Folate Receptor Research Articles

Exploring the Role of Nanotherapeutics for Diagnosis and Treatment of Solid Tumor

Background: Tumors are increasingly heterogeneous throughout the process of their growth, producing a mixed-cell community with a range of molecular features and susceptibility to therapies. Nanotechnology has shown tremendous potential in diagnosing and treating solid tumors. Objective: Most cancer-related deaths are attributed to the lack of early detection and effective treatment. Its early diagnosis helps overall survival and health-related quality of life in patients identified with cancer. Nanosystems are favorable for endocytic intracellular retention, high drug loading, enhanced therapeutic efficacy, greater drug-circulation time, superior dose scheduling for patient compliance, and site-specific targeting. Integrating nanosystems into biomedical applications will also reintroduce medicines that are no longer used in clinical practice because of certain drawbacks and help the identification of new active medicines with their sub-optimal kinetic profiles. This review provides insights about the targeted cancer treatment based on active targeting (folate receptor-α, heat shock protein, receptor 2 for epidermal human growth factor, and CD44 receptor) and various nano device-based systems. Methodology: The highly relevant articles were retrieved using various search engines, including Web of Sciences, Science Direct, Scihub, PubMed, Scopus, PubChem, Google Scholar, and others. The keywords and phrases used for the search are “liposomes,” “quantum dots,” “nanoparticles,” “nanocrystals,” “photodynamic therapy,” “passive targeting,” “active targeting,” “nanomaterials,” “nanotechnology,” “cancer,” “nanotheranostics” and several others. In this review, we briefly introduced the concept of the contribution of nanotheranostics to cancer therapy with their recent findings. We also discuss the role of biosensor-based nanosystems in cancer. Conclusion: This review addresses nanotechnology’s exciting role in identifying, imaging, and managing solid tumors and their immense potential.

Chitosan nanoplatform for the co-delivery of palbociclib and ultra-small magnesium nanoclusters: dual receptor targeting, therapy and imaging.

Theranostic nanoparticles have gained significant attention in cancer diagnosis and therapy. In this study, estrone (ES) and folic acid (FA) functionalized single and dual receptor targeted theranostic chitosan nanoparticles were developed for breast cancer imaging and therapy. These nanoparticles (NPs) were loaded with palbociclib (PB) and ultra-small magnesium nanoclusters (UMN). The developed nontargeted theranostic NPs (PB-UMN-CS-NPs), estrogen receptor targeted theranostic NPs (PB-UMN-CS-ES-NPs), folate receptor targeted theranostic NPs (PB-UMN-CS-FA-NPs), and dual targeted theranostic NPs (PB-UMN-CS-ES-FA-NPs) have particle sizes of 178.4 ± 1.21 nm, 181.6± 1.35 nm, 185.1± 1.33 nm, and 198.2± 1.43 nm with surface charges of +19.02± 0.382 mV, +13.89±0.410 mV, +16.72±0.527 mV and +15.23±0.377 mV, respectively. Cytotoxicity studies on estrogen receptor (ER) and folate receptor (FR) expressing breast cancer cells revealed that dual-targeted theranostic NPs (PB-UMN-CS-FA-ES-NPs) were more effective, inhibiting cell growth by 54.17 and 42.23 times in MCF-7 and T-47D cells compared to free PB, respectively. Additionally, developed NPs were capable of inhibiting the cell cycle progression of MCF-7 cells from the G1 phase to the S phase more efficiently compared to free PB. Ultrasound and photoacoustic (USG/PA) imaging demonstrated that dual targeted theranostic NPs were capable of effectively reducing hypoxic tumor volume and significantly suppressing tumor vascularity compared to free PB, nontargeted, FR targeted and ER targeted NPs. Moreover, in vivo optical imaging demonstrated tumor specific accumulation of the dual-targeted theranostic NPs. Furthermore, in vitro hemocompatibility and histopathological studies confirmed the biocompatibility of developed nanoformulations.

