could improve diagnostic screening of several cancer types, thereby facilitating better clinical management of the disease. Towards this, the present work aims to develop and evaluate a radioactive technetium-99m (99mTc) labeled gold nanoparticle (NP) preparation modified with folic acid, so as to diagnose folate receptor positive cancers viz. ovarian, breast, etc. 11-Bromoundecanoic acid (UA) was synthetically modified both with folic acid and Hydrazinonicotinic acid (HYNIC) chelate at the carboxylic acid end and subsequently converted to thiol functionality at the bromo terminal to yield folic acid-UA-SH and HYNIC-UA-SH ligands respectively. Gold NPs modified with folic acid and HYNIC chelator were obtained on direct addition of folic acid-UA-SH and HYNIC-UA-SH to chloroauric acid in polysorbate 80 solution under reducing conditions. These NPs were then radiolabeled with 99mTc following HYNIC labeling approach. Both the inactive and 99mTc-labeled gold NPs were then tested for their biological efficacy in folate receptor (FR) positive KB cancer cell lines. Also, biodistribution studies of 99mTc-labeled gold NPs were carried in KB tumor xenografts to ascertain the efficacy towards FR in in vivo system. Polysorbate 80 could stabilize the gold NP preparation with average size <10 nm as determined by TEM. Inhibition of 3H]folic acid with functionalized gold nanoparticle revealed affinity towards FR positive KB cell lines with an IC 50 ~ 9 μM. Biodistribution studies of 99mTc-labeled gold NP preparation in SCID mice bearing KB tumor showed an uptake of 1.39 ± 0.18%ID/g in tumor and 5.48 ± 0.72%ID/g in kidneys at 3 h post-injection. In vivo distribution in folic acid pre-treated animals could not establish the specificity towards folate receptors. Biological evaluation of functionalized gold NP showed affinity towards FR positive cancer cell lines. 99mTc-labeled NP exhibited target uptake in both in vitro and in vivo models, but folic acid inhibition could not establish the target specificity. Nevertheless, in vivo pharmacokinetics envisaged in the present design was achieved using the present gold functionalized NP preparation. [ABSTRACT FROM AUTHOR]

Folic acid (FA), also termed folate, is an essential vitamin for health at all ages since it participates in the biosynthesis of nucleotides, amino acids, neurotransmitters, and certain vitamins. It is therefore crucial for rapidly growing tissues such as those of the fetus. It is becoming clear that FA deficiency and impaired folate pathways are implicated in many diseases of both early life and old age. FA can be transported into the cell by the folate receptor, the reduced folate transporter, and proton-coupled folate transporter. Folate transport proteins are present in certain eye tissues, which explains why FA plays an important role in eye development. The purpose of this literature review is to investigate the evidence relating FA deficiency to eye diseases. [ABSTRACT FROM AUTHOR]

Since the overexpression of folate receptors (FRs) in certain types of cancers, a variety of FR-targeted fluorescent probes for tumor detection have been developed. However, the reported probes almost all have the same targeting ligand of folic acid with various fluorophores and/or linkers. In the present study, a series of novel tumor-targeted near-infrared (NIR) molecular fluorescent probes were designed and synthesized based on previously reported 6-substituted pyrrolo[2,3- d ]pyrimidine antifolates. All newly synthesized probes showed specific FR binding in vitro , whereas GT-NIR-4 and GT-NIR-5 with a benzene and a thiophene ring, respectively, on the side chain of pyrrolo[2,3- d ]pyrimidine exhibited better FR binding affinity than that of GT-NIR-6 with folic acid as targeting ligand. GT-NIR-4 also showed high tumor uptake in KB tumor-bearing mice with good pharmacokinetic properties and biological safety. This work demonstrates the first attempt to replace folic acid with antifolates as targeting ligands for tumor-targeted NIR probes. We first attempted to replace folic acid with antifolates as targeting ligands to design and synthesize novel tumor-targeted Near-Infrared probes. [Display omitted] • Developed a series of novel tumor targeting near-infrared fluorescence probes mediated by folate receptors for fluorescence guided surgery. • This was the first attempt to replace folic acid with pyrrolo[2,3- d ]pyrimidine antifolates as targeting ligands for tumor-targeted NIR probes. • Both in vitro and in vivo investigations revealed that the probe GT-NIR-4 exhibited high FR binding avidity. [ABSTRACT FROM AUTHOR]

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors.

