Folate Receptor Overexpressing Research Articles

A self-targeting MOFs nanoplatform for treating metastatic triple-negative breast cancer through tumor microenvironment remodeling and chemotherapy potentiation

Triple-negative breast cancer (TNBC) is the most aggressive and fatal subtype of breast cancer with disappointing treatment and high mortality. Tumor microenvironment (TME) plays an important role in the invasion and metastasis of TNBC through multiple complex processes. Most anti-metastatic therapies only focus on cancer cells themselves or interfering with single factors of the metastasis process, which is often related to poor outcomes. Thus, effective TNBC treatment relies on regulating multiple key metastasis-related aspects of the TME. Herein, a self-targeting Metal-Organic Frameworks (MOFs) nanoplatform (named as MTX-PEG@TPL@ZIF-8) was designed to improve treatment of TNBC through tumor microenvironment remodeling and chemotherapy potentiation. The self-targeting MOF nanoplatform is consist of ZIF-8 nanoparticles loaded triptolide (TPL) and followed by the coating with methotrexate-polyethylene glycol conjugates (MTX-PEG). Due to MTX’s affinity for the overexpressed folate receptor on tumor cell surfaces, MTX-PEG@TPL@ZIF-8 enables effective accumulation and deep penetration in the tumor area by an MTX-mediated self-targeting strategy. This MOF nanoplatform could promptly release the medication after penetrating the tumor cell, due to pH-triggered degradation. Its anti-metastasis mechanism is to inhibit tumor invasion and metastasis by down-regulating the expression of Vimentin, MMP-2 and MMP-9 and increasing the expression of E-cadherin, upregulation of cleaved caspase-3 and cleaved caspase-9 protein expression promote the apoptosis of tumor cells, thereby reducing their migration. It also downregulated the expression of VEGF and CD31 protein to inhibit the generation of neovascularization. Overall, these findings suggest the self-targeting MOF nanoplatform offers new insights into the treatment of metastatic TNBC by TME remodeling and potentiating chemotherapy.

Direct radiolabeling of Folate with Tc-99m using QbD approach: A step closer to folate based diagnostic agent

The aim of the presented work was to develop folate based radiolabeled compound intended to be used as diagnostic aid for the various folate-receptor overexpressing cancers eg. breast cancer, brain tumors, lung cancer etc. Folate was directly radiolabeled with Tc-99m using Quality-by-Design and encapsulated in micellar nanocarriers. The authors are of the view that the stable radiolabeled folate could be of potential diagnostic value in cancers overexpressing folate receptors thereby opening novel possibilities to diagnostic applications of radiolabeled folate. Summary for technical notesFolic acid was directly radiolabeled with Tc-99m utilizing a quality by design approach. The experimental trials were designed using the Box-Behenken design with the concentration of drug, concentration of reducing agent and the incubation time as dependent variable and percent radiolabeling as the response for the same. The applied design in the method section was validated with a series of experiments and the percent labeling of the FA with Tc-99m was found to be around 94%. The radiolabeled compound was imperilled to stability evaluation by incubating the same with serum and physiological pH and the same was found to be stable at the end of 4h. On subjecting to DTPA challenge test, the compound displayed no change in the radiolabeling percentage thereby indicating the robustness of the formed Tc-99m-FA complex, The radiolabeled Tc-99m-FA was further encapsulated into micellar nanocarriers and the same were also found to be robust and stable.

Targeted Liposomal Co-delivery of an Immunogenic Cell Death Inducer and a Toll-Like Receptor 4 Agonist for Enhanced Cancer Chemo-immunotherapy.