Folic acid promotes myoblast migration through Folr1 interacting with RhoA and improves skeletal muscle regeneration

Folic acid (FA) plays multiple roles in many biological processes. Myoblast intakes FA through endocytosis by folate receptor 1 (Folr1), which has vital role in regulating muscle development. However, the mechanism remains unclear. In this study, FA supplement experiment showed that FA promoted C2C12 cell differentiation through Folr1. Further exploration found that FA could promote C2C12 cell migration through Folr1 interacting with RhoA. Then stimulated RhoA/ROCK/LIMK/cofilin signaling pathway, and affected the distribution of microfilaments to improve C2C12 cell migration. Meanwhile, mice experiments also proved that FA could activate the expression of RhoA/ROCK/LIMK/cofilin signaling pathway in vivo and accelerate the process of skeletal muscle regeneration in mice. This discovery is helpful to further understand the molecular mechanism of FA regulating muscle development and provide new ideas for the treatment of muscle diseases.

Antibody-Drug Conjugates in Gynecologic Cancers.

Antibody-drug conjugates (ADCs) are a novel class of targeted cancer therapies with the ability to selectively deliver a cytotoxic drug to a tumor cell using a monoclonal antibody linked to a cytotoxic payload. The technology of ADCs allows for tumor-specificity, improved efficacy, and decreased toxicity compared to standard chemotherapy. Common toxicities associated with ADC use include ocular, pulmonary, hematologic, and neurologic toxicities. Several ADCs have been approved by the United States Food and Drug Administration (FDA) for the management of patients with recurrent or metastatic gynecologic cancers, a population with poor outcomes and limited effective treatment options. The first FDA-approved ADC for recurrent or metastatic cervical cancer was tisotumab vedotin, a tissue factor-targeting agent, after demonstrating response in the innovaTV 204 trial. Mirvetuximab soravtansine targets folate receptor alpha and is approved for use in patients with folate receptor alpha-positive, platinum-resistant, epithelial ovarian cancer based on results from the SORAYA trial. While there are no FDA-approved ADCs for the treatment of uterine cancer, trastuzumab deruxtecan, an anti-human epidermal growth factor receptor 2 (HER2) agent, is actively being investigated. In this review, we will describe the structure and mechanism of action of ADCs, discuss their toxicity profiles, review ADCs both approved and under investigation for the management of gynecologic cancers, and discuss mechanisms of ADC resistance.

A self-assembled three-dimensional hierarchical nanoflower: an efficient enzyme-mimetic material for cancer cell detection that improves ROS generation for therapy.

Three-dimensional (3D) nanomaterials with high functional properties are emerging as the most promising artificial enzymes for overcoming the significant disadvantages of natural enzymes. Anticancer therapy using 3D-enzyme mimetic materials has emerged as an essential development for catalyzing cancer cell destruction. We report for the first time a novel 3D-based enzyme mimetic material, CaMoO4/MoS2/CuS nanoflower (CMC NF), that exhibits a large specific surface area, uniform flower-like structure, excellent biocompatibility, and high porosity, making it a suitable candidate for cancer detection and therapy. Additionally, CMC NFs were conjugated with folic acid (FA) to selectively target cancer cells, resulting in FA-CMC NFs explicitly binding to overexpressed folate receptor alpha (FRα) in MDA-MB-231 cells. Based on the peroxidase activity, the FA-CMC NFs are an effective nanoprobe for the selective detection of MDA-MB-231 cells over a wide detection range (50 to 5.5 × 104 cells per mL) with a low limit of detection (LOD) value of 10 cells per mL. In addition to their cancer detection capability, the FA-CMC NFs also effectively generated ˙OH radicals in a concentration-dependent manner to treat cancer cells. Under light conditions, the FA-CMC NFs with H2O2 solution showed efficient degradation of methylene blue (MB) dye, and the solution color appeared to fade within 15 min, indicating that they generated ˙OH radicals, which can efficiently kill cancer cells. Thus, the superior functionality of FA-CMC NFs offers cost-effective, facile, and reliable cancer cell detection, providing a new treatment option for cancer treatment and diagnosis.