A glycosylphosphatidylinositol (GPI)-anchored glycoprotein called the folate receptor 1 (FOLR1) facilitates the transportation of folate by mediating receptor-mediated endocytosis in response to ligand binding. While FOLR1 expression is typically restricted to the apical surfaces of the epithelium in the lung, kidney, and choroid plexus in healthy people, it is overexpressed in a number of solid tumours, including high-grade osteosarcoma, breast cancer, ovarian cancer, and non-small cell lung cancer. As a result, FOLR1 has become an attractive target for cancer detection and therapy, particularly for cancers that affect women. A number of methods have been developed to target FOLR1 in cancer therapy, including the development of FOLR1-targeted imaging agents for cancer diagnosis and the use of folate conjugates to deliver cytotoxic agents to cancer cells that overexpress FOLR1. Therefore, we focus on the most recent developments in employing FOLR1 for cancer diagnosis and treatment in this review, particularly with regard to cancers that affect women. [Display omitted] [ABSTRACT FROM AUTHOR]

The effect of folic acid (FA) on breast cancer (BC) risk is uncertain. We hypothesised that this uncertainty may be due, in part, to differential effects of FA between BC cells with different phenotypes. To test this we investigated the effect of treatment with FA concentrations within the range of unmetabolised FA reported in humans on the expression of the transcriptome of non-transformed (MCF10A) and cancerous (MCF7 and Hs578T) BC cells. The total number of transcripts altered was: MCF10A, seventy-five (seventy up-regulated); MCF7, twenty-four (fourteen up-regulated); and Hs578T, 328 (156 up-regulated). Only the cancer-associated gene TAGLN was altered by FA in all three cell lines. In MCF10A and Hs578T cells, FA treatment decreased pathways associated with apoptosis, cell death and senescence, but increased those associated with cell proliferation. The folate transporters SLC19A1, SLC46A1 and FOLR1 were differentially expressed between cell lines tested. However, the level of expression was not altered by FA treatment. These findings suggest that physiological concentrations of FA can induce cell type-specific changes in gene regulation in a manner that is consistent with proliferative phenotype. This has implications for understanding the role of FA in BC risk. In addition, these findings support the suggestion that differences in gene expression induced by FA may involve differential activities of folate transporters. Together these findings indicate the need for further studies of the effect of FA on BC.

The proton-coupled folate transporter (PCFT-SLC46A1) is the mechanism by which folates are absorbed across the brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder “hereditary folate malabsorption” (HFM), results in a syndrome characterized by severe systemic and cerebral folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in “cerebral folate deficiency” (CFD), the designation for this disorder. This paper reviews the current understanding of the functional and structural properties and regulation of PCFT, an electrogenic proton symporter, and contrasts PCFT properties with those of the reduced folate carrier (RFC), an organic anion antiporter, that is the major route of folate transport to systemic tissues. The clinical characteristics of HFM and its treatment, based upon the thirty-seven known cases with the clinical syndrome, of which thirty have been verified by genotype, are presented. The ways in which PCFT and FRα might interact at the level of the choroid plexus such that each is required for folate transport from blood to cerebrospinal fluid are considered along with the different clinical presentations of HFM and CFD. [ABSTRACT FROM AUTHOR]

The effect of folic acid (FA) on breast cancer (BC) risk is uncertain. We hypothesised that this uncertainty may be due, in part, to differential effects of FA between BC cells with different phenotypes. To test this we investigated the effect of treatment with FA concentrations within the range of unmetabolised FA reported in humans on the expression of the transcriptome of non-transformed (MCF10A) and cancerous (MCF7 and Hs578T) BC cells. The total number of transcripts altered was: MCF10A, seventy-five (seventy up-regulated); MCF7, twenty-four (fourteen up-regulated); and Hs578T, 328 (156 upregulated). Only the cancer-associated gene TAGLN was altered by FA in all three cell lines. In MCF10A and Hs578T cells, FA treatment decreased pathways associated with apoptosis, cell death and senescence, but increased those associated with cell proliferation. The folate transporters SLC19A1, SLC46A1 and FOLR1 were differentially expressed between cell lines tested. However, the level of expression was not altered by FA treatment. These findings suggest that physiological concentrations of FA can induce cell type-specific changes in gene regulation in a manner that is consistent with proliferative phenotype. This has implications for understanding the role of FA in BC risk. In addition, these findings support the suggestion that differences in gene expression induced by FA may involve differential activities of folate transporters. Together these findings indicate the need for further studies of the effect of FA on BC. [ABSTRACT FROM AUTHOR]