Anticancer chemo-immunotherapy has gained considerable attention across various scientific domains as a prospective approach for the comprehensive eradication of malignant tumors. Recent research has particularly been focused on traditional anthracycline chemo drugs, such as doxorubicin and mitoxantrone. These compounds trigger apoptosis in tumor cells and evoke immunogenic cell death (ICD). ICD is a pivotal initiator of the cancer-immunity cycle by facilitating the release of damage-associated molecular patterns (DAMPs). The resultant DAMPs released from cancer cells effectively activate the immune system, resulting in an increase in tumor-infiltrating T cells. In this study, we have innovated a co-delivery strategy involving folate-modified liposomes to deliver doxorubicin and monophosphoryl lipid A (MPLA) simultaneously to tumor tissue. The engineered liposomes exploit the overexpression of folate receptors within the tumor tissues. Delivered doxorubicin initiates ICD at the tumor cells, further enhancing the immunogenic stimulus. Additionally, MPLA helps T cell priming by activating antigen-presenting cells. This intricate interplay culminates in a synergistic effect, ultimately resulting in an augmented and potentiated anticancer chemo-immunotherapeutic liposomal treatment.

Folic Acid-Functionalized β-Cyclodextrin for Delivery of Organelle-Targeted Peptide Chemotherapeutics in Cancer.

Recent emphasis on the design of drug delivery systems typically involves the effective transport of a pharmaceutical substance to the disease site with the desired therapeutic efficacy and minimal cytotoxicity. Organelle-targeted peptides have become an integral part of designing an important class of prodrug/prodrug assemblies for new supramolecular therapeutics owing to their favorable biocompatibility, synthetic ease, tunability of their aggregation behavior, and desired functionalization for site-specificity. However, it is still limited due to the low selectivity. We designed a folic acid-functionalized β-cyclodextrin (FA-CD) as a delivery platform for specific and selective delivery of organelle-targeted (such as microtubule, lysosome, and mitochondria) peptide chemotherapeutics to the folate receptor (FR) overexpressing cancer cell lines. Low toxicity was found for the FA-CD and organelle-targeted peptide inclusion complex in FR-negative normal cells, but superior inhibition of tumor growth with no in vivo toxicity was found for the inclusion complex in the xenograft tumor model.

H2O2 Self‐Supplied Chemodynamic Nanosystem Enhanced by Ca2+ Interference and Starvation Strategy for Targeted Cancer Therapy

AbstractChemodynamic therapy (CDT) has received increasing attention in recent years due to its effectiveness and specificity. However, the limited endogenous hydrogen peroxide (H2O2) concentration and resistance to reactive oxygen species in cancer cells hinder the further application of CDT. Here, an H2O2 self‐supplied nanosystem FCaO2@ZIF‐67‐2‐DG‐FA (FZDF) is synthesized to achieve efficient CDT improvement by Ca2+ overload and starvation therapy. Under folic acid‐mediated tumor targeting and endocytosis, the ZIF‐67 layer of FZDF is cleaved in the mildly acidic environment, releasing Co2+ and 2‐deoxy‐D‐glucose (2‐DG). The decomposition of exposed FCaO2 generates sufficient H2O2, which further produces abundant •OH via the Fenton‐like reaction of Co2+. Simultaneously, Ca2+ overload‐triggered mitochondrial dysfunction couples with glycolysis inhibition via 2‐DG‐induced starvation, which disrupts intracellular adenosine triphosphate (ATP) synthesis and amplifies the efficacy of CDT. Silicon nanoparticles released from FCaO2 are applied as in vitro fluorescent probes to image tumor cells overexpressing folate receptors. The results have presented that FZDF can actively accumulate in tumor cells, causing the mitochondrial membrane potential abnormality and a decrease in intracellular ATP content, thereby enhancing the self‐supplied CDT with less effect on normal cells and tissues. This work provides a novel strategy for constructing effective CDT nanosystems by hindering intracellular energy supply.

Integration of STING activation and COX-2 inhibition via steric-hindrance effect tuned nanoreactors for cancer chemoimmunotherapy

