Folic Acid Molecules Research Articles

Photothermal-accelerated urease-powered human serum albumin nanomotor for rapid and efficient photothermal and photodynamic cancer combination therapy

Nanomotors, as a new type of micro-device, show good performance in terms of rapid transportation and deep penetration through their autonomous motion. However, their ability to efficiently break physiological barriers still remains a great challenge. Herein, we first developed a thermal-accelerated urease driven human serum albumin (HSA) nanomotor based on photothermal intervention (PTI) to achieve chemotherapy drugfree-phototherapy. The HANM@FI (HSA-AuNR@FA@Ur@ICG) is composed of a main body of biocompatible HSA, modified by gold nanorods (AuNR) and loaded with functional molecules of folic acid (FA) and indocyanine green (ICG). It promotes its own motion by breaking down urea to produce carbon dioxide and ammonia. In particular, the nanomotor is conveniently operated via near-infrared combined photothermal therapy (PTT)/ photodynamic therapy (PDT) to achieve an accelerated De value from 0.73 μm2s−1 to 1.01μm2s−1, and ideal tumor ablation at the same time. In contrast to customary urease-driven nanodrug-stacked engine, this HANM@FI has both targeting and imaging-guided capabilities, and finally achieves superior anti-tumor effects without chemotherapy drugs, through a “two-in-one” (motor mobility plus unique phototherapy in chemotherapy-drugfree phototherapy) strategy. This PTI effect with urease-driven nanomotors may offer further possibilities for future clinical applications of nanomedicines by enabling deep penetration and a subsequent chemotherapy-drugfree combination therapy strategy.

Role of Nutrition in the Etiopathogenesis and Prevention of Nonalcoholic Fatty Liver Disease (NAFLD) in a Group of Obese Adults.

Nonalcoholic fatty liver disease (NAFLD) is liver damage characterized by an accumulation of triglycerides in hepatocytes of >5% (due to an alteration of the balance of the lipid metabolism in favour of lipogenesis compared to lipolysis) that is not induced by the consumption of alcohol. The pathology includes simple steatosis and nonalcoholic steatohepatitis, or NASH (steatosis associated with microinflammatory activities), which can evolve in 15% of subjects with hepatic fibrosis to cirrhosis and the development of hepatocellular carcinoma. The aim of this study is to report the role of macro- and micronutrients in the pathogenesis and prevention of NAFLD in obese subjects. A total of 22 obese or overweight patients with hepatic steatosis were monitored periodically, evaluating their eating habits, fasting glycaemia, lipid picture, liver enzymes, anthropometric parameters, nutrition status, liver ultrasound, oxidative stress, and adherence to the Mediterranean diet. A statistical analysis shows a significant positive relationship between total cholesterol and the Mediterranean adequacy index (MAI) (r = -0.57; p = 0.005) and a significant negative relationship between ALT transaminases and the MAI (r = -0.56; p = 0.007). Nutrition and diet are important factors in the pathogenesis and prevention of NAFLD. The dietary model, based on the canons of the Mediterranean diet, prevents and reduces the accumulation of fat in hepatocytes. Therefore, in agreement with other studies in the literature, we can state that a dietary model characterized by foods rich in fibre, carotenoids, polyphenols, ω3 fatty acids, folic acid, and numerous other molecules is inversely correlated with the serum levels of ALT transaminases, an enzyme whose level increases when the liver is damaged and before the most obvious symptoms of organ damage appear.

Enhancing catalase-like activity of Prussian blue nanozyme by gadolinium-doping for imaging-guided antitumor amplification via photodynamic therapy and chemotherapy

Deprivation of O2 in most solid tumors greatly limits the effectiveness of photodynamic therapy. Prussian blue nanozyme (PBzyme) are reported to possess catalase-like (CAT) activity to alleviate tumor hypoxia. However, the low catalytic activity is far from satisfactory. Metal doping may improve the catalytic activity of PBzyme, but there are few reports in this regard. Herein, by a screening of metal dopants, Gd-doped PB with enhanced CAT activity is constructed on the basis of small-sized hollow mesoporous silica nanoparticles. Theoretical calculation demonstrates that Gd regulates the state density population of Fe in PBzyme and reduces the Gibbs free energy of CAT catalytic cycle, thus improving its CAT activity (approximately 4 times higher than that of pure PBzyme). After conjugated with photosensitizer Ce6 and tumor-targeted molecule folic acid and loaded with chemotherapy drug doxorubicin, the nanoplatform displays dual-enhanced T1 and T2 imaging capacity simultaneously. Upon high accumulation in tumors, the nanoplatform demonstrates augmented antitumor effects by combining enhanced photodynamic therapy and doxorubicin-mediated chemotherapy both in vitro and in vivo. This work demonstrates that the integration of Gd into PBzyme is an effective strategy to improve the catalytic activity of PBzyme and further potentiate the effectiveness of tumor theranostics.

Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer.

The hypoxia microenvironment of solid tumors poses a technological bottleneck for ferroptosis and immunotherapy in clinical oncology. Nanoreactors based on special physiological signals in tumor cells are able to avoid various tumor tolerance mechanisms by alleviating the intracellular hypoxia environment. Herein we reported a nanoreactor Cu2-xSe that enabled the conversion of Cu elements between Cu+ and Cu2+ for the generation of O2 and the consumption of intracellular GSH content. Furthermore, to enhance the catalytic and ferroptosis-inducing activities of the nanoreactors, the ferroptosis agonist Erastin was loaded on the ZIF-8 coating on the surface of Cu2-xSe to up-regulate the expression of NOX4 protein, increase the intracellular H2O2 content, catalyze the Cu+ to produce O2 and activate ferroptosis. In addition, the nanoreactors were simultaneously surface functionalized with PEG polymer and folic acid molecules, which ensured the in vivo blood circulation and tumor-specific uptake. In vitro and in vivo experiments demonstrated that the functionalized self-supplying nanoreactors can amplify the ability to generate O2 and consume intracellular GSH via the interconversion of Cu elements Cu+ and Cu2+, and impair the GPX4/GSH pathway and HIF-1α protein expression. At the same time, by alleviating the intracellular hypoxia environment, the expression of miR301, a gene in the secreted exosomes was decreased, which ultimately affected the phenotype polarization of TAMs and increased the content of IFN γ secreted by CD8+ T cells, which further promoted the ferroptosis induced by Erastin-loaded nanoreactors. This combined therapeutic strategy of activating the tumor immune response and ferroptosis via self-supplying nanoreactors provides a potential strategy for clinical application.

Para-Acetamidobenzoylglutamate Is a Suitable Indicator of Folate Catabolism in Rats

The amount of biologically active folate excreted in the urine corresponds to a small fraction of the recommended dietary allowance, suggesting that a large amount of folate is excreted as its catabolites. A strategy of assessing folate requirement by measuring the daily urinary levels of products of folate catabolism depends on the demonstration of an exclusive mechanism of breakdown as well as a suitable marker of the catabolic process. Rats were given [3H] and [14C]folic acid by gastric intubation daily for 10 d to simulate normal dietary intake of the vitamin. Total urine was collected throughout this period as well as for the following 10 d. Reverse-phase HPLC of the radiolabeled urinary products revealed the presence of a variety of intact folates as well as products of C9-N10 scission of the folate molecule, pteridines, para-aminobenzoylglutamate and para-acetamidobenzoylglutmate. We detected no other N10-containing catabolites, nor did we find the oxidized folate derivative ‘4α-hydroxy-5-methyltetrahydrofolate’. Of all the urinary folate metabolites, only para-acetamidobenzoylglutmate persisted at high levels up to 10 d after radiolabel treatment was withdrawn. We conclude that folate catabolism occurs exclusively through C9-N10 cleavage and that measurement of urinary para-acetamidobenzoylglutmate provides a suitable indicator of daily folate turnover.

Chlorambucil-Loaded Graphene-Oxide-Based Nano-Vesicles for Cancer Therapy.

