Folate Conjugates Research Articles

Redox-responsive tumor targeted dual-drug loaded biocompatible metal\u2013organic frameworks nanoparticles for enhancing anticancer effects

Metal–organic frameworks (MOFs) have proven to be a promising class of drug carriers due to their high porosity, crystalline properties with defined structure information, and abundant surface chemistry for further functionalization. However, there has not been extensive research on MOF-based drug carriers with stimuli-responsive, dual-drug delivery, and tumor targeting functions. Here, we demonstrate the strategy of constructing a redox responsive and tumor-targeted MOF as dual-drug carrier by anchoring functional disulfide anhydride and folic acid molecules to the organic links of MOFs, respectively. The MOF composites show the controlled release of loaded 5-fluorouracil (5-FU) entrapped within UiO-66-NH2 nanostructures modified with dichloroacetic acid, which acts as a synergistical drug to 5-FU in cancer cells. In addition, the overexpressed GSH in cancer cells attacks the thiolate moiety and is oxidized in the process as it cleaves the disulfide bonds, thereby achieving redox stimuli-responsive drugs release in MOFs. The confocal laser scanning microscopy further proved that conjugation of folic acid to the MOF surface can significantly enhance the targeting uptake of cancer cells. This work paves the way to the construction of stimuli responsive tumor-targeted Nano MOF based drug carriers with potential for cancer therapies.

Folate targeted PEGylated liposomes for the oral delivery of insulin: In vitro and in vivo studies

In this study using phospholipids with high transition temperature and taking advantage of PEGylation, we designed liposomal formulation targeted with folic acid (FA) to improve the stability of liposomes with high penetration efficiency at the same time. The results of characterization demonstrated that liposomal formulations are in range of 150−210 nm size with negative surface charge. The results of cell uptake indicated that FA conjugation resulted in the more uptake of insulin. However, the results of transepithelial electrical resistance (TEER) showed no statistical differences among the formulations. The results of biodistribution also demonstrated that PEGylated liposome targeted with FA had more residence time in stomach and intestine along with higher amounts in blood and liver. The anti-diabetic effects of formulation in vivo indicated the efficacy of PEGylated liposome targeted with FA had promising results in decreasing blood glucose and increasing insulin levels. The results of this study indicated that using phospholipids with high Tm along with PEGylation and using targeting ligand could improve efficiency of oral delivery of liposomes which merit further investigation.

An outlook on procedures of conjugating folate to (co)polymers and drugs for effective cancer targeting.

Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)polymers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel synthetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputation, validating its usefulness in targeted cancer therapeutics. The present review summarizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are discussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications.

Role of folate-conjugated glycol-chitosan nanoparticles in modulating the activated macrophages to ameliorate inflammatory arthritis: in vitro and in vivo activities.

Activated macrophages are the primary targets in rheumatoid arthritis (RA) management. So, we report efficacious, dual-functional Methotrexate (MTX) loaded folate-conjugated pH-responsive glycol-chitosan nanoparticles (MFGCN) prepared by nano-precipitation and zero-order cross-linking reaction for targeting inflamed arthritic tissue. Physical characterization by DLS, SEM and TEM indicated a spherical, smooth morphology with a diameter ~ 300nm. 1H NMR and FTIR indicated folic acid conjugation to GC by zero-order cross-linkers. In vitro release kinetics in PBS showed pH-responsive and sustained release behaviour of MFGCN. Enhanced cellular uptake and cytotoxicity of MFGCN in LPS(+)RAW and activated peritoneal macrophages (Mϕ) were observed when compared to LPS(-)RAW cells. MFGCN-induced mitochondrial membrane potential (MMP) perturbations indicated apoptosis. Oxidative stress was evident by significant increase in ROS and RNS, 4h post incubation with MFGCN. Negligible hemolysis by FGCN and MFGCN on rat RBC's indicated biocompatibility. In vivo biodistribution of MFGCN in adjuvant-induced arthritis (AIA) rats indicated RA targetability. Prolonged blood circulation coupled with higher concentrations of 99mTc-MFGCN at the arthritic site was observed post 24h of injection. The gamma scintigraphic image confirmed accumulation of radiolabelled MFGCN in arthritic paw when compared to the non-inflamed paw, confirming the selective uptake of 99mTc-MFGCN by folate-overexpressing macrophages in the arthritic synovium thereby proving its targeted efficacy and theranostic potential. In AIA rats, MFGCN lowers arthritic signs, improves antioxidant response and decreases pro-inflammatory cytokines, suggesting its potential in targeting activated macrophages of synovium. Graphical abstract.

