Folate Receptor Research Articles

Folate Receptor Targeting Mn(II) Complex Encapsulated Porous Silica Nanoparticle as an MRI Contrast Agent for Early-State Detection of Cancer.

Cancer is recognized as one of the major causes of mortality, however, early-stage detection can increase the survival chance greatly. It is recognized that folate receptors are gradually overexpressed in the cellular membrane with the progress of cancer from stage 1 to stage 4. Utilizing the fact, herein, developed a porous silica nanoparticle system C1@SiO2-FA-NP; A) impregnated with thermodynamically stable Mn(II) complex (1) molecules within the core of the nanoparticle, and B) surface functionalized with folate units. It exhibited a high longitudinal relaxivity value r1 = 21.45 mM-1s-1 that substantially increased to r1 = 40.97 mM-1s-1 in the presence of 0.67mM concentration of BSA under the physiological condition. The in vitro fluorescent images after surface conjugation of C1@SiO2-FA-NP with FITC (fluorescein isothiocyanate) buttressed the inclusion of the nanoparticle exclusively within the cancerous HeLa cells than that of healthy HEK293 cells. The importance of the surface-bound folate unit in the nanoparticle is further established by comparing the fluorescent images of HeLa cells in the absence of the group. Finally, the applicability of C1@SiO2-FA-NP as the T1-weighted MRI contrast agent for early-stage cancer diagnosis is established within C57BL/6 mice after infecting the mice with HeLa cells.

Mirvetuximab soravtansine: A breakthrough in targeted therapy for platinum-resistant ovarian cancer.

Ovarian cancer, ranked as the second leading cause of gynecologic malignancy-related deaths globally, poses a formidable challenge despite advances in early detection and treatment modalities. This paper explores the efficacy and safety of mirvetuximab soravtansine, the first folate receptor alpha (FRα)-targeting antibody-drug conjugate, in platinum-resistant ovarian cancer expressing FRα. A review of 4 key studies involving 453 participants consistently demonstrates mirvetuximab soravtansine's clinically meaningful antitumor activity and favorable safety profile. Clinical implications emphasize mirvetuximab soravtansine's pivotal role in targeted therapy, especially for high FRα-expressing tumors, potentially reshaping platinum-resistant ovarian cancer management. The combination therapy approach introduces a novel dimension, suggesting enhanced therapeutic outcomes. Even in heavily pretreated patients, mirvetuximab soravtansine's favorable tolerability positions it as a viable option. The reliability of archival tissue for FRα assessment simplifies patient selection, streamlining accessibility to targeted therapies. However, identified gaps, including limited diversity in patient populations, sparse quality of life data, and the need for long-term safety information, indicate areas for future research. Exploration of additional biomarkers predicting mirvetuximab soravtansine responsiveness is essential for personalized treatment.

In-silico Screening of Novel Drug Against Ovarian Cancer by Phytochemicals from Carica Papaya

Most of the women population suffer from many kinds of reproductive health issues. The cause of the diseases may be genetic or acquired causes. Ovarian cancer is a genetic aberration caused in females generation after generation. Various genes cause the genetic disorder, mainly BRCA 1 and BRCA 2. These major genes are present in chromosome 17q. 77% of the epithelial ovarian cancer tumor genes are in chromosome 17q. The disorder can be a germline mutation in females who express this disease before age 30. By DNA sequencing technology, the functioning of BRCA1 and BRCA2 can be discovered along with the involvement of the additional genes that compromise the homologous recombination (HR) pathway. Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer and presents a major clinical challenge due to limited treatment options. Folate receptor alpha (FRα), encoded by the FOLR1 gene in chromosome 11q13.4, is an attractive therapeutic target due to its prevalent and high expression in EOC cells. The folate receptors FOLR1 and FOLR2 are overexpressed in multiple cancers. The overexpression of FOLR1 is often associated with increased cancer progression and poor patient prognosis. There is emerging evidence that FOLR1 is involved in signaling pathways that are independent of one-carbon metabolism.

Dolutegravir induces FOLR1 expression during brain organoid development.