Binding Folate Receptor Alpha Autoantibody Is a Biomarker for Leucovorin Treatment Response in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects up to 1 in 36 children in the United States. It is a heterogeneous neurodevelopmental disorder with life-long consequences. Patients with ASD and folate pathway abnormalities have demonstrated improved symptoms after treatment with leucovorin (folinic acid), a reduced form of folate. However, biomarkers for treatment response have not been well investigated and clinical trials are lacking. In this retrospective analysis, a cohort of prospectively collected data from 110 consecutive ASD clinic patients [mean (SD) age: 10.5 (6.2) years; 74% male] was examined. These patients all underwent testing for folate receptor alpha autoantibodies (FRAAs) and soluble folate binding proteins (sFBPs) biomarkers and were treated with leucovorin, if appropriate. Analyses examined whether these biomarkers could predict response to leucovorin treatment as well as the severity of ASD characteristics at baseline. The social responsiveness scale (SRS), a measure of core ASD symptoms, and the aberrant behavior checklist (ABC), a measure of disruptive behavior, were collected at each clinic visit. Those positive for sFBPs had more severe ASD symptoms, and higher binding FRAA titers were associated with greater ABC irritability. Treatment with leucovorin improved most SRS subscales with higher binding FRAA titers associated with greater response. Leucovorin treatment also improved ABC irritability. These results confirm and expand on previous studies, underscore the need for biomarkers to guide treatment of folate pathways in ASD, and suggest that leucovorin may be effective for children with ASD.

Covalently hybridized carbon dots@mesoporous silica nanobeads as a robust and versatile phosphorescent probe for time-resolved biosensing and bioimaging.

Phosphorescence analyses have attracted broad attention due to their remarkable merits of the elimination of auto-fluorescence and scattering light. However, it remains a great challenge to develop novel materials with uniform size and morphology, stability, long lifetime, and aqueous-phase room temperature phosphorescence (RTP) characteristics. Herein, monodisperse and uniform RTP nanobeads were fabricated by an in situ covalent hybridization of carbon dots (CDs) and dendritic mesoporous silicon nanoparticles (DMSNs) via silane hydrolysis. The formation of Si-O-C and Si-C/N covalent bonds is beneficial for the fixation of vibrations and rotations of the luminescent centers. Specially, the nanopores of DMSNs provide a confined area that can isolate the triplet state of CDs from water and oxygen and thus ensure the occurrence of aqueous-phase RTP with an ultra-long lifetime of 1.195 s (seen by the naked eye up to 9 seconds). Through surface modifying folic acid (FA), CDs@DMSNs can serve as a probe to distinguish different cell lines that feature varying FA receptor expression levels. In addition, taking MCF-7 as the model, highly sensitive and quantitative detection (linear range: 103-106 cells per mL) has been achieved via an RTP probe. Furthermore, their potential applications in cellular and in vivo time-gated phosphorescence imaging have been proposed and demonstrated, respectively. This work would provide a new route to design CD-based RTP composites and promote their further applications in the medical and biological fields.

Water solubility and folate receptor affinity-driven plasma membrane-targeted carbon dots for cancer cell imaging.

Long-term labeling of the plasma membrane is crucial for visualizing membrane protein expression and morphological changes but is challenging due to the high fluidity of the plasma membrane, which can lead to probe diffusion or internalization of cells. Here, we precisely control the localization of carbon dots (M-CDs) on the plasma membrane without internalization after long-term observation under fluorescence microscopy. Adjusting the molar ratio of folic acid to o-phenylenediamine allowed fine-tuning of the water solubility and fluorescence emission of the carbon dots. Notably, carbon dots synthesized with a folic acid to o-phenylenediamine molar ratio of 1 : 10 (referred to as M-CD) exhibit excellent cell membrane targeting, likely due to the combination of suitable water-solubility and FA-FR affinity. The photostability of M-CDs is significantly superior to that of the commercial CellMask Crimson, allowing for specific recognition of folic acid receptor-positive cancer cells and minimal internalization over a period of up to 9 hours. This photostable, membrane-targeting M-CD provides a powerful tool for accurately, real-time, and non-invasively assessing the expression of folic acid receptors on cancer cell membranes and tumor metastasis.