In this study, the authors have designed biocompatible nano-vesicles using graphene oxide (GO) for the release of chlorambucil (CHL) drugs targeting cancerous cells. The GO sheets were first sulfonated and conjugated with folic acid (FA) molecules for controlled release and high loading efficiency of CHL. The chlorambucil (CHL) drug loading onto the functionalized GO surface was performed through π-π stacking and hydrophobic interactions with the aromatic planes of GO. The drug loading and "in vitro" release from the nano-vesicles at different pH were studied. The average particle size, absorption, and loading efficiency (%) of FA-conjugated GO sheets (CHL-GO) were observed to be 300 nm, 58%, and 77%, respectively. The drug release study at different pH (i.e., 7.4 and 5.5) showed a slight deceleration at pH 7.4 over pH 5.5. The amount of drug released was very small at pH 7.4 in the first hour which progressively increased to 24% after 8 h. The rate of drug release was faster at pH 5.5; initially, 16% to 27% in the first 3 h, and finally it reached 73% after 9 h. These observations indicate that the drug is released more rapidly at acidic pH with a larger amount of drug-loading ability. The rate of drug release from the CHL-loaded GO was 25% and 75% after 24 h. The biotoxicity study in terms of % cell viability of CHL-free and CHL-loaded GO against human cervical adenocarcinoma cell line was found to have lower cytotoxicity of CHL-loaded nano-vesicles (IC50 = 18 μM) as compared to CHL-free (IC50 = 8 μM). It is concluded that a high drug-loading efficiency and controlled release with excellent biotoxicity of CHL-GO offers an excellent application in the biomedical field.

Precise tumor resection under the navigation of Tumor-Microenvironment pH-activated NIR-II fluorescence imaging via calcium Carbonate/Polydopamine Co-packed Nd-doped downshifting nanoprobes

Photobleaching resistance, high quantum yield and deep tissue imaging of Nd-doped nanocrystals with fluorescence in the second near infrared region (NIR-II, 1000–1700 nm) occupied an indispensable position for precisely navigating tumor resection. However, these NIR-II nanoprobes often encounter high passive accumulation in reticuloendothelial system (RES) organs that attenuates signal to background ratio (SBR), resulting in the impediment of their application for accurate tumor outline delineation. Herein, a hollow-structured CaCO3 and polydopamine co-packed shell has been co-cladded on the Nd-doped down-shifting nanocrystals (DSNCs@hPCa). After conjugating folic acid molecules on the hollowed surface (DSNCs@hPCa-FA), this fascinating NIR-II contrast nanoagent can further specifically enhance tumor targeting capacity and gratifyingly restrain the NIR-II fluorescence in the “OFF” state. It sensitively responds to the weak acid tumor microenvironment, consequently, the hybrid nanoshell is degraded and the NIR-II fluorescence is efficiently turn “ON”. Robust fluorescent imaging with the augmented SBR has been demonstrated to accurately identify tumor borderlines from normal tissue. Tumors were thoroughly removed under the navigation of this novel pH stimuli-responsive NIR-II fluorescence imaging with ignorable in situ recurrence or metastases after 28 days post-surgery. This strategy indicates the preclinical potential of tumor microenvironment activated nanoprobes for assisting the accurate delineation of tumor margins.

Polyhedral Oligomeric Silsesquioxane-Based Nanoparticles for Efficient Chemotherapy of Glioblastoma.

Glioblastoma (GBM) is the most common lethal brain tumor with dismal treatment outcomes and poor response to chemotherapy. As the regulatory center of cytogenetics and metabolism, most tumor chemotherapeutic molecules exert therapeutic effects in the nucleus. Nanodrugs showing the nuclear aggregation effect are expected to eliminate and fundamentally suppress tumor cells. In this study, a nanodrug delivery system based on polyhedral oligomeric silsesquioxane (POSS) is introduced to deliver drugs into the nuclei of GBM cells, effectively enhancing the therapeutic efficacy of chemotherapy. The nanoparticles are modified with folic acid and iRGD peptides molecules to improve their tumor cell targeting and uptake via receptor-mediated endocytosis. Nuclear aggregation allows for the direct delivery of chemotherapeutic drug temozolomide (TMZ) to the tumor cell nuclei, resulting in more significant DNA damage and inhibition of tumor cell proliferation. Herein, TMZ-loaded POSS nanoparticles can significantly improve the survival of GBM-bearing mice. Therefore, the modified POSS nanoparticles may serve as a promising drug-loaded delivery platform to improve chemotherapy outcomes in GBM patients.

Fabrication of Functional bioMOF-100 Prototype as Drug Delivery System for Breast Cancer Therapy.