During the first month of pregnancy, the brain and spinal cord are formed through a process called neurulation. However, this process can be altered by low serum levels of folic acid, environmental factors, or genetic predispositions. In 2018, a surveillance study in Botswana, a country with a high incidence of human immunodeficiency virus (HIV) and lacking mandatory food folate fortification programs, found that newborns whose mothers were taking dolutegravir (DTG) during the first trimester of pregnancy had an increased risk of neural tube defects (NTDs). As a result, the World Health Organization and the U.S. Food and Drug Administration have issued guidelines emphasizing the potential risks associated with the use of DTG-based antiretroviral therapies during pregnancy. To elucidate the potential mechanisms underlying the DTG-induced NTDs, we sought to assess the potential neurotoxicity of DTG in stem cell-derived brain organoids. The gene expression of brain organoids developed in the presence of DTG was analyzed by RNA sequencing, Optical Coherence Tomography (OCT), Optical Coherence Elastography (OCE), and Brillouin microscopy. The sequencing data shows that DTG induces the expression of the folate receptor (FOLR1) and modifies the expression of genes required for neurogenesis. The Brillouin frequency shift observed at the surface of DTG-exposed brain organoids indicates an increase in superficial tissue stiffness. In contrast, reverberant OCE measurements indicate decreased organoid volumes and internal stiffness.

Folic acid-mediated enhancement of the diagnostic potential of luminescent europium-doped hydroxyapatite nanocrystals for cancer biomaging

Early and accurate cancer diagnosis is crucial for improving patient survival rates. Luminescent nanoparticles have emerged as a promising tool in fluorescence bioimaging for cancer diagnosis. To enhance diagnostic accuracy, ligands promoting endocytosis into cancer cells are commonly incorporated onto nanoparticle surfaces. Folic acid (FA) is one such ligand, known to specifically bind to folate receptors (FR) overexpressed in various cancer cells such as cervical and ovarian carcinoma. Therefore, surface modification of luminescent nanoparticles with FA can enhance both luminescence efficiency and diagnostic accuracy. In this study, luminescent europium-doped hydroxyapatite (EuHAp) nanocrystals were prepared via hydrothermal method and subsequently modified with (3-Aminopropyl)triethoxysilane (APTES) followed by FA to target FR-positive human cervical adenocarcinoma cell line (HeLa) cells. The sequential grafting of APTES and then FA formed a robust covalent linkage between the nanocrystals and FA. Rod-shaped FA-modified EuHAp nanocrystals, approximately 100 nm in size, exhibited emission peaks at 589, 615, and 650 nm upon excitation at 397 nm. Despite a reduction in photoluminescence intensity following FA modification, fluorescence microscopy revealed a remarkable 120-fold increase in intensity compared to unmodified EuHAp, attributed to the enhanced uptake of FA-modified EuHAp. Additionally, confocal microscope observations confirmed the specificity and the internalization of FA-modified EuHAp nanocrystals in HeLa cells. In conclusion, the modification of EuHAp nanocrystals with FA presents a promising strategy to enhance the diagnostic potential of cancer bioimaging probes.

Targeted delivery of interleukin-12 plasmid into HepG2 cells through folic acid conjugated graphene oxide nanocarrier.

Successful gene therapy relies on carriers to transfer genetic materials with high efficiency and low toxicity in a targeted manner. To enhance targeted cell binding and uptake, we developed and synthesized a new gene delivery vector based on graphene oxide (GO) modified by branched polyethyleneimine (BPEI) and folic acid (FA). The GO-PEI-FA nanocarriers exhibit lower toxicity compared to unmodified PEI, as well as having the potential to efficiently condense and protect pDNA. Interestingly, increasing the polymer content in the polyplex formulation improved plasmid transfer ability. Substituting graphene oxide for PEI at an N/P ratio of 10 in the HepG2 and THP1 cell lines improved hIL-12 expression by up to approximately eightfold compared to simple PEI, which is twice as high as GO-PEI-FA in Hek293 at the same N/P ratio. Therefore, the GO-PEI-FA described in this study may serve as a targeting nanocarrier for the delivery of the hIL-12 plasmid into cells overexpressing folic acid receptors, such as those found in hepatocellular carcinoma.

Fullerene C60 Conjugate with Folic Acid and Polyvinylpyrrolidone for Targeted Delivery to Tumor Cells.