Electrochemical sensor for cancer cell detection using calix[8]arene/polydopamine/phosphorene nanocomposite based on host−guest recognition

The detection of tumor cells plays an important role in the early diagnosis and treatment of cancer. In this paper, we reported a novel cytosensing platform based on the supermolecular recognition using p-sulfonated calix [8]arene (SCX8)/polydopamine (PDA) /black phosphorene (BPene) nanocomposite as a receptor for cancer cells. Then, dopamine was in situ polymerized on the BPene surface to construct the BPene@PDA nanocomposite. Furthermore, SCX8 was functionalized with BPene@PDA to produce BPene@PDA − SCX8 nanocomposite. The SCX8 in BPene@PDA − SCX8 can bind to folic acid (FA) and form a stable BPene@PDA − SCX8·FA conjugate through host-guest recognition. Cancer cells can bind to the BPene@PDA − SCX8·FA modified electrode through FA and the folic receptor (FR) on the cancer cells by forming an SCX8−FA − FR sandwich-type conjugate, resulting in increased impedance that was proportional to the cell amount. Therefore, cancer cells were detected. The cytosensor exhibited a linear relation with LNCaP cells concentration within the range of 2 × 102 to 1 × 105 cells mL−1 with a detection limit of 36 cells mL−1. The constructed cytosensing platform demonstrated good sensitivity, acceptable stability, and favorable reproducibility due to specific supramolecular recognition, which has the potential applications in cancer recognition and diagnosis.

Design and preparation of a new multi-targeted drug delivery system using multifunctional nanoparticles for co-delivery of siRNA and paclitaxel

Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents. Administration of these drugs with siRNA is an efficacious strategy in this battle. Here, the present study tried to incorporate siRNA and paclitaxel (PTX) simultaneously into a novel nanocarrier. The selectivity of carrier to target cancer tissues was optimized through conjugation of folic acid (FA) and glucose (Glu) onto its surface. The structure of nanocarrier was formed from ternary magnetic copolymers based on FeCo-polyethyleneimine (FeCo-PEI) nanoparticles and polylactic acid-polyethylene glycol (PLA-PEG) gene delivery system. Biocompatibility of FeCo-PEI-PLA-PEG-FA(NPsA), FeCo-PEI-PLA-PEG-Glu (NPsB) and FeCo-PEI-PLA-PEG-FA/Glu (NPsAB) nanoparticles and also influence of PTX-loaded nanoparticles on in vitro cytotoxicity were examined using MTT assay. Besides, siRNA-FAM internalization was investigated by fluorescence microscopy. The results showed the blank nanoparticles were significantly less cytotoxic at various concentrations. Meanwhile, siRNA-FAM/PTX encapsulated nanoparticles exhibited significant anticancer activity against MCF-7 and BT-474 cell lines. NPsAB/siRNA/PTX nanoparticles showed greater effects on MCF-7 and BT-474 cells viability than NPsA/siRNA/PTX and NPsB/siRNA/PTX. Also, they induced significantly higher anticancer effects on cancer cells compared with NPsA/siRNA/PTX and NPsB/siRNA/PTX due to their multi-targeted properties using FA and Glu. We concluded that NPsAB nanoparticles have a great potential for co-delivery of both drugs and genes for use in gene therapy and chemotherapy.