Breast cancer is the most frequent cause of cancer death in women, representing the fifth leading cause of cancer death overall. Therefore, the growing search for the development of new treatments for breast cancer has been developed lately as well as drug delivery systems such as biocompatible metal-organic Frameworks (bio-MOFs). These may be promising and attractive for drug incorporation and release. The present study aims to develop a drug carrier system RCA (bioMOF-100 submitted to the activation process) containing incorporated curcumin (CCM), whose material surface is coated with folic acid molecules (FA) to promote the targeting of drug carrier systems to the tumor region. They were synthesized and characterized using several characterization techniques. The materials were submitted to drug encapsulation tests, whose encapsulation efficiency was 32.80% for CCM@RCA-1D. Using the 1H nuclear magnetic resonance (NMR) spectroscopy technique, it was possible to verify the appearance of signals referring to folic acid, suggesting success in the functionalization of these matrices. In vitro tests such as cell viability and type of cell death were evaluated in both series of compounds (CCM@RCA-1D, CCM@RCA-1D/FA) in breast tumor lines. The results revealed low toxicity of the materials and cell death by late apoptosis. Thus, these results indicate that the matrices studied can be promising carriers in the treatment of breast cancer.

Therapeutic and Diagnostic Analysis of Cadmium Sulfide Quantum Dots Conjugated with Cysteine, Anticancer Drug and Folate

Background: Nanotechnology is evolving in the field of cancer drug design and cancer therapy. The ultrafine nanoparticles that have a size range of 1-10nm are called Quantum Dots. The ability to fluorescence has deemed quantum dots as suitable candidate for diagnostic imaging. Upon proper structural arrangement these quantum dots can be engineered to detect specifically cancer cells and deliver anticancer agents to the targeted site for cancer cell apoptosis. Aim: Cadmium sulfide (CdS) nanoparticles conjugated with cysteine were prepared by wet method under high temperature and pressure Methods: Folic acid receptor has shown overexpression in multiple types of cancers therefore the binding of folate to the composite ensures that only the cancer cells are targeted and normal cells remain unaffected. HeLa cells were opted to check the composite activity. Results: Composite showed 23% cell death in the first 2 hours of delivery. FTIR analysis confirmed conjugation of CdS with cysteine and further conjugation of dacarbazine and folate to cysteine. The molecules of folic acid attached to cysteine could be measured to be 2.545× 1018 molecules which were attached to 0.996× 〖10〗^22 molecules of cysteine that were attached 1.66 x〖 10〗^(20 ) molecules of CdS. Similarly, 2.3103 × 1019 of doxorubicin were attached to 0.996× 〖10〗^22 molecules of of cysteine attached to 1.66 x〖 10〗^(20 ) molecules of CdS. Furthermore, the cytotoxic nature of Cadmium Sulfide also gives an advantage two way cancer cell death. Conclusion: Quantum dots attached to specific ligands that bind to cancer antigens, antibodies, proteins, Receptors etc. can be used for effective diagnosis of cancer. They can act as probe and detect thousands of molecules simultaneously by using only a small quantity of nanoComposite. Keywords: Cadmium sulfide, Cancer, Quantum dots, Dacarbazine

Ultra-Small and Metabolizable Near-Infrared Au/Gd Nanoclusters for Targeted FL/MRI Imaging and Cancer Theranostics.

Tumor accurate imaging can effectively guide tumor resection and accurate follow-up targeted therapy. The development of imaging-stable, safe, and metabolizable contrast agents is key to accurate tumor imaging. Herein, ultra-small and metabolizable dual-mode imaging probe Au/Gd@FA NCs is rationally engineered by a simple hydrothermal method to achieve accurate FL/MRI imaging of tumors. The probes exhibit ultra-small size (2.5–3.0 nm), near-infrared fluorescence (690 nm), high quantum yield (4.4%), and a better T1 nuclear magnetic signal compared to commercial MRI contrast agents. By modifying the folic acid (FA) molecules, the uptake and targeting of the probes are effectively improved, enabling specific fluorescence imaging of breast cancer. Au/Gd@FA NCs with good biosafety were found to be excreted in the feces after imaging without affecting the normal physiological metabolism of mice. Intracellular reactive oxygen species (ROS) increased significantly after incubation of Au/Gd@FA NCs with tumor cells under 660 nm laser irradiation, indicating that Au/Gd@FA NCs can promote intracellular ROS production and effectively induce cell apoptosis. Thus, metabolizable Au/Gd@FA NCs provide a potential candidate probe for multimodal imaging and tumor diagnosis in clinical basic research. Meanwhile, Au/Gd@FA NCs mediated excessive intracellular production of ROS that could help promote tumor cell death.

Flower-like Composite Material Delivery of Co-Packaged Lenvatinib and Bufalin Prevents the Migration and Invasion of Cholangiocarcinoma.