The use of targeted drug delivery systems, including those based on selective absorption by certain receptors on the surface of the target cell, can lead to a decrease in the minimum effective dose and the accompanying toxicity of the drug, as well as an increase in therapeutic efficacy. A fullerene C60 conjugate (FA-PVP-C60) with polyvinylpyrrolidone (PVP) as a biocompatible spacer and folic acid (FA) as a targeting ligand for tumor cells with increased expression of folate receptors (FR) was obtained. Using 13C NMR spectroscopy, FT-IR, UV-Vis spectrometry, fluorometry and thermal analysis, the formation of the conjugate was confirmed and the nature of the binding of its components was established. The average particle sizes of the conjugate in aqueous solutions and cell culture medium were determined using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). The FA-PVP-C60 showed antiradical activity against •DPPH, •OH and O2•-, but at the same time, it was shown to generate 1O2. It was found that the conjugate in the studied concentration range (up to 200 μg/mL) is non-toxic in vitro and does not affect the cell cycle. To confirm the ability of the conjugate to selectively accumulate through folate-mediated endocytosis, its uptake into cells was analyzed by flow cytometry and confocal microscopy. It was shown that the conjugate is less absorbed by A549 cells with low FR expression than by HeLa, which has a high level of expression of this receptor.

Chemical potential and biomedical activity of gold nanoparticles in cancer and drug delivery systems: an updat

Gold nanoparticles (AuNPs) are broadly utilized in medical fields because of its unique potential, biomedical activity and physicochemical properties. The biocompatible nature, optical properties, and minor cytotoxicity are the key features of AuNPs which make them valuable for biomedical applications. Today, AuNPs are widely used for cancer therapy, bioimaging, biosensing, radiotherapy, photodynamic therapy and drug delivery system. The present article illustrates the current progress in AuNPs synthesis, properties of AuNPs, various biomedical activity of AuNPs in therapeutic fields and drug delivery systems. Apart from numerous benefits the chemically synthesized AuNPs also creates certain level of toxicity in the living system which represents confronts of AuNPs against biomedical applications. Reducing its cytotoxic nature and development of green AuNPs can led to development of new history in field of medical science and clinical trials. Thus, the present review article deals with the compiled study of various fundamental research over AuNPs such as its chemical and bio-synthesis, biomedical and therapeutic applications viz. plasmonic photothermal therapy, photodynamic therapy, folate receptor targeting, targeted drug delivery etc. The article also finds some of its confronts against biomedical application because of its cytotoxic nature and its possible future prospects.

Enhanced localized therapeutic precision: A face-to-face folate-targeted Cu2+-mediated nanotherapy with thermosensitive sustained-release system

Safe and effective Cu2+ supplementation in local lesion is crucial for minimizing toxicity of DSF-based chemotherapy. Targeted delivery of Cu2+ appears more promising. Intraperitoneal chemotherapy for peritoneal carcinoma (PC) establishes “face-to-face” contact between targeted nanocarriers and tumor tissue. Herein, this study developed a biodegradable, injectable thermosensitive hydrogel that coencapsulating DSF submicroemulsion (DSF-SE) and folate-modified liposome loading glycyrrhizic acid-Cu (FCDL). FCDL acted as ‘beneficial horse’ to target the tumor-localized folate receptor, thus liberating Cu2+ in tumor nidus. The prepared FCDL and DSF-SE were found with uniform sizes (160.2 nm, 175.4 nm), low surface charge (−25.77 mV, −16.40 mV) and high encapsulation efficiency (97.93 %, 90.08 %). In vitro drug release profile of FCDL, DSF-SE and FCDL＆DSF-SE@G followed a sustained release pattern. And the release behavior of Cu2+ from FCDL was pH-related, i.e., Cu2+ was released faster under acidic condition. When FCDL and DSF-SE were loaded into an PLGA-PEG-PLGA-based hydrogel system, FCDL＆DSF-SE@G was formed to ensure separated delivery of Cu2+ and DSF in space but synchronized release over time. The rheology experiment showed a satisfactory gelling temperature of 32.7 °C. In vitro cytotoxicity study demonstrated that FCDL＆DSF-SE@G significantly lowered the IC50 of free Cu2+/DSF, Cu2+/DSF hydrogel and non-targeted analogue by almost 70 %, 65 % and 32 %, respectively. Accordingly, in tumor-bearing mice, FCDL＆DSF-SE@G augmented the tumor inhibition rates for the same formulations by 352 %, 145 % and 44 %, respectively. The main mechanism was attributed to higher uptake of FCDL and DSF-SE, resulting in increased Cu(DDTC)2 formation, ROS production and cell apoptosis. In conclusion, this targeted nanotherapy approach with dual-nanocarriers loaded hydrogel system, with its focus on face-to-face contact between nanocarriers and tumor tissues in the peritoneal cavity, holds significant promise for intraperitoneal chemotherapy in PC.