PEGylation and folate conjugation effects on the stability of chitosan-tripolyphosphate nanoparticles

Chitosan-based nanoparticles (Ch-NPs) prepared via ionotropic gelation of Ch with sodium tripolyphosphate (TPP) have been widely examined as potential drug carriers. Yet, recent studies have shown these particles to be unstable in model (pH 7.2–7.4) physiological media. To this end, here we explored the possibility of improving TPP-crosslinked Ch-NP stability through chemical Ch modification. Specifically, Ch samples with either 76% or 92% degrees of deacetylation (DD) were grafted with either polyethylene glycol (PEG), a hydrophilic molecule, or folic acid (F), a hydrophobic molecule. Limited variation in dispersion light scattering intensity, particle size and apparent ζ-potential, and lack of macroscopic precipitation were chosen as analytical evidence of dispersion stability. TPP titrations were performed to determine the optimal TPP:glucosamine molar ratio for preparing particles with near 200-nm diameters, which are desirable for systemic administration of drugs, cellular uptake, and enhancing NP blood circulation. Both DD and Ch modification influenced the particle formation process and the evolution in NP size and ζ-potential upon 30-day storage in virtually salt-free water at 25 °C and 37 °C, where the NPs underwent partial aggregation (along with possible dissolution and swelling) but remained colloidally dispersed. Under model physiological (pH 7.2; 163 mM ionic strength) conditions, however (where the chitosan amine groups were largely deprotonated), the particles quickly became destabilized, evidently due to particle dissolution followed by Ch precipitation. Overall, within the degrees of substitution used for this work (~1% for PEG, and 3 and 6% for F), neither PEG nor F qualitatively improved Ch-NP stability at physiological pH 7.2 conditions. Thus, application of TPP-crosslinked Ch-NPs in drug delivery (even when Ch is derivatized with PEG or F) should likely be limited to administration routes with acidic pH (at which these NPs remain stable).

Microemulsion and bovine serum albumin nanoparticles as a novel hybrid nanocarrier system for efficient multifunctional drug delivery.

The present study aims to: (a) design the versatile microemulsions (MEs) system for drug delivery; (b) use the bovine serum albumin nanoparticles for MEs system development; (c) characterize the physicochemical properties, cytotoxicity, and biocompatibility of the modified MEs (MMEs) system; (d) load of paclitaxel (PTX) and folate conjugate of MEs system; and (e) assess the potential of anticancer activity of MEs system. The physicochemical possessions, in vitro and in vivo cytotoxicity, and stability of MMEs system were characterized. The results of our study show that the MEs system was stable, having narrow particle size distribution, nontoxic, biocompatible, and not active for leukocyte proliferation. So it can be concluded that the MMEs system as a promising candidate for a targeted multifunctional drug delivery system (PTX and folate) that is called a smart MEs system.

In vitro Anti-cancer Efficacy and Cellular Interaction of Cubic Phases Containing Cinnamic Acid, Poly(ethyleneimine), and Doxorubicin

Folate-decorated monoolein (MO) cubosomes containing poly(ethyleneimine) (PEI), cinnamic acid (CA), and doxorubicin (DOX) were prepared to deliver the anticancer drug specifically to cancer cells (KB cells) and boost the anti-cancer efficacy without causing an acute toxicity. Hydrophobically modified (Hm) gelatin (Gel)-folate (FA) conjugate (HmGel-FA) was prepared through amidation reaction among Gel, decanoyl chloride, and FA. HmGel-FA and Pluronic F127 were used as stabilizers for the cubosomal particles. According to the measurement of air/water interfacial tension, the surface activity was greater in the order of HmGel > HmGel-FA > Gel. Since it was reported that PEI and CA formed a self-assembly in the water channel of cubosomes and the dissolving property of the self-assembly was dependent on the pH value of medium, they were included in the water channel as a controller for DOX release. On the TEM micrographs of the cubosomes, water channels were surrounded by MO bilayers, and the payload (i.e. PEI, CA, DOX) had little effect on the structure. The in vitro anti-cancer efficacy of folate-decorated cubosomes containing PEI, CA, and DOX was higher than that of folate-free ones. According to flow cytometric analysis and confocal laser scanning microscopy, DOX fluorescence intensity was greater in the order of KB cells treated with folate-decorated cubosomes containing PEI, CA, and DOX > folate-free ones > free DOX. The folate-decorated cubosomes would be able to target the cancer cells and subsequently the receptor-mediated endocytosis would take place.

Synthesis of Tryptophan–Folate Conjugates

A mild protocol for the synthesis of folate–peptide/protein conjugates targeting tryptophan residues is described. This synthetic protocol is advantageous for homogeneous conjugation of chemically sensitive folates to biomolecules, with potential applications in cancer therapy and diagnostics.