Relationship between Changes of Serum Vascular Endothelial Growth Factor and Folate Receptor-α Levels and Clinical Efficacy of Toripalimab in Patients with Bladder Cancer.

This study aims to explore the changes of serum vascular endothelial growth factor (VEGF) and folate receptor-α (FR-α) levels in patients with bladder cancer before and after treatment with toripalimab and to analyse the relationship between the changes of VEFG and FR-α and the clinical efficacy of patients. A total of 176 patients with bladder cancer admitted to our hospital from January 2020 to January 2022 were selected as the research subjects. All patients were treated with toripalimab. The clinical efficacy and changes of serum VEGF and FR-α levels before and after treatment were observed. Logistic regression was used to analyse the relationship between serum VEGF and FR-α levels and the therapeutic effect of toripalimab, and receiver operating characteristic curve was used to evaluate the predictive value of serum VEGF and FR-α on the efficacy. The objective response rate and disease control rate after treatment were 31.82% and 70.45%, respectively. The serum VEGF and FR-α levels in patients after treatment were significantly lower than those before treatment (p < 0.001). The patients were divided into an effective group (n = 124) and an ineffective group (n = 52) according to clinical efficacy. The serum VEGF and FR-α levels of patients in the effective group were significantly lower than those of the ineffective group (p < 0.001). Logistic regression analysis showed that the elevated levels of serum VEGF (odds ratio = 1.226) and FR-α (odds ratio = 1.384) were the risk factors affecting the therapeutic effect of toripalimab (p < 0.05). The area under curve of the combined prediction of VEGF and FR-α was 0.920, the Youden index was 0.722, the sensitivity was 89.52%, the specificity was 82.69%, and the predictive value was higher than the single detection of VEGF or FR-α (p = 0.001, p < 0.001). The changes of serum VEGF and FR-α levels in patients with bladder cancer can predict the therapeutic effect of toripalimab. Before clinical treatment, the detection of the two indicators must be strengthened, and intervention measures must be formulated as early as possible to improve the prognosis of patients.

Mirvetuximab soravtansine in platinum-resistant recurrent ovarian cancer with high folate receptor-alpha expression: a cost-effectiveness analysis.

Mirvetuximab soravtansine (MIRV), a new antibody-drug conjugate, versus the investigator's choice of chemotherapy (IC) was the first treatment to demonstrate benefits for progression-free and overall survival in platinum-resistant recurrent ovarian cancer (PROC) with high folate receptor-alpha (high-FRα) expression. Efficacy, safety, and economic effectiveness make MIRV the new standard of care for these patients. Based on patients and clinical parameters from MIRASOL (GOG 3045/ENGOT-ov55) phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost and efficacy of MIRV and IC for PROC with high-FRα expression, considering the bevacizumab-pretreated situation from the American healthcare system. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net health benefits were the main outcome indicators and compared with willingness-to-pay threshold of $100,000/QALY. Sensitivity and scenario analyses were conducted. Compared with the IC, MIRV was associated with incremental costs of $538,251, $575,674, and $188,248 with the corresponding QALYs (LYs) increased by 0.90 (1.55), 1.09 (1.88), and 0.53 (0.79), leading to ICERs of $596,189/QALY ($347,995/LY), $530,061/QALY ($306,894/LY), and $1,011,310/QALY ($680,025/LY) in the overall, bevacizumab-naïve, and bevacizumab-pretreated patients, respectively. When MIRV is reduced by more than 75%, it may be a cost-effective treatment. At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

Nonclinical pharmacodynamics of boron neutron capture therapy using direct intratumoral administration of a folate receptor targeting novel boron carrier.

Boron neutron capture therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via convection-enhanced delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional nonclinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration. In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration. The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols. This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.