Folate is essential for fetal development, and its deficiency during gestation causes behavioural deficits in the offspring. The present study investigated its influence during weaning on brain function in the pups of rats that were put on a folate-deficient (FD) diet on postnatal day (PND) 1. Systemic folate deficiency in pups on the FD diet (n 15) was evident from the dramatically lower hepatic folate concentrations (median 23·7, range 8·1–48·4 ng/mg protein) and higher homocysteine concentrations (median 27·7, range 14·7–45·5 pmol/mg protein), respectively, compared with those of pups on the normal diet (ND; n 9) (median 114·5, range 64·5–158·5 ng/mg protein and median 15·5, range 11·6–18·9 pmol/mg protein) on PND 23. Brain folate concentrations although low were similar in pups on the FD diet (median 10·5, range 5·5–24·5 ng/mg protein) and ND (median 11·1, range 7·1–24·2 ng/mg protein). There was a high accumulation of homocysteine in the brain of FD pups, mostly in the hippocampus (median 58·1, range 40·8–99·7 pmol/mg protein) and cerebellum (median 69·1, range 50·8–126·6 pmol/mg protein), indicating metabolic folate deficiency despite normal brain folate concentrations. Developmental deficits or autistic traits were more frequent in the FD group than in the ND group and repetitive self-grooming occurred, on average, three times (range 1–8) v. once (range 0–3) during 5 min, respectively. Long-term memory or spatial learning and set-shifting deficits affected 12 to 62 % of rats in the FD group compared with none in the ND group. Post-weaning folic acid supplementation did not correct these deficits. These observations indicate that folate deficiency during weaning affects postnatal development even when gestational folate supply is normal. [ABSTRACT FROM PUBLISHER]

Since recombinant viral vectors have been associated with serious side effects, such as immunogenicity and oncogenicity, synthetic delivery systems represent a realistic alternative for achieving efficacy in gene therapy. A major challenge for non-viral nanocarriers is the optimization of transgene expression in the targeted cells. This goal can be achieved by fine-tuning the chemical carriers and the adding specific motifs to promote cellular penetration. Our study focuses on the development of novel folate-based complexes that contain varying quantities of folate motifs. After controlling for their physical properties, neutral folate-modified lipid formulations were compared in vitro to lipoplexes leading to comparable expression levels. In addition, no cytotoxicity was detected, unlike what was observed in the cationic controls. Mechanistically, the delivery of the transgene appeared to be, in part, due to endocytosis mediated by folate receptor targeting. This mechanism was further validated by the observation that adding free folate into the medium decreased luciferase expression by 50%. In vivo transfection with the folate-modified MM18 lipid, containing the highest amount of FA-PEG570-diether co-lipid (w:w; 90:10), at a neutral charge ratio, gave luciferase transgene expression. These studies indicate that modification of lipids with folate residues could enhance non-toxic, cell-specific gene delivery. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Thymidylate synthase and folate receptors are well-developed targets of cancer therapy. Discovery of a simple and fast method for the conversion of 11CH3Ito[11C]-formaldehyde (11CH2O) encouraged us to label the co-factor of this enzyme. Preliminary studies conducted on cell lines have demonstrated a preferential uptake of [11-14C]-(R)-N 5,N 10-methylene-5,6,7,8-tetrahydrofolate (14CH2H4folate) by cancerous cell vs. normal cells from the same organ (Saeed M., Sheff D. and Kohen A. Novel positron emission tomography tracer distinguishes normal from cancerous cells. J Biol Chem 2011;286:33872–33878), pointing out 11CH2H4folate as a positron emission tomography (PET) tracer for cancer imaging. Herein we report the synthesis of 11CH2H4folate, which may serve as a potential PET tracer. Methods: In a remotely controlled module, methyl iodide (11CH3I) was bubbled into a reaction vial containing trimethylamine N-oxide in N,N-Dimethylformamide (DMF) and heated to 70°C for 2 min. Formaldehyde (11CH2O) formed after the completion of reaction was then mixed with a solution of freshly prepared tetrahydrofolate (H4folate) by using a fast chemoenzymatic approach to accomplish synthesis of 11CH2H4folate. Purification of the product was carried out by loading the crude reaction mixture on a SAX cartridge, washing with water to remove unbound impurities and finally eluting with a saline solution. Results: The synthesis and purification of 11CH2H4folate were completed within 5 min. High-performance liquid chromatography analysis of the product after SAX purification indicates that more than 90% of the radioactivity that was retained on the SAX cartridge was in 11CH2H4folate, with minor (<10%) radioactivity due to unreacted 11CH2O. Conclusion: We present a fast (∼5 min) synthesis and purification of 11CH2H4folate as a potential PET tracer. The final product is received in physiologically compatible buffer (100 mM sodium phosphate, pH 7.0 containing 500 mM NaCl) and ready for use in vivo. [Copyright &y& Elsevier]