Integrating immunotherapy with nanomaterials-based chemotherapy presents a promising avenue for amplifying antitumor outcomes. Nevertheless, the suppressive tumor immune microenvironment (TIME) and the upregulation of cyclooxygenase-2 (COX-2) induced by chemotherapy can hinder the efficacy of the chemoimmunotherapy. This study presents a TIME-reshaping strategy by developing a steric-hindrance effect tuned zinc-based metal-organic framework (MOF), designated as CZFNPs. This nanoreactor is engineered by in situ loading of the COX-2 inhibitor, C-phycocyanin (CPC), into the framework building blocks, while simultaneously weakening the stability of the MOF. Consequently, CZFNPs achieve rapid pH-responsive release of zinc ions (Zn2+) and CPC upon specific transport to tumor cells overexpressing folate receptors. Accordingly, Zn2+ can induce reactive oxygen species (ROS)-mediated cytotoxicity therapy while synchronize with mitochondrial DNA (mtDNA) release, which stimulates mtDNA/cGAS-STING pathway-mediated innate immunity. The CPC suppresses the chemotherapy-induced overexpression of COX-2, thus cooperatively reprogramming the suppressive TIME and boosting the antitumor immune response. In xenograft tumor models, the CZFNPs system effectively modulates STING and COX-2 expression, converting “cold” tumors into “hot” tumors, thereby resulting in ≈ 4-fold tumor regression relative to ZIF-8 treatment alone. This approach offers a potent strategy for enhancing the efficacy of combined nanomaterial-based chemotherapy and immunotherapy.

Synergistic anticancer activity of Sulphoraphane and Teriflunomide co loaded lignin nanoparticles against triple negative breast cancer: Targeted nanoparticle delivery and drug repurposing

Triple negative breast cancer stands out as the most aggressive subtype within the spectrum of breast malignancies, characterized by increased risks of recurrence, metastasis, and dismal prognosis. Notably, TNBC cells exhibit extensive overexpression of folate receptors, particularly folate receptor alpha, which drives tumor cell proliferation and migration. Addressing TNBC remains a formidable challenge in oncology, necessitating innovative therapeutic strategies. While chemotherapy serves as the cornerstone of TNBC treatment, its efficacy is often compromised by systemic toxicity, resulting in suboptimal clinical outcomes. This hypothesis proposes a novel approach utilizing lignin nanoparticles functionalized with folic acid for targeted delivery to FRα-overexpressing TNBC cells. These nanoparticles will encapsulate both the chemopreventive agent Sulphoraphane and the chemotherapeutic agent Teriflunomide, offering advantages such as enhanced drug targeting, synergistic therapeutic effects, cost-effectiveness, and reduced off-target toxicity. Additionally, this hypothesis highlights the repurposing of Teriflunomide to overcome drug resistance and the antioxidant properties of lignin. Furthermore, the ease of nanoparticle fabrication via self-assembly presents a promising avenue for streamlined production and clinical translation.

Chitosan-modified manganese oxide-conjugated methotrexate nanoparticles delivering 5-aminolevulinic acid as a dual-modal T1-T2* MRI contrast agent in U87MG cell detection.

Glioblastoma multiforme is a highly aggressive form of brain cancer, and early diagnosis plays a pivotal role in improving patient survival rates. In this regard, molecular magnetic resonance imaging has emerged as a promising imaging modality due to its exceptional sensitivity to minute tissue changes and the ability to penetrate deep into the brain. This study aimed to assess the efficacy of a novel contrast agent in detecting gliomas during MRI scans. The contrast agent utilized modified chitosan coating on manganese oxide nanoparticles. The modification included adding methotrexate and 5-aminolevulinic acid (MnO2/CS@5-ALA-MTX) to target cells with overexpressed folate receptors and breaking down excess hydrogen peroxide in tumor tissue, resulting in enhanced signal intensity in T1-weighted MR images but diminished signal intensity in T2*-weighted MR images. The nanosystem was characterized and evaluated in MR imaging, safety, and ability to target cells both in vivo and in vitro. MTX-free nanoparticles (MnO2/CS@5-ALA NPs) had no obvious cytotoxicity on cell lines U87MG and NIH3T3 after 24/48 h at a concentration of up to 160 µgr/mL (cell viability more than 80%). In this system, methotrexate enables tumor targeting and the MnO2/5-ALA improves T1-T2*-weighted MRI. In addition, MRI scans of mice with M109 carcinoma indicated significant tumor uptake and NP capacity to improve the positive contrast effect. This developed MnO2/CS@5-ALA-MTX nanoparticle system may exhibit great potential in the accurate diagnosis of folate receptor over-expressing cancers such as glioblastoma.

Therapeutic and Diagnostic Potential of Folic Acid Receptors and Glycosylphosphatidylinositol (GPI) Transamidase in Prostate Cancer.