The co-delivery of multiple drugs using nanocarriers has been recognized as a promising strategy for cancer treatment to enhance therapeutic efficacy. In this study, a monodisperse mesoporous silica nanoparticle (mSiO2) is prepared and functionalized into high-efficiency loaded Lenvatinib and Bufalin for targeted delivery to Cholangiocarcinoma (CCA). mSiO2 was synthesized on solid silica nanoparticles by oil–water interface method, and highly monodisperse mSiO2 with uniform morphology was obtained. mSiO2 was then sequentially modified by polyethylene glycol (PEG) and the targeting molecule folic acid (FA). mSiO2-FA was designed as co-delivery system for Lenvatinib (Le) and Bufalin (Bu) to increase drug availability and highly target tumor cells. Compared with unfunctionalized mSiO2, mSiO2-FA can more efficiently enter human CCA cell lines (9810 cells) and enhance intracellular drug delivery. Moreover, drug-loaded mSiO2-FA (Le/Bu@mSiO2-FA) significantly inhibited the viability, migration and invasion of 9810 cells. In vivo, the nanocomplex significantly reduced the tumor load in CCA tumor-bearing mouse models compared to Le or Bu alone. The current work provides a useful strategy for highly targeted and multidrug-resistance reversal therapy for CCA.

Platinum-Based Nanocomposite Pt@BSA as an Efficient Electrochemical Biosensing Interface for Rapid and Ultrasensitive Determination of Folate Receptor-Positive Tumor Cells.

Developing a cytosensing strategy based on electrochemical approaches has attracted wide interest due to the low cost, rapid response, and simple instrumentation. In this work, an electrochemical cytosensor employing the Pt@BSA nanocomposite as the biosensing substrate along with the covalent cross-linking of targeting molecules folic acid (FA) was constructed for highly sensitive determination of folate receptor (FR)-positive tumor cells. The prepared Pt@BSA nanocomposite revealed excellent biocompatibility for cell adhesion and proliferation, which was confirmed by cell viability evaluation using thiazolyl blue tetrazolium bromide (MTT) colorimetric methods. Due to the satisfactory electrical conductivity originating from Pt@BSA and the high binding affinity of FA to FR on the cell surface, an ultrasensitive and specific cytosensing device was designed for rapid and quantitative determination of HeLa cells (a model system) by differential pulse voltammetry (DPV) tests. This proposed cytosensor resulted in a wide HeLa cell determination range of 2.8 × 101-2.8 × 106 cells mL-1 with a low DPV detection limit of 9 cells mL-1. The developed cytosensing approach exhibited highly specific recognition of FR-positive tumor cells, excellent inter-assay reproducibility with a relative standard deviation (RSD) of 4.7%, acceptable intra-assay precision, and favorable storage stability, expanding the application of electrochemical measurement technology in the biomedical field of early detection and diagnosis of cancers.

Study on lipid nanomicelles targeting placenta for the treatment of preeclampsia

: In view of the serious clinical harm of preeclampsia and the lack of effective treatment methods, a PEG-modified lipid hybrid micelle was designed with folic acid molecule on the surface, containing siRNA, targeted delivery to the placenta, interfering the expression of sFlt-1 and treating preeclampsia. In this paper, the preparation and characterization of lipid hybrid micelles were investigated in detail, the cytology in vitro and in vivo distribution, pharmacodynamics, safety and action mechanism of the preparation were studied, which laid a foundation for gene therapy of preeclampsia.

Efficient Synthesis of Yellow-Green Carbon Quantum Dots as a Sensitive Fluorescent Probe of Folic Acid.

Bright yellow-green carbon quantum dots (YGCDs) have been successfully synthesized by a simple and efficient hydrothermal method. Their luminescent absolute quantum yield reached 30.0% in 4 h. Compared with commonly reported solvothermal methods, the synthesis time was reduced by more than 70% by using tin oxide nanoparticles as a catalyst. Moreover, the fluorescence of YGCDs could be selectively quenched by folic acid (FA) molecules, and the relative fluorescence intensities of F/F0 was fitted perfectly in line decay curve versus the concentration of FA in the range of 2.0×10-8 mol/l to 1.0×10-5 mol/l (R2 =0.9988). The detection limit of FA was below 2.0×10-8 mol/l, suggesting a promising fluorescent probe of folic acid.