Low-dose daily folic acid (400 μg) supplementation does not affect regulation of folate transporters found present throughout the terminal ileum and colon of humans: a randomized clinical trial

BackgroundFolic acid supplementation during the periconceptional period reduces the risk of neural tube defects in infants, but concern over chronic folic acid exposure remains. An improved understanding of folate absorption may clarify potential risks. Folate transporters have been characterized in the small intestine, but less so in the colon of healthy, free-living humans. The impact of folic acid fortification or supplementation on regulation of these transporters along the intestinal tract is unknown. ObjectiveThe objective was to characterize expression of folate transporters/receptor (FT/R) and folate hydrolase, glutamate carboxypeptidase II (GCPII), from the terminal ileum and throughout the colon of adults and assess the impact of supplemental folic acid. MethodsIn this 16-wk open-labeled randomized clinical trial, adults consumed a low folic acid-containing diet, a folate-free multivitamin, and either a 400 μg folic acid supplement or no folic acid supplement. Dietary intakes and blood were assessed at baseline, 8 wk, and 16 wk (time of colonoscopy). Messenger RNA (mRNA) expression and protein expression of FT/R and GCPII were assessed in the terminal ileum, cecum, and ascending and descending colon. ResultsAmong 24 randomly assigned subjects, no differences in dietary folate intake or blood folate were observed at baseline. Mean ± SD red blood cell folate at 16 wk was 1765 ± 426 and 911 ± 242 nmol/L in the 400 and 0 μg folic acid group, respectively (P < 0.0001). Reduced folate carrier, proton-coupled folate transporter, and folate-receptor alpha expression were detected in the terminal ileum and colon, as were efflux transporters of breast cancer resistance protein and multidrug resistance protein-3. Other than a higher mRNA expression of FR-alpha and GCPII in the 400 μg supplement group in the ascending colon, no treatment differences were observed (P < 0.02). ConclusionsFolate transporters are present throughout the terminal ileum and colon; there is little evidence that a low dose of folic acid supplementation affects colonic absorption.This trial was registered at clinicaltrials.gov as NCT03421483.

Optimizing the Synthesis of Folic Acid Conjugated Silver Nanoparticles by Box-Behnken Design to Target Breast Cancer Cells

In this study, the synthesis of folic acid conjugated silver nanoparticles (FA&amp;AgNPs) was optimized. FA&amp;AgNPs were synthesized by reduction of silver nitrate with folic acid, which is widely used to target folate receptors in cancer cells. Five independent variables (stirring speed, AgNO3 concentration, folic acid concentration, AgNO3 volume/folic acid volume, and temperature) that were effective on silver nanoparticle synthesis were determined. Based on the independent variables, an experimental plan consisting of 46 experiments was created using the Box-Behnken design (BBD). Nanoparticle formation, physical color change, UV-Vis absorption spectroscopy, Dynamic Light Scattering (DLS) analysis, and Fourier Transform Infrared (FTIR) analysis were evaluated. The mean particle size and zeta potential of FA&amp;AgNPs produced under optimized conditions were measured as 207±4.3 nm and -51.6 mV±2.5, respectively. Cytotoxicity tests were performed to evaluate the anticancer activity of FA&amp;AgNPs in breast cancer cell lines. The IC50 values for MDA-MB-231 breast cancer cells at 24 hours and 48 hours were 20.0 µg/mL and 16.9 µg/mL, respectively, and 26.3 µg/mL and 31.5 µg/mL for MCF-7 cells. The findings indicated that FA&amp;AgNPs have the potential to be an effective anticancer agent in breast cancer cells.

Fluorescence mechanism and biomedical applications of graphene quantum dots

Graphene quantum dots (GQDs) are fluorescent graphene nanoparticle that have tunable emission wavelength, high emission intensity and biocompatibility. The fluorescence mechanism is still indecisive, yet explanations exist. Surface or edge defects and quantum confinement are two major explanations and they accounted for the florescence properties observed so far. GQDs quantum confinement is applied to change the emission wavelength. Surface functional groups usually improve biocompatibility and solubility. Under several cases, surface defects are also engineered to tune emission wavelength and intensity to serve specific engineering propose. GQDs have found applications in bioimaging, biosensing, and therapy. GQDs can generate high intensity emission in the NIR-II window which is ideal in in vivo bioimaging. GQDs can be generated from folic acid in a one-step procedure. The GQDs generated this way can track folate receptor and help cancer diagnostics. High intensity emission also enables GQDs to be used in photothermal or photodynamic therapy. Future applications will be promoted by a better understanding of GQDs fluorescence mechanisms.