Folic acid-tripeptide-conjugated synthetic biodegradable nanoparticle-loaded with Ormeloxifene potentially inhibited breast cancer xenograft tumor

ObjectivesOrmeloxifene (OLF) is an estrogen receptor modulator used in breast cancer treatment with highly favorable pharmacodynamics and pharmacokinetic properties. Folic acid (FA) receptor overexpresses in breast cancer cells. Hence, the study was intended to evaluate the therapeutic potential of OLF-encapsulated FA-peptide-conjugated nanoparticles (FA-Pep-OLF-NP) for breast cancer treatment. MethodsWe prepared folic acid tripeptide conjugated OLF-encapsulated PLGA nanoparticles. The surface conjugation of folic acid-tripeptide was assessed by FTIR and XPS analysis. Selectivity, cytotoxicity, apoptosis, mitochondrial depolarization, reactive oxygen species, and cell cycle analysis of the experimental nanoparticles were tested on human breast cancer cells, MDA-MB-231 and MCF-7. The therapeutic efficacy of FA-Pep-OLF-NP and unconjugated nanoparticle OLF-NP was compared in the MDA-MB-231-xenograft tumor animal model. ResultsOLF-NP and FA-Pep-OLF-NP exhibited 4.8 % and 4.5 % w/w of drug loading, respectively. The particles were spherical with a smooth surface and uniform size distribution. FA-Pep-OLF-NP revealed higher cytotoxicity, mitochondrial depolarization, and apoptosis potential in MDA-MB-231 cells compared to MCF-7 cells. Tumor uptake and tumor volume reduction by FA-Pep-OLF-NP and OLF-NP were established in MDA-MB-231 tumor-bearing nude mice. ConclusionFA-Pep-OLF-NP showed preferential delivery of OLF to the breast cancer cells and in breast tumors compared to OLF-NP and showed more drug accumulation in breast cancer xenograft models. FA-Pep-OLF-NP delayed the progress of folate receptor overexpressed breast cancer.

Enhanced efficiency of photodynamic therapy-mediated the plant pigment hypericin through Folate-PEG functionalized chitosan nanoparticles

Hypericin (Hy), an anthraquinone-derived pigment, has recently attracted attention as a safe and natural photosensitizer for photodynamic therapy (PDT). However, its clinical applications have been limited by its hydrophobicity and off-target photoactivity. This work aimed to enhance efficacy of Hy-based PDT using a high-efficiency and high-specificity vehicle for targeted delivery Hy to the cancer cells. Hy-loaded chitosan nanoparticles (Hy-CNs) were prepared using the ionic gelation technique, and further functionalized with folic acid (FA) and PEG. These generated nanoparticles (PEG-FA-Hy-CNs) were physicochemically characterized using, FT-IR spectroscopy, UV–Vis spectroscopy, dynamic light scattering, and SEM analysis and then compared with other Hy formulations in terms the singlet oxygen production, intra cellular uptake, and phototoxicity under suitable irradiation (590 nm, 10 Jcm−2). All the formed nanostructures presented a mean particle size about 200–300 nm and greater than 80 % entrapment efficiency. Drug release data of PEG-FA-Hy-CNs indicated a sustained release of Hy and a good correlation with Higuchi model. PEG-FA-Hy-CNs induced a much higher singlet oxygen formation, cellular uptake, photoactivity, and apoptosis compared to Hy-CN, Hy-FA, Hy-PEG, and free Hy. Additionally, these effects were much higher in FA receptors over-expressing breast cancer cells than healthy cell lines. Results suggest that PEG-FA-Hy-CNs can be used for controlled Hy release and active targeting of breast cancer cells, which are beneficial for Hy-based PDT.