Due to the proliferation-induced high demand of cancer cells for folic acid (FA), significant overexpression of folate receptors 1 (FR1) is detected in most cancers. To our knowledge, a detailed characterization of FR1 expression and regulation regarding therapeutic and diagnostic feasibilities in prostate cancer (PCa) has not been described. In the present study, cell cultures, as well as tissue sections, were analyzed using Western blot, qRT-PCR and immunofluorescence. In addition, we utilized FA-functionalized lipoplexes to characterize the potential of FR1-targeted delivery into PCa cells. Interestingly, we detected a high level of FR1-mRNA in healthy prostate epithelial cells and healthy prostate tissue. However, we were able to show that PCa cells in vitro and PCa tissue showed a massively enhanced FR1 membrane localization where the receptor can finally gain its function. We were able to link these changes to the overexpression of GPI-transamidase (GPI-T) by image analysis. PCa cells in vitro and PCa tissue show the strongest overexpression of GPI-T and thereby induce FR1 membrane localization. Finally, we utilized FA-functionalized lipoplexes to selectively transfer pDNA into PCa cells and demonstrate the therapeutic potential of FR1. Thus, FR1 represents a very promising candidate for targeted therapeutic transfer pathways in PCa and in combination with GPI-T, may provide predictive imaging in addition to established diagnostics.

Direct radiolabeling of methotrexate and methotrexate micelles with Tc-99m using QbD approach

The aim of the work presented in this manuscript was to radiolabel methotrexate and prepare radiolabeled methotrexate micelles, an antifolate drug with Tc-99m using QbD approach. The radiolabeling was executed using the experimental design and the radiolabeled drug was further encapsulated in micelles. The authors are of the view that the radiolabeled MTX could be used to target the folate receptor overexpressing cancers such as the kidney, colorectal, breast, brain etc thereby opening newer possibilities to the theranostic applications of the formed conjugate.

Abstract 1376: Engineered exosomes for the delivery of PD-L1 siRNA for lung cancer immunotherapy

Abstract Cancer immunosurveillance involves a dynamic interplay between the host’s innate and adaptive immunity. The regulation of programmed death ligand-1 (PD-L1) expression on cancer cells has emerged as an attractive approach for cancer treatment. However, challenges such as the immunosuppressive tumor microenvironment, ineffective trafficking, and tumor antigen heterogeneity limit the applications of cancer immunotherapy for solid tumors. Small interfering RNA (siRNA) against PD-L1 presents a compelling alternative to antibody treatment to reduce PD-L1 presentation on cancer cells, thereby enhancing T-cell detection and preventing tumor progression. Bovine milk/colostrum serve as a biocompatible source for exosomes for delivery biologics such as siRNA. Here, we demonstrate exosomes mediated delivery of siPD-L1 for lung cancer immunotherapy. Exosomes were isolated from bovine colostrum powder using ultracentrifugation. The average particle size of exosomes was 66 ± 2.5 nm, with polydispersity index (pdi) 0.27 ± 0.01 and a zeta potential -9.2 ± 0.70 mV, as analyzed by Zetasizer and validated by atomic force microscopy (AFM) and transmission electron microscopy (TEM). Formulations of exosomes with polyethyleneimine (EPM) and siRNA (1 - 20 μg), when mixed with 5’-32P-labeled siRNA as a tracer resulted in over 90% entrapment of siRNA. Biodistribution studies of exosomes and EPM, with or without the tumor-targeting ligand folic acid (FA), revealed predominantly similar distribution patterns. Notably, FA-EPM exhibited enhanced tumor accumulation compared to EPM, attributed to the overexpression of folate receptors on tumor cells.To assess the functionality of EPM-siRNA, we screened 4 different siPD-L1 sequences in LLC-1 and A549 lung cancer cells. Following 48 h of EPM-siPD-L1 treatment, cells were harvested. Analysis of protein lysates by western blot showed a significant downregulation of the PD-L1 expression, ranging from 55% - 80% in LLC-1 cells and over 80% in A549 cells. In vivo mouse study with orthotopic Lewis lung carcinoma (LL/2-Luc2) tumors is underway to validate the effective silencing of PD-L1 and its effect on tumor inhibition and immune markers. In summary, our targeted EPM technology represents a novel nanoplatform for siRNA therapeutics delivery. As milk/colostrum are the most abundant sources of exosomes, clinical translatability of this novel approach is eminent. Funding: This research work was supported from the Kentucky Lung Cancer Research Program (GB170558) and Immunotherapy CCII CoBRE pilot project (P20GM135004). Keywords: Exosomes, siPD-L1, siRNA delivery, Lung cancer, Immunotherapy Citation Format: Raghuram Kandimalla, Disha N. Moholkar, Margaret Wallen, Chuanlin Ding, Ramesh C. Gupta, Farrukh Aqil. Engineered exosomes for the delivery of PD-L1 siRNA for lung cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1376.