The over-expression of folate receptors in variety of neoplastic tissues makes radiolabeled folate conjugates potential agents for imaging and therapy of such cancers. With the aim of preparing an imaging agent for targeting folate receptors, folic acid has been conjugated with homocysteine for complexation with [Tc(CO)(HO)] core. The radiolabeled complex of the homocysteine-folate could be obtained in >95% radiochemical yield as observed by HPLC. Stability of complex in saline was studied and challenge studies with histidine and cysteine revealed kinetic stability of the complex. Lipophilicity of the radiolabeled complex (log P) was found to be 0.45. In vitro uptake of Tc(CO)-labeled folic acid derivative was studied in KB cells and inhibition studies were carried out using H-folic acid and cold homocysteine-folate conjugate. The in vitro studies indicated loss of binding affinity of the derivative towards folate receptors. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to analyze the diagnostic and clinical role of the folate receptor-α (FOLR1) and folate receptor-γ (FOLR3) genes in effusion cytology. Expression of the FOLR1 protein product, FR-α, was additionally studied. Ninety-one effusions (71 ovarian carcinomas, 10 breast carcinomas, 10 malignant mesotheliomas) were assayed for FOLR1 and FOLR3 gene expression using quantitative polymerase chain reaction. FR-α expression was analyzed using flow cytometry. Ovarian carcinoma expression levels were analyzed for association with clinicopathologic parameters and survival. Quantitative polymerase chain reaction analysis showed significantly higher FOLR1and FOLR3 mRNA levels in ovarian carcinomas compared with both breast carcinomas and mesotheliomas (P < .001). FOLR1 and FOLR3 mRNA levels were directly interrelated in ovarian carcinoma (P < .001). FR-α protein levels were similarly higher in ovarian carcinoma compared with the 2 other cancer types (P < .001). FOLR1and FOLR3 mRNA and FR-α protein expression in ovarian carcinoma effusions showed no association with clinical parameters or survival. Our data suggest that folate receptor levels effectively differentiate ovarian carcinoma from other cancers affecting the serosal cavities and that folate receptor genes are coexpressed in this tumor. The high expression of folate receptors in ovarian carcinoma supports their validity as molecular therapeutic targets in this disease. [Copyright &y& Elsevier]

Cell membrane-associated folate receptors are selectively overexpressed in certain human tumors. The high affinity of folic acid for folate receptors provides a unique opportunity to use folic acid as a targeting ligand to deliver chemotherapeutic agents to cancer cells. Folate-tethered liposomes bearing pteroyl-γ-glutamate-cysteine-polyethylene glycol (PEG)-distearoylphosphatidylethanolamine (DSPE) as the targeting component are under investigation as mediators of drug and gene delivery to cancer cells that overexpress folate receptors. Pteroyl-γ-glutamate-cysteine synthesis is one of the crucial starting steps in the preparation of pteroyl-γ-glutamate-cysteine-PEG-DSPE. However, published methods for the synthesis of pteroyl-γ-glutamate-cysteine provide low yields and are not easily reproducible. Therefore, we developed a modified synthetic method for the removal of the N10-trifluoroacetyl group after cleavage/deprotection that is reliable, is easily reproducible, and has high yield (38%) compared with an unreliable yield of 3–20% with the earlier methods. Folate-tethered liposomes containing calcein or doxorubicin were prepared using pteroyl-γ-glutamate-cysteine-PEG-DSPE as the targeting component along with nontargeted liposomes with PEG-DSPE. The results of the uptake of calcein and cytotoxicity of doxorubicin in human cervical cancer HeLa-IU1 cells and human colon cancer Caco-2 cells demonstrated that folate-tethered liposomes were efficient in selective delivery to cancer cells overexpressing folate receptors. The improvement in yield of the targeting component can significantly facilitate “scale up” of folate receptor-mediated liposomal cancer therapy to the preclinical and clinical levels of investigations. [Copyright &y& Elsevier]