Expression of Potential Antibody-Drug Conjugate Targets in Cervical Cancer.

(1) Background: There is a huge unmet clinical need for novel treatment strategies in advanced and recurrent cervical cancer. Several cell membrane-bound molecules are up-regulated in cancer cells as compared to normal tissue and have revived interest with the introduction of antibody-drug conjugates (ADCs). (2) Methods: In this study, we characterize the expression of 10 potential ADC targets, TROP2, mesotheline, CEACAM5, DLL3, folate receptor alpha, guanylatcyclase, glycoprotein NMB, CD56, CD70 and CD138, on the gene expression level. Of these, the three ADC targets TROP2, CEACAM5 and CD138 were further analyzed on the protein level. (3) Results: TROP2 shows expression in 98.5% (66/67) of cervical cancer samples. CEACAM5 shows a stable gene expression profile and overall, 68.7% (46/67) of cervical cancer samples are CEACAM-positive with 34.3% (23/67) of cervical cancer samples showing at least moderate or high expression. Overall, 73.1% (49/67) of cervical cancer samples are CD138-positive with 38.8% (26/67) of cervical cancer samples showing at least moderate or high expression. (4) Conclusions: TROP2, CEACAM5 or CD138 do seem suitable for further clinical research and the data presented here might be used to guide further clinical trials with ADCs in advanced and recurrent cervical cancer patients.

The role of singlet oxygen and hydroxyl radical in the photobleaching of meso-substituted cationic pyridyl porphyrins in the presence of folic acid

Using a photosensitizer (PS), light, and oxygen, photodynamic therapy creates cytotoxic reactive oxygen species, such as singlet oxygen (1O2), that kill cancer cells. Many cancer cell lines have up to 300 times more folic acid receptors than healthy cells. Therefore, folic acid is often used to improve selectivity of PSs. Photobleaching poses a disadvantage for PSs. In this paper, we have studied the photoinduced changes of meso-substituted cationic pyridyl porphyrins in the presence of folic acid using fluorescence and absorption spectroscopy. In this work, it was demonstrated that L-histidine, which is a 1O2 quencher, and D-mannitol, which is a hydroxyl radical quencher, can reduce photobleaching of cationic porphyrins and their interaction products with FA. This implies both singlet oxygen and hydroxyl radicals are involved in photobleaching. Additionally, our study revealed certain important features of the photobleaching of cationic porphyrins in the presence of folic acid.

Two-photon NIR-responsive carbon dots incorporated into NMOFs for targeted photodynamic therapy

In recent years, Photodynamic therapy (PDT) has shown great potential in clinics to treat cancer. Due to the limited depth range of UV or visible laser light penetration, the eradication of solid tumors using traditional photosensitizer is difficult. Here, we report the development of a new NIR active photosensitizer covalently conjugated to nanoscale metal-organic frameworks (NMOFs) for the eradication of deep-seated tumors. This photosensitizer can generate reactive oxygen species (ROS) in the presence of near-infrared light irradiation (980 nm) for PDT. Therefore, we use a strategy to develop two-photon absorbing carbon dots with a fluorescence quantum yield of 13%. The NMOFs are fabricated in the presence of folic acid, which enables them to target cancer cells that overexpress the folate receptor. NMOFs are used as a nanocarrier for CDs and are employed to achieve targeted PDT. This study is the first to observe that carbon dots embedded in NMOF composite could generate singlet oxygen (1O2) under the 980 nm laser light irradiation and also specifically target cancer cells. At a concentration of 100 μg/ml, the nanocomposite demonstrated a 73% rate of cell inhibition. The primary results reported here will show great potential in the future to develop multifunctional carbon dots for targeted two-photon PDT in the presence of higher wavelength light irradiation.

Combined ROS Sensitive Folate Receptor Targeted Micellar Formulations of Curcumin Effective Against Rheumatoid Arthritis in Rat Model.

Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for RA therapy remain unsatisfactory because of their low efficiency and obvious adverse effects. Therefore, we here established RA microenvironment-responsive targeted micelles that can respond to the increase in reactive oxygen species (ROS) levels in the joint and improve macrophage-specific targeting of loaded drugs. We here prepared ROS-responsive folate-modified curcumin micelles (TK-FA-Cur-Ms) in which thioketal (TK) was used as a ROS-responsive linker for modifying polyethylene glycol 5000 (PEG5000) on the micellar surface. When micelles were in the ROS-overexpressing inflammatory microenvironment, the PEG5000 hydration layer was shed, and the targeting ligand FA was exposed, thereby enhancing cellular uptake by macrophages through active targeting. The targeting, ROS sensitivity and anti-inflammatory properties of the micelles were assessed in vitro. Collagen-induced arthritis (CIA) rats model was utilized to investigate the targeting, expression of serum inflammatory factors and histology change of the articular cartilage by micelles in vivo. TK-FA-Cur-Ms had a particle size of 90.07 ± 3.44 nm, which decreased to 78.87 ± 2.41 nm after incubation with H2O2. The micelles exhibited in vitro targeting of RAW264.7 cells and significantly inhibited inflammatory cytokine levels. Pharmacodynamic studies have revealed that TK-FA-Cur-Ms prolonged the drug circulation and exhibited augmented cartilage-protective and anti-inflammatory effects in vivo. The unique ROS-responsive targeted micelles with targeting, ROS sensitivity and anti-inflammatory properties were successfully prepared and may offer an effective therapeutic strategy against RA.

In silico modeling, development, characterization, in-vitro cytotoxicity, pharmacokinetic, and toxicological studies of folate-receptor targeted micelles containing cisplatin and upconversion nanoparticles for lung cancer therapy

Folate receptor α (FRα) is one of the best motifs to recognize lung cancer, therefore it can be utilized for targeted delivery of therapeutic agents in lung cancer therapy. Herein, we developed folate-receptor-targeted micelles (CPTT-FA) for the co-delivery of cisplatin (CDDP) and upconversion nanoparticles (UCNP) as theranostics for lung cancer therapy. Initially, the binding affinity of FRα (4MK6) was studied, resulting in good docking scores of −7.6 towards 4MK6 by stimulating PI3K inhibition in lung cancer cells. Micelles, fabricated using the solvent-casting technique, exhibited favorable characteristics, including an average size ranging from 80 to 190 nm with a narrow size distribution and spherical morphology. The zeta potential of −29.4 mV indicates stability and potential for targeted delivery. The drug encapsulation efficiency of the micelles was high, ranging from 70 % to 90 %. In vitro, release studies demonstrated an initial burst release of 40 % within 4 h, the release rate was controlled up to 72 h in PBS at pH 6.8. Afterthat, IC50 of the CPTT-FA micelles was found to be 11.6-fold lower than Ciszest-50. Heamolysis study has proven the greater biocompatibility of CPTT-FA. Pharmacokinetic investigations exhibited a significant enhancement with a three-fold increase in the area under the concentration-time curve (AUC0-t) and a 3.7-fold extension in half-life (t1/2). CDDP resistance in lung cancer presents a promising avenue for targeted therapy using UCNP, addressing challenges posed by FRα-positive cases and improving prognosis. Further clinical investigations are needed to validate the effectiveness and safety of this approach before its widespread implementation.

Conjugation of folic acid onto poly (acrylic acid-co-allylamine)-grafted mesoporous silica nanoparticles for controlled methotrexate delivery

A new drug delivery system (DDS) was designed using mesoporous silica nanoparticles functionalized with a copolymer of poly(acrylic acid-co-allylamine) conjugated with folic acid. DDS was developed to enable targeted and controlled delivery of methotrexate to cancer cells. The DDS pores were utilized for loading methotrexate through multilayer physical adsorption, which occurred spontaneously and exothermically. The methotrexate adsorption capacity of the DDS was 673.001 ± 4.518 mg/g. The copolymer acted as a gatekeeper, regulating the entry and exit of methotrexate from the pores. The DDS exhibited minimal methotrexate leakage at high pH levels but showed a significantly increased release at lower pH levels, demonstrating a pH-controlled drug release pattern. Mathematical modeling indicated that diffusion played a major role in drug release, and the DDS functioned as a reservoir system with a declining release rate over time. Importantly, the DDS displayed significant cytocompatibility, as demonstrated by MTT assays. Furthermore, the methotrexate-loaded DDS showed remarkable efficacy in killing MCF-7 cells, suggesting that folic acid facilitates DDS-specific targeting of MCF-7 cells via folic acid receptors.