Folate-Targeted Anticancer Drug Delivery via a Combination Strategy of a Micelle Complex and Reducible Conjugation.

Conjugation of various active targeting ligands to the surface of nanocarriers to realize specific recognition by the corresponding receptors localized on the membrane of the cancer cells has provided a powerful means toward enhanced cancer therapy. Folic acid (FA) is one of the most used targeting ligands due to the overexpressed FA receptors in many cancer cell lines. However, conjugation of hydrophobic FA to the surface of nanocarriers usually alters the hydrophilic/hydrophobic balance of the stabilized nanoparticles, leading to their thermodynamic instability and subsequent formation of aggregates, which apparently compromises the in vivo long circulation and minimized side effects of nanocarriers. The currently leading strategy to overcome this issue is to incorporate a protecting hydrophilic stealth that can be deshielded to expose the targeting ligand at the desired tumor site, which generally involves multistep chemical modifications, conjugations, and purifications. To develop a simple alternative toward FA-mediated enhanced anticancer drug delivery, a combination strategy of micelle complex and reducible conjugation was reported in this study. FA was first conjugated to the terminus of the hydrophilic block of a reduction-sensitive miktoarm star-shaped amphiphilic copolymer, PCL3-SS-POEGMA1, with the previously optimized star structure by click coupling via a reducible disulfide link. The resulting PCL3-SS-POEGMA1-SS-FA was further mixed with the parent PCL3-SS-POEGMA1 to afford a micelle complex with both reducibly conjugated and relatively low amount of FA-targeting ligands toward excellent FA-mediated targeted drug delivery without compromised salt stability in vitro and in vivo. Therefore, the combined strategy developed herein provides a simple and powerful means to promote FA-mediated anticancer drug delivery.

Folate conjugation improved uptake and targeting of porous hydroxyapatite nanoparticles containing epirubicin to cancer cells

As hydroxyapatite (HAp) with the hexagonal crystal structure is biocompatible and bioactive. In the present study, HAp nanoparticles were synthesized and functionalized with polyethylene glycol and folic acid. The anticancer drug, epirubicin, was loaded to the folic acid-conjugated polyethylene glycol-coated HAp (FA-PEG-HAp) nanoparticles. The prepared nanoparticles were used for in vitro and in vivo experiments. Particle size analyzer showed that the hydrodynamic size of PEG-HAp and FA-PEG-HAp nanoparticles was 150.3 ± 1.5 nm and 217.2 ± 14.9 nm, respectively. The release behavior of epirubicin from nanoparticles showed an increase in the rate of release in acidic pH. The released drug in acidic pH was 2.5 fold more than pH 7.4. The results of in vitro study indicated an increase in cellular uptake of nanoparticles due to folate ligand. In vivo treatment with both PEG-HAp and FA-PEG-HAp nanoparticles had notably higher inhibition efficacy towards tumor growth than free epirubicin. In conclusion, folate conjugation provided higher uptake and better targeting of hydroxyapatite nanoparticles to cancer cells.

Investigating the Potential of Conjugated Selenium Redox Folic Acid as a Treatment for Triple Negative Breast Cancer

Previous studies have demonstrated that redox selenium compounds arrest cancer cell viability in vitro through their pro-oxidative activity by generating superoxide (O2•−). Currently, there are no efficacious treatment options for women with Triple Negative Breast Cancer (TNBC). However, the association between the over-expression of the Folate Receptor Alpha (FRA) in TNBC and other cancer cells, has led to the possibility that TNBCs might be treated by targeting the FRA with redox selenium covalent Folic Acid conjugates. The present study reports the synthesis of the redox active vitamer, Selenofolate, generating superoxide. Superoxide (O2•−) catalytic generation by Selenofolate was assessed by an in vitro chemiluminescence (CL) assay and by a Dihydroethidium (DHE) in vivo assay. Cytotoxicity of Selenofolate was assessed against the TNBC cell line MDA-MB-468 and an immortalized, mammary epithelial cell line, HME50-5E. Cytotoxicity of Selenofolate was compared to Folic Acid and sodium selenite, in a time and dose dependent manner. Selenofolate and selenite treatments resulted in greater inhibition of MDA-MB-468 cell proliferation than HME50-5E as evaluated by Trypan Blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay and Annexin V apoptosis assays. Folate receptor alpha (FRA) protein expression was assessed by Western blotting, with the experimental results showing that redox active Selenofolate and selenite, but not Folic Acid, was cytotoxic to MDA-MB-468 cells in vitro, suggesting a possible clinical option for treating TNBC and other cancers over-expressing FRA.