Targeted nanocarriers could reach new levels of drug delivery, bringing new tools for personalized medicine. It is known that cancer cells overexpress folate receptors on the cell surface compared to healthy cells, which could be used to create new nanocarriers with specific targeting moiety. In addition, magnetic nanoparticles can be guided under the influence of an external magnetic field in different areas of the body, allowing their precise localization. The main purpose of this paper was to decorate the surface of magnetic nanoparticles with poly(2-hydroxyethyl methacrylate) (PHEMA) by surface-initiated atomic transfer radical polymerization (SI-ATRP) followed by covalent bonding of folic acid to side groups of the polymer to create a high specificity magnetic nanocarrier with increased internalization capacity in tumor cells. The biocompatibility of the nanocarriers was demonstrated by testing them on the NHDF cell line and folate-dependent internalization capacity was tested on three tumor cell lines: MCF-7, HeLa and HepG2. It has also been shown that a higher concentration of folic acid covalently bound to the polymer leads to a higher internalization in tumor cells compared to healthy cells. Last but not least, magnetic resonance imaging was used to highlight the magnetic properties of the functionalized nanoparticles obtained. [ABSTRACT FROM AUTHOR]

• LNC-L-CS-Zn2+-DOX-FA reduced cell viability, migration, and colony formation1 • qRT-PCR analysis showed that LNC-L-CS-Zn2+-DOX-FA induced apoptosis of MDA-MB-231 cells. • LNC-L-CS-Zn2+-DOX-FA showed high uptake in MDA-MB-231 cells. Breast cancer is the most common cancers among women and is one of the main causes of morbidity and mortality in this population. In this study, we aimed to conjugate doxorubicin (DOX), a drug widely used in cancer chemotherapy, and folic acid (FA), a ligand targeted for cancer therapy, to lipid-core nanocapsules (LNC), and evaluate the efficacy of the nanoformulation against triple-negative breast cancer (TNBC) MDA-MB-231 cells that overexpress folate receptors (FRs). We performed cell viability assays, quantitative real-time PCR (qRT-PCR), cell migration assay, and clonogenic assay, as well as measured the levels of nitric oxide (NO) generated and cellular uptake. The results showed that the nanoformulation reduced cell viability. The results of qRT-PCR analysis revealed that the nanoformulation induced apoptosis of MDA-MB-231 cells. The mRNA expression levels of Cat and MnSod were increased when the nanoformulation was compared to the doxorubicin solution. Furthermore, the nanoformulation significantly decreased the migration of breast cancer cells in vitro and inhibited colony formation. Additionally, the expression of iNOS in MDA-MB-231 cells was higher when the nanoformulation was used compared to the doxorubicin solution. Cellular uptake was observed after incubating the MDA-MB-231 cells with the fluorescent-labeled nanoformulation. In conclusion, we developed a promising nanoformulation for the treatment of TNBC. Further studies are necessary to demonstrate the in vivo efficacy of this formulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors. [ABSTRACT FROM AUTHOR]

Folic acid, due to its high affinity toward folate receptors (FR), is recognized as one of the most promising cancer targeting vectors. However, the inherent defects of low water solubility (1.6 µg mL−1), high sensitivity toward photo‐bleaching, low fluorescent quantum yields (QYs, <0.5%) seriously limit its practical application. Herein, ultrastable, highly luminescent graphene quantum dots (GQDs) that selectively target diverse cancer cells are prepared and tested. The new GQDs present step changes compared to common folic acid through an ≈6250 times increase in water solubility (to ≈10 mg mL−1), more than 150 times in QYs (up to ≈77%), while maintaining luminescence stability up to 98% when subjected to UV, visible light, and heating over 360 min. It is shown that the suppression of nonradiative transitions by amino groups pyrolyzed from pterin plays a key role in the mechanism of high QYs and excellent stability. The functional groups that are likely responsible for the selective targeting of cancer cells with different levels of folate receptor expression on the surface are identified. Collectively with these promising properties, the new functional graphene quantum dots may open a new avenue for cancer diagnosis, drug delivery, and therapies. Ultrastable, highly luminescent graphene quantum dots (GQDs) that selectively target diverse cancer cells are prepared and tested. The new GQDs present step changes compared to folic acid. New functional groups for folate receptor cancer targeting, other than pterin, emerges during the synthetic process. The new functional graphene quantum dots may open a new avenue for cancer diagnosis and therapies. [ABSTRACT FROM AUTHOR]