Folate receptor overexpression induces toxicity in a diet-dependent manner in C. elegans

Folate receptor (FR) alpha (FOLR1) and beta (FOLR2) are membrane-anchored folate transporters that are expressed at low levels in normal tissues, while their expression is strongly increased in several cancers. Intriguingly, although the function of these receptors in, for example, development and cancer has been studied intensively, their role in aging is still unknown. To address this, we utilized Caenorhabditis elegans, in which FOLR-1 is the sole ortholog of folate receptors. We found that the loss of FOLR-1 does not affect reproduction, physical condition, proteostasis or lifespan, indicating that it is not required for folate transport to maintain health. Interestingly, we found that FOLR-1 is detectably expressed only in uterine-vulval cells, and that the histone-binding protein LIN-53 inhibits its expression in other tissues. Furthermore, whereas knockdown of lin-53 is known to shorten lifespan, we found that the loss of FOLR-1 partially rescues this phenotype, suggesting that elevated folr-1 expression is detrimental for health. Indeed, our data demonstrate that overexpression of folr-1 is toxic, and that this phenotype is dependent on diet. Altogether, this work could serve as a basis for further studies to elucidate the organismal effects of abnormal FR expression in diseases such as cancer.

Folate receptor-mediated delivery system based on chitosan coated polymeric nanoparticles for combination therapy of breast cancer

Combination therapy using two or more drugs with different mechanisms of action is an effective strategy for treating cancer. This is because of the synergistic effect of complementary drugs that enhances their effectiveness. However, this approach has some limitations, such as non-specific distribution of the drugs in the tumor and the occurrence of dose-dependent toxicity to healthy tissues. To overcome these issues, we have developed a folate receptor-mediated co-delivery system that improves the access of chemotherapy drugs to the tumor site. We prepared a nanoplatform by encapsulating paclitaxel (PTX) and curcumin (CUR) in poly(caprolactone)-poly(ethylene glycol)-poly(caprolactone) (PCL-PEG-PCL) co-polymer using a double emulsion method and coating nanoparticles with pH-responsive chitosan-folic acid (CS-FA) conjugate. The nanocarrier’s physicochemical properties were studied, confirming successful preparation with appropriate size and morphology. PTX and CUR could be released synchronously in a controlled and acid-facilitated manner. The dual drug-loaded nanocarrier exhibited excellent anti-tumor efficiency in MDA-MB-231 cells in vitro. The active targeting effect of FA concluded from the high inhibitory effect of dual drug-loaded nanocarrier on MDA-MB-231 cells, which have overexpressed folate receptors on their surface, compared to Human umbilical vein endothelial cells (HUVEC). Overall, the nanoengineered folate receptor-mediated co-delivery system provides great potential for safe and effective cancer therapy.

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.

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.