Design and synthesis of a folate-receptor targeted diazepine-ring-opened pyrrolobenzodiazepine prodrug conjugate

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed and synthesized a diazepine-ring-opened bis-PBD prodrug (pro-PBD-PBD) folate conjugate lacking the one of the two imine moieties found in the corresponding free bis-PBD. Upon entering a targeted cell, cleavage of the linker system, including the hydrolysis of an oxazolidine moiety, results in the formation of a reactive intermediate which possesses a newly formed aldehyde as well as an aromatic amine. A fast and spontaneous intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring, thereby delivering the bis-PBD to the targeted cell. The in vitro and in vivo activity of this conjugate has been evaluated on folate receptor positive KB cells. Sub-nanomolar activity with good specificity and high cure rates with minimal toxicity have been observed.

Kinetic Modeling and Optimization of the Release Mechanism of Curcumin from Folate Conjugated Hybrid BSA Nanocarrier

Abstract Nanocarriers have been explored widely for targeted and sustainable delivery of drugs and other bioactive molecules. Kinetic modeling on the drug release and optimization of the process parameters offers a fundamental explanation for the release mechanism along with an insight on the properties of the carrier. In the present work, a hybrid Bovine serum albumin- Calcium ferrite (BSA-CFNP) nanocarrier in conjugation with folic acid has been developed for the controlled release of curcumin, as a model anticancer drug. Super paramagnetic calcium ferrite nanoparticles were synthesized by sol-gel method. Curcumin was loaded onto the BSA and hybrid BSA-CFNP carriers by desolvation technique. Folic acid conjugation was performed, using EDC coupling reaction, to enable the receptor mediated endocytosis of the drug. The synthesized samples were characterized by FTIR, XRD and SEM techniques. Optimization of curcumin loading on the carrier was evaluated using Taguchi method, which provided a simpler yet effective route to study the influence of the process parameters under consideration. In-vitro stimuli responsive curcumin release studies were investigated. The amount of FA conjugated was also optimized. The drug release trends were studied at different simulated physiological environments. The drug release mechanism was evaluated by applying various kinetic models such as zero order, first order, Higuchi, Korsmeyer Peppas and Hixson Crowell. The controlling parameters and their effects on the release of curcumin from the devised system were elucidated from the best fit model.

Folic acid-modified Laponite®-stabilized Fe3O4 nanoparticles for targeted T2-weighted MR imaging of tumor

In this study, a targeted T2-weighted MR imaging agent based on laponite (LAP) was constructed for cancer cells overexpressing folate receptors. Firstly, LAP stabilized Fe3O4 NPs are synthesized by a controlled co-precipitation route, and then amphiphilic copolymer poly(lactic acid)-poly(ethylene glycol) (PLA-PEG-COOH) is assembled on the surface of LAP/Fe3O4 NPs to provide additional stability, followed by the conjugate of folic acid modified generation 2 polyamidoamine dendrimer (G2-FA) via EDC coupling chemistry. The formed LAP/Fe3O4-PLA-PEG-G2-FA NPs can display good colloidal stability and an enhanced r2 relaxivity of 327.6 mM−1 s−1. In vitro experiments demonstrate that the hybrid nanoparticles are cytocompatible in the studied concentration range, and could specific target cancer cells with FA receptors overexpression. Finally, the xenografted tumor model experiment verifies that LAP/Fe3O4-PLA-PEG-G2-FA NPs can significantly reduce the MR signal of tumor site by specific accumulation, and be metabolized from the mice within 24 h. Therefore, LAP/Fe3O4-PLA-PEG-G2-FA NPs with good biocompatibility, a high r2 relaxivity, and FA targetability show a huge potential as a targeted T2-weighted MR imaging contrast for the early diagnosis of tumors overexpressing FA receptors.