A surface architectured metal–organic framework for targeting delivery: Suppresses cancer growth and metastasis

Porous nanosized metal–organic frameworks (MOFs) are becoming possible candidates as drug-delivery nanocarriers for their versatile porous structures and large loadings of drugs. However, controlling synthesis of MOFs with uniform morphology, good biocompatibility and targeting drug delivery is still a challenge, which greatly limits their clinical applications. Herein, a multifunctional nano-sized drug-delivery material MIL-101(Fe)@FU@FA with a uniform particle size about 500 nm was successfully synthesized for targeting therapeutic purposes. The targeting reagent folic acid (FA) molecules are connected on the surface of 5-FU-loaded nanoparticle MIL-101(Fe)-NH 2 by a covalent conjugation. Cytotoxicity tests showed that the synthesized nanoparticles are biocompatible and can significantly inhibit cell proliferation on SMMC-7721 cells compared with MIL-101(Fe)@FU and free 5-FU. The cell metastasis and invasion experiments proved that the nanoparticles had a good anti-metastasis ability to tumor cells. Mechanistically, MIL-101(Fe)@FU@FA induces apoptosis of SMMC-7721 cells and block cell cycle progression in the G2/M phase. Taken together, the drug-loaded nanoparticles MIL-101(Fe)@FU@FA have the effect of targeting and sustained release to achieve the therapeutic effect.

Design and Evaluation of Novel Albumin-Binding Folate Radioconjugates: Systematic Approach of Varying the Linker Entities.

Tumor targeting using folate radioconjugates is a promising strategy for theragnostics of folate receptor-positive tumors. The aim of this study was to investigate the impact of structural modifications of folate radioconjugates on their pharmacokinetic properties. Four novel folate radioconjugates ([177Lu]Lu-OxFol-2, [177Lu]Lu-OxFol-3, [177Lu]Lu-OxFol-4, and [177Lu]Lu-OxFol-5), modified with a lipophilic or hydrophilic linker entity in close proximity to the albumin-binding 4-(p-iodophenyl)butanoate entity or the DOTA chelator, respectively, were designed and evaluated for comparison with the previously developed [177Lu]Lu-OxFol-1. A hydrophobic 4-(aminomethyl)benzoic acid linker, incorporated in close proximity to the 4-(p-iodophenyl)butanoate entity, enhanced the albumin-binding properties (relative affinity 7.3) of [177Lu]Lu-OxFol-3 as compared to those of [177Lu]Lu-OxFol-1 (relative affinity set as 1.0). On the other hand, a hydrophilic d-glutamic acid (d-Glu) linker entity used in [177Lu]Lu-OxFol-2 compromised the albumin-binding properties. [177Lu]Lu-OxFol-4 and [177Lu]Lu-OxFol-5, in which the respective linker entities were incorporated adjacent to the DOTA chelator, showed similar albumin-binding properties (0.6 and 1.0, respectively) as [177Lu]Lu-OxFol-1. Biodistribution studies in KB tumor-bearing nude mice revealed twofold higher tumor-to-kidney ratios at 4 h and 24 h after injection of [177Lu]Lu-OxFol-3 (∼1.2) than after injection of [177Lu]Lu-OxFol-1 (∼0.6). The tumor-to-kidney ratios of [177Lu]Lu-OxFol-2 were, however, much lower (∼0.2) due to the high kidney retention of this radioconjugate. The tumor-to-kidney ratios of [177Lu]Lu-OxFol-5 were only slightly increased (∼0.9), and the ratios for [177Lu]Lu-OxFol-4 (∼0.7) were in the same range as for [177Lu]Lu-OxFol-1. SPECT/CT imaging studies demonstrated similar tumor uptake of all radioconjugates but a clearly improved tumor-to-kidney ratio for [177Lu]Lu-OxFol-3 as compared to that for [177Lu]Lu-OxFol-1. Based on these data, it can be concluded that the linker entity in close proximity to the 4-(p-iodophenyl)butanoate entity affects the radioconjugate's pharmacokinetic profile considerably due to the altered affinity to albumin. Changes in the linker entity, which connects the DOTA chelator with the folate molecule, do not have a major impact on the radioconjugate's tissue distribution profile, however. As a result of these findings, [177Lu]Lu-OxFol-3 had a comparable therapeutic effect to that of [177Lu]Lu-OxFol-1 but appeared advantageous in preventing kidney damage. Provided that the kidneys will present the dose-limiting organs in patients, [177Lu]Lu-OxFol-3 would be the preferred candidate for a clinical translation.