Electrochemical biosensor based on PAMAM functionalized MXene nanoplatform for detection of folate receptor

The level of folate receptor (FR) has become one of the independent factors for measuring human tumor diseases. The precise quantification of FR is helpful for the early diagnosis and subsequent treatment of tumors. The modification of electrodes is a key issue in ensuring and enhancing the electrochemical biosensing ability. In this study, we in-situ synthesized a nanocomposite material with excellent conductivity and stability by grafting first-generation poly(amidoamine) dendrimers onto the MXene (Ti3C2TX) as the immobilized matrix (PAMAM@MXene). An electrochemical sensor was developed for FR monitor by loading the PAMAM@MXene on screen-printed carbon electrodes (SPCEs). Scanning electron microscopy (SEM) supported the effective synthesis of PAMAM@MXene. Under optimal conditions, the prepared sensor achieved the quantification of FR with a wide range of concentrations from 10 ng/mL to 1000 ng/mL with a detection limit (LOD) of 5.6 ng/mL. It also exhibited satisfactory selectivity, reproducibility, and stability, which provided the possibility for expanding new pathways in the detection of clinical FR.

Folate regulation of planar cell polarity pathway and F-actin through folate receptor alpha.

Folate deficiency contribute to neural tube defects (NTDs) which could be rescued by folate supplementation. However, the underlying mechanisms are still not fully understood. Besides, there is considerable controversy concerning the forms of folate used for supplementation. To address this controversy, we prepared culture medium with different forms of folate, folic acid (FA), and 5-methyltetrahydrofolate (5mTHF), at concentrations of 5 μM, 500 nM, 50 nM, and folate free, respectively. Mouse embryonic fibroblasts (MEFs) were treated with different folates continuously for three passages, and cell proliferation and F-actin were monitored. We determined that compared to 5mTHF, FA showed stronger effects on promoting cell proliferation and F-actin formation. We also found that FOLR1 protein level was positively regulated by folate concentration and the non-canonical Wnt/planar cell polarity (PCP) pathway signaling was significantly enriched among different folate conditions in RNA-sequencing analyses. We demonstrated for the first time that FOLR1 could promote the transcription of Vangl2, one of PCP core genes. The transcription of Vangl2 was down-regulated under folate-deficient condition, which resulted in a decrease in PCP activity and F-actin formation. In summary, we identified a distinct advantage of FA in cell proliferation and F-actin formation over 5mTHF, as well as demonstrating that FOLR1 could promote transcription of Vangl2 and provide a new mechanism by which folate deficiency can contribute to the etiology of NTDs.

Functionalized Carbon Nano-Onions as a Smart Drug Delivery System for the Poorly Soluble Drug Carmustine for the Management of Glioblastoma.

The drug delivery system for transporting anticancer agents to targeted tissues in the body is a challenging issue. In search of a suitable biocompatible carrier having controlled and sustained drug release properties of poorly soluble drugs, carbon nano-onions (CNOs) were loaded with an anticancer drug, bis-chloroethyl nitrosourea (BCNU/carmustine). CNOs being autofluorescent, drug-loaded functionalized CNOs (f-CNO-BCNU) can be detected in vivo. Transmission electron microscopy (TEM) and differential light scattering (DLS) techniques were used to analyze the sizes of these f-CNOs. The molecular study revealed that the f-CNO-BCNU readily and noncovalently binds with the folate receptors present on the cancer cell surface in excess. Computer modeling and molecular dynamics simulation followed by binding free energy calculation shows f-CNOs have -29.9 kcal/mol binding free energy, and it noncovalently binds the receptor FRα using loop dynamics of three essential loops present in the protein along with polar stabilization interactions provided by Asp55 and Glu86 residues present in the active site. The f-CNO effectively decreased cancer cell viability with a low IC50 value (the concentration that led to 50% killing of the cells). The cell-based Franz diffusion assay was performed to study the drug release profile. The f-CNO-BCNUs also decreased the mitochondrial membrane potential of U87 cells, increased reactive oxygen species release, and caused a loss of mitochondrial membrane integrity. The f-CNOs also increased the percentage of apoptotic cells observed by the Annexin V assay. Based on observed results, it can be concluded that the f-CNO-BCNU efficiently targets the cancer cells, enhances the bioavailability of carmustine, and can be used as a smart chemotherapeutic agent. This strategy offers better patient compliance and greater bioavailability of the drug.