Folate-conjugated Helix lucorum hemocyanin - preparation, stability, and cytotoxicity.

This is the first report on the modification of a hemocyanin from Helix lucorum (HlH), a large molluscan respiratory protein, with folic acid (FA). In a two-step synthetic reaction, we prepared samples of HlH conjugated with 20 and 50 FA residues denoted as FA-HlH-1 and FA-HlH-2, respectively. Comparison of the attenuated total reflectance-Fourier transform infrared spectra in the amide I band region showed a structural rearrangement in the HlH that is due to FA conjugation. The changes in the secondary structure were more noticeable for FA-HlH-2. The thermal stability of HlH was not significantly affected by the FA modification, which is consistent with the observed structural similarities with the native protein. Preliminary cytotoxicity assays showed that FA-HlH-1 and FA-HlH-2 stimulate fibroblast proliferation when applied in concentrations of 50 and 100 μg/well. A negligible reduction of fibroblast growth was observed only for FA-HlH-1 and FA-HlH-2, exposed to 200 μg/well for 48 h. We found that FA-HlH-2 exhibits a low to moderate cytotoxic effect on two breast cancer cell lines, which express folate receptors, a hormone-dependent (MCF-7) and a hormone-independent (MDA-MB-231). FA-HlH-2 protects nontransformed cells and affects only neoplastic cells, which could be an advantage, and the protein could have potential in combination with other chemotherapeutics.

Folate-conjugated hydrophobicity modified glycol chitosan nanoparticles for targeted delivery of methotrexate in rheumatoid arthritis.

Targeted delivery to the Rheumatoid arthritis (RA) which is characterized by destruction and degeneration of bones due to chronic inflammation is of great need. RA being a chronic autoimmune disorder might result in severe disability and morbidity. A targeted delivery system is designed to deliver methotrexate (MTX) for RA. Here, we synthesized folic acid (FA) conjugated hydrophobically modified glycol chitosan (GC) self-assembled nanoparticles (FA-GC-SA) for the targeted delivery of MTX to RA. The FA conjugation and hydrophobic modification of GC by stearic acid (SA) was confirmed by Fourier-transform infrared spectroscopy (FTIR). The FA-GC-SA was exploited for developing targeted nanoparticles encapsulating MTX by the ionic gelation method. The particles were characterized and evaluated for their targeting potential in in vitro cell culture studies. Further their in vivo efficacy in arthritis induced rats using collagen was also evaluated. FTIR confirms the successful modification of GC-SA and FA-GC-SA. The FA-GC-SA-MTX of size 153 ± 9 nm were prepared with high encapsulation efficiency of MTX. The FA-GC-SA-MTX size was further confirmed by transmission electron microscopy (TEM). In vitro cell studies revealed the superior efficacy of FA-GC-SA-MTX in cell cytotoxicity. Also, significantly higher cellular uptake of FA functionalized FA-GC-SA-MTX was observed in comparison to non-functionalized GC-SA-MTX attributed to folate receptors (FRs) mediated endocytosis. In vivo results confirms the potential of FA-GC-SA-MTX which reduces reduces the pro-inflammatory cytokines, paw thickness, and arthritis score in collagen induced rats. The results shows that FRs targeted FA-GC-SA-MTX has superior efficacy in the treatment of RA.

Synthesis, characterization, and anticancer activity of folate γ-ferrocenyl conjugates

Novel folate γ-ferrocene conjugates were synthesized through a regiospecific route, and showed selectivity and enhanced cytotoxicity against Frα-positive malignant cells.

Induction of ADCC by a folic acid-mAb conjugate prepared by tryptophan-selective reaction toward folate-receptor-positive cancer cells.

We developed conjugates between monoclonal antibody (mAb) and folic acid (FA) by using a tryptophan (Trp)-selective reaction, which yields relatively homogenous products compared to conventional methods. The obtained mAb–FA conjugates showed significant cellular cytotoxicity toward folate receptor-expressing cancer cells, demonstrating that the conjugates retained the Fc region's original function.