SERS nanotags for folate receptor α detection at the single cell level: discrimination of overexpressing cells and potential for live cell applications.

Folate receptor α (FRα) is a high affinity folate membrane receptor that is overexpressed in a wide variety of cancers. Detecting the overexpression of this receptor is important for cancer cells identification and to potentially guide the choice of treatment since several FRα-targeted drugs are currently in clinical trials. In this work, we built SERS nanotags based on core@shell Au@Ag nanoparticles labelled with resonant Raman-reporter and functionalised with a thiolated PEG linker bearing folic acid at the chain end. Using SERS mapping on single cells, we showed that the nanotags (FR-nanotags) could specifically target FRα on overexpressing HeLa cells and could measure the gradual blocking of FRα by free folic acid introduced in the media along the nanotags. With a control nanotag, we showed that the SERS response was 10-fold higher on HeLa cells when folic acid is present on the PEG linker compared to PEG chains without folic acid. Non-specific binding of the FR-nanotags was demonstrated to be low and mainly caused by the folic acid molecule at the PEG chain end. When comparing cancer cells with different expression levels of FRα, we obtained 4-fold higher SERS response on overexpressing HeLa cells compared to non-overexpressing A549 cells, allowing the discrimination of both cell lines with a high contrast. Owing to the biocompatibility of the developed nanotags, we demonstrated that measurements of FRα on live HeLa cells were also possible and gave similar results to measurements on fixed cells, indicating the versatility of the developed nanotags for detecting FRα under various experimental conditions.

Bifunctional folic-conjugated aspartic-modified Fe3O4 nanocarriers for efficient targeted anticancer drug delivery.

Functionalization of nanocarriers has been considered the most promising way of ensuring an accurate and targeted drug delivery system. This study reports the synthesis of bifunctional folic-conjugated aspartic-modified Fe3O4 nanocarriers with an excellent ability to deliver doxorubicin (DOX), an anticancer drug, into the intercellular matrix. Here, the presence of amine and carboxylate groups enables aspartic acid (AA) to be used as an efficient anchoring molecule for the conjugation of folic acid (FA) (EDC–NHS coupling) and DOX (electrostatic interaction). Based on the results, surface functionalization showed little effect on the physicochemical properties of the nanoparticles but significantly influenced both the loading and release efficiency of DOX. This is primarily caused by the steric hindrance effect due to large and bulky FA molecules. Furthermore, in vitro MTT assay of B16–F1 cell lines revealed that FA conjugation was responsible for a significant increase in the cytotoxicity of DOX-loaded nanocarriers, which was also found to be proportional to AA concentration. This high cytotoxicity resulted from an efficient cellular uptake induced by the over-expressed folate receptors and fast pH triggered DOX release inside the target cell. Here, the lowest IC50 value of DOX-loaded nanocarriers was achieved at 2.814 ± 0.449 μg mL−1. Besides, further investigation also showed that the drug-loaded nanocarriers exhibited less or no toxicity against normal cells.

Supramolecular Chemistry of Folic Acid — Experimental and Computational Investigation

Supramolecular chemistry of folic acid is studied and revealed by exploring its assembly and disassembly process in a liquid–liquid interface. Experimental and computational studies are conducted to understand the interfacial interactions of folic acid in a oil-in-water interface by investigating the role of folic acid’s critical aggregation concentration (CAC), molecular arrangement, and intermolecular interactions at the molecular level. The folic acid’s CAC, determined from the concentration-dependent UV–vis absorption spectra in water/methanol solvent system, is found to be 2.72[Formula: see text][Formula: see text]M. The sigmoidal behavior of folic acid’s maximum absorbances with respect to different folic acid concentrations reveals the nature of the self-assembly dynamics and aggregative assemblies’ formation by three signature phases, in which CAC lies in the second phase — the growth phase. The computational studies reveal the intermolecular interactions and molecular orientation of folic acid molecules. They interact each other via H2-bonding between carboxylic acid groups in two glutamate units and two amine groups in pteridine units and [Formula: see text]–[Formula: see text] interactions between pteridine units and phenyl units, orienting two units in a parallel stacked arrangement. Correlating the computed intermolecular interactions and structural orientation of folic acid with its solid-state crystal packing structure has provided strong evidence supporting its supramolecular chemistry and assembly dynamics to make nanoassemblies in a liquid–liquid interface.