Folate decorated chitosan-chondroitin sulfate nanoparticles loaded hydrogel for targeting macrophages against rheumatoid arthritis

Inflammatory cell infiltration, particularly macrophages, plays a major contribution to the pathogenesis of Rheumatoid Arthritis (RA). Exploiting the overexpression of folate receptors (FR-β) on these recruited macrophages has gained significant attraction for ligand-targeted delivery. Leflunomide (LEF), being an immunomodulatory agent is considered the cornerstone of the therapy, however, its oral efficacy is impeded by low solubility and escalating adverse effects profile. Therefore, in the present work, we developed Folate-conjugated chitosan-chondroitin sulfate nanoparticles encapsulating LEF for selective targeting at inflammatory sites in RA. For this purpose, the folate group was first conjugated with the chitosan polymer. After which, Folate Leflunomide Nanoparticles (FA-LEF-NPs) were synthesized through the ionotropic gelation method by employing FA-CHI and CHS. The polymers CHI and CHS were also presented with innate anti-inflammatory and anti-rheumatic attributes that were helpful in provision of synergistic effects to the formulation. These nanoparticles were further fabricated into a hydrogel, employing almond oil (A.O) as a permeation enhancer. The in vivo studies justified the preferential accumulation of FA-conjugated nanoparticles at inflamed joints more than any other organ in comparison to the free LEF and LEF-NPs formulation. The FA-LEF-NPs loaded hydrogel also ascertained a minimal adverse effect profile with an improvement of inflammatory cytokines expression.

CAR-T cell immunotherapy for ovarian cancer: hushing the silent killer.

As the most lethal gynecologic oncological indication, carcinoma of the ovary has been ranked as the 5th cause of cancer-related mortality in women, with a high percentage of the patients being diagnosed at late stages of the disease and a five-year survival of ~ 30%. Ovarian cancer patients conventionally undergo surgery for tumor removal followed by platinum- or taxane-based chemotherapy; however, a high percentage of patients experience tumor relapse. Cancer immunotherapy has been regarded as a silver lining in the treatment of patients with various immunological or oncological indications; however, mirvetuximab soravtansine (a folate receptor α-specific mAb) and bevacizumab (a VEGF-A-specific mAb) are the only immunotherapeutics approved for the treatment of ovarian cancer patients. Chimeric antigen receptor T-cell (CAR-T) therapy has achieved tremendous clinical success in the treatment of patients with certain B-cell lymphomas and leukemias, as well as multiple myeloma. In the context of solid tumors, CAR-T therapies face serious obstacles that limit their therapeutic benefit. Such hindrances include the immunosuppressive nature of solid tumors, impaired tumor infiltration, lack of qualified tumor-associated antigens, and compromised stimulation and persistence of CAR-Ts following administration. Over the past years, researchers have made arduous attempts to apply CAR-T therapy to ovarian cancer. In this review, we outline the principles of CAR-T therapy and then highlight its limitations in the context of solid tumors. Ultimately, we focus on preclinical and clinical findings achieved in CAR-T-mediated targeting of different ovarian cancer-associated target antigens.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer

BackgroundMirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody–drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States.MethodsWe conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator’s choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes.ResultsA total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P=0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).ConclusionsAmong participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.)