CAR-T Cell Therapy in Ovarian Cancer: Where Are We Now?

The success of chimeric antigen receptor T-cell (CAR-T) therapies in the treatment of hematologic malignancies has led to the investigation of their potential in the treatment of solid tumors, including ovarian cancer. While the immunosuppressive microenvironment of ovarian cancer has been a barrier in their implementation, several early phase clinical trials are currently evaluating CAR-T cell therapies targeting mesothelin, folate receptor a, HER2, MUC16, and B7H3. Ongoing challenges include cytokine-associated and "on-target, off-tumor" toxicities, while most common adverse events include cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation-like syndrome (HLH/MAS), and neurotoxicity. In the present review, we summarize the current status of CAR-T therapy in ovarian cancer and discuss future directions.

Customizable Porphyrin Platform Enables Folate Receptor PET Imaging Using Copper-64.

Folate receptors including folate receptor α (FRα) are overexpressed in up to 90% of ovarian cancers. Ovarian cancers overexpressing FRα often exhibit high degrees of drug resistance and poor outcomes. A porphyrin chassis has been developed that is readily customizable according to the desired targeting properties. Thus, compound O5 includes a free base porphyrin, two water-solubilizing groups that project above and below the macrocycle plane, and a folate targeting moiety. Compound O5 was synthesized (>95% purity) and exhibited aqueous solubility of at least 0.48 mM (1 mg/mL). Radiolabeling of O5 with 64Cu in HEPES buffer at 37 °C gave a molar activity of 1000 μCi/μg (88 MBq/nmol). [64Cu]Cu-O5 was stable in human serum for 24 h. Cell uptake studies showed 535 ± 12% bound/mg [64Cu]Cu-O5 in FRα-positive IGROV1 cells when incubated at 0.04 nM. Subcellular fractionation showed that most radioactivity was associated with the cytoplasmic (39.4 ± 2.7%) and chromatin-bound nuclear (53.0 ± 4.2%) fractions. In mice bearing IGROV1 xenografts, PET imaging studies showed clear tumor uptake of [64Cu]Cu-O5 from 1 to 24 h post injection with a low degree of liver uptake. The tumor standardized uptake value at 24 h post injection was 0.34 ± 0.16 versus 0.06 ± 0.07 in the blocking group. In summary, [64Cu]Cu-O5 was synthesized at high molar activity, was stable in serum, exhibited high binding to FRα-overexpressing cells with high nuclear translocation, and gave uptake that was clearly visible in mouse tumor xenografts.

In Vivo Labeling and Detection of Circulating Tumor Cells in Mice Using OTL38

PurposeWe recently developed an optical instrument to non-invasively detect fluorescently labeled circulating tumor cells (CTCs) in mice called ‘Diffuse in vivo Flow Cytometry’ (DiFC). OTL38 is a folate receptor (FR) targeted near-infrared (NIR) contrast agent that is FDA approved for use in fluorescence guided surgery of ovarian and lung cancer. In this work, we investigated the use OTL38 for in vivo labeling and detection of FR + CTCs with DiFC.ProceduresWe tested OTL38 labeling of FR + cancer cell lines (IGROV-1 and L1210A) as well as FR- MM.1S cells in suspensions of Human Peripheral Blood Mononuclear cells (PBMCs) in vitro. We also tested OTL38 labeling and NIR-DIFC detection of FR + L1210A cells in blood circulation in nude mice in vivo.Results62% of IGROV-1 and 83% of L1210A were labeled above non-specific background levels in suspensions of PBMCs in vitro compared to only 2% of FR- MM.1S cells. L1210A cells could be labeled with OTL38 directly in circulation in vivo and externally detected using NIR-DiFC in mice with low false positive detection rates.ConclusionsThis work shows the feasibility of labeling CTCs in vivo with OTL38 and detection with DiFC. Although further refinement of the DiFC instrument and signal processing algorithms and testing with other animal models is needed, this work may eventually pave the way for human use of DiFC.