Potential applications of Folate-conjugated Chitosan Nanoparticles for Targeted delivery of Anticancer drugs

Folate-conjugated chitosan nanoparticles represent a promising nanoplatform for targeted delivery of anticancer drugs. The nanoparticle carrier can protect the therapeutic agents from degradation and offer the ability to target cancer cells overexpressing folate receptors. This review summarizes recent research progress in synthesizing folate-conjugated chitosan nanoparticles as well as evaluating their potential as targeted drug delivery systems. The chemical conjugation of folic acid to chitosan is first discussed followed by an overview of different techniques for preparation of stable folate-conjugated chitosan nanoparticles less than 200 nm in size. Recent studies loading various anticancer drugs into these nanoparticles and investigating their in vitro cytotoxicity against multiple cancer cell lines are then summarized. The results indicate that folate-conjugated nanoparticles exhibit higher cytotoxicity and targeting efficiency compared to non-conjugated nanoparticles due to receptor-mediated endocytosis. Lastly, future challenges and opportunities are outlined including in vivo investigations to determine the effectiveness, toxicity, and pharmacokinetics of folate-conjugated chitosan nanoparticle systems as well as their potential clinical translation as targeted drug carriers for cancer chemotherapy.

Discovery of novel tumor-targeted near-infrared probes with 6-substituted pyrrolo[2,3-d]pyrimidines as targeting ligands

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

A sub-10-nm, folic acid-conjugated gold nanoparticle as self-therapeutic treatment of tubulointerstitial fibrosis

Nanomedicines for treating chronic kidney disease (CKD) are on the horizon, yet their delivery to renal tubules where tubulointerstitial fibrosis occurs remains inefficient. We report a folic acid-conjugated gold nanoparticle that can transport into renal tubules and treat tubulointerstitial fibrosis in mice with unilateral ureteral obstruction. The 3-nm gold core allows for the dissection of bio-nano interactions in the fibrotic kidney, ensures the overall nanoparticle (~7 nm) to be small enough for glomerular filtration, and naturally inhibits the p38α mitogen-activated protein kinase in the absence of chemical or biological drugs. The folic acids support binding to selected tubule cells with overexpression of folate receptors and promote retention in the fibrotic kidney. Upon intravenous injection, this nanoparticle can selectively accumulate in the fibrotic kidney over the nonfibrotic contralateral kidney at ~3.6% of the injected dose. Delivery to the fibrotic kidney depends on nanoparticle size and disease stage. Notably, a single injection of this self-therapeutic nanoparticle reduces tissue degeneration, inhibits genes related to the extracellular matrix, and treats fibrosis more effectively than standard Captopril therapy. Our data underscore the importance of constructing CKD nanomedicines based on renal pathophysiology.

Targeted cancer treatment using folate-conjugated sponge-like ZIF-8 nanoparticles: a review.

ZIF-8 (zeolitic imidazolate framework-8) is a potential drug delivery system because of its unique properties, which include a large surface area, a large pore capacity, a large loading capacity, and outstanding stability under physiological conditions. ZIF-8 nanoparticles may be readily functionalized with targeting ligands for the identification and absorption of particular cancer cells, enhancing the efficacy of chemotherapeutic medicines and reducing adverse effects. ZIF-8 is also pH-responsive, allowing medication release in the acidic milieu of cancer cells. Because of its tunable structure, it can be easily functionalized to design cancer-specific targeted medicines. The delivery of ZIF-8 to cancer cells can be facilitated by folic acid-conjugation. Hence, it can bind to overexpressed folate receptors on the surface of cancer cells, which holds the promise of reducing unwanted deliveries. As a result of its importance in cancer treatment, the folate-conjugated ZIF-8 was the major focus of this review.

The development of folate-functionalised palladium nanoparticles for folate receptor targeting in breast cancer cells.

Folate receptor-targeted therapy has excellent prospects for the treatment of breast cancer. A non-toxic concentration of folate-conjugated palladium-based nanoparticles was used to target the overexpressed folate receptor on breast cancer cells. The folate-conjugated nanoparticles were tailored to accumulate selectively in cancer cells relative to normal cells via the folate receptor. The MDA-MB-231, MDA-MB-468, MCF-7 breast cancer cell lines, and MCF-10A normal cell lines were used in the study. Qualitative and quantitative analysis of nanoparticle cellular uptake and accumulation was conducted using transmission electron microscopy and inductively coupled plasma-optical emission spectroscopy. The findings proved that folate-conjugated palladium nanoparticles successfully and preferentially accumulated in breast cancer cells. We conclude that folate-conjugated palladium nanoparticles can be potentially used to target breast cancer cells for radiopharmaceutical applications.