Folate Conjugates Research Articles

Preparation and Evaluation of pH-Sensitive Chitosan/Alginate Nanohybrid Mucoadhesive Hydrogel Beads: An Effective Approach to a Gastro-Retentive Drug Delivery System

Background: Despite extensive research over the decades, cancer therapy is still a great challenge because of the non-specific delivery of chemotherapeutic agents, which could be overcome by limiting the distribution of chemotherapeutic agents toward cancer cells. Objective: To reduce the cytolytic effects against cancer cells, graphene oxide (GO) nanoparticles (NPs) can load anticancer medicines and genetic tools. Methodology: During the current study, folic-acid-conjugated graphene oxide (Fa-GO) hybrid mucoadhesive chitosan (CS)-based hydrogel beads were fabricated through an “ion-gelation process”, which allows for regulated medication release at malignant pH. Results: The fabricated chitosan–alginate (SA-CS) hydrogel beads were examined using surface morphology, optical microscopy, XRD, FTIR, and homogeneity analysis techniques. The size analysis indicated that the size of the Fa-GO was up to 554.2 ± 95.14 nm, whereas the beads were of a micrometer size. The folic acid conjugation was confirmed by NMR. The results showed that the craggy edges of the graphene oxide were successfully encapsulated in a polymeric matrix. The mucoadhesive properties were enhanced with the increase in the CS concentration. The nanohybrid SA-CS beads exhibited good swelling properties, and the drug release was 68.29% at pH 5.6 during a 24 h investigation. The accelerated stability study, according to ICH guidelines, indicated that the hydrogel beads have a shelf-life of more than two years. Conclusions: Based on the achieved results, it can be concluded that this novel gastro-retentive delivery system may be a viable and different way to improve the stomach retention of anticancer agents and enhance their therapeutic effectiveness.

Next-generation cancer nanotherapeutics: Pluronic® F127 based mixed micelles for enhanced drug delivery.

Cancer, projected to become the second leading cause of mortality globally, underscores the critical need for precise drug delivery systems. Nanotechnology, particularly micelles, has emerged as a promising avenue. These nano-sized colloidal dispersions (< 100 nm) utilize amphiphilic molecules featuring a hydrophilic tail and hydrophobic core, facilitating efficient drug encapsulation and delivery. Pluronic® F127, a triblock copolymer (PEO101-PPO56-PEO101), has emerged as a promising drug carrier due to its non-ionic, less-toxic nature, which prolongs drug circulation time and improves drug delivery across blood-brain and intestinal barriers. Mixed micelles, formed using Pluronic® F127 combined with other polymers, surfactants, and drugs, enhance drug solubility, stability, and targeted delivery. This review highlights the key features of mixed micelles, including enhanced pharmacokinetics and targeting abilities, folic acid (FA) conjugation strategies, superior cytotoxicity with reduced side effects, overcoming multidrug resistance, and versatility across various cancer types and compounds. Additionally, the potential for clinical translation of Pluronic® F127-based mixed micelle in cancer treatment is discussed, addressing current challenges and paving the way for optimized applications.

Co-delivery of temozolomide and quercetin with folic acid-conjugated exosomes in glioblastoma treatment.

Aim: The study aims to improve glioblastoma multiforme (GBM) treatment by combining temozolomide (TMZ) and quercetin (Qct), using folic acid (FA)-conjugated exosomes to overcome TMZ resistance and enhance blood-brain barrier (BBB) penetration.Methods: Exosomes were isolated and after characterizing and modifying their surfaces with FA, drug loading of TMZ and Qct into exosomes was done. In vitro assays, including cell viability tests, RT-PCR, Western-blotting and flow-cytometry, were performed using U87MG and U251MG GBM cell lines. In vivo analysis included administering exosome-drug formulations to glioblastoma-bearing Wistar rats, monitored through optical imaging and PET scans, followed by post-mortem immunohistochemistry and histological examination.Results: The results showed successful exosome isolation and FA conjugation, with drug release studies indicating accelerated release of TMZ and Qct in acidic conditions, enhancing cytotoxicity. Immunofluorescence indicated greater exosome uptake in GBM cells due to FA conjugation. Cell viability assays demonstrated increased toxicity of the combination therapy, correlating with elevated apoptosis. In vivo studies revealed significant tumor size reduction, alongside increased apoptosis and reduced angiogenesis, particularly in the TMZ-Qct-Exo-FA group.Conclusion: FA-conjugated exosomes loaded with TMZ and Qct represent a promising strategy to enhance GBM treatment efficacy by improving drug delivery, apoptosis induction and inhibiting the PI3K/Akt/mTOR pathway.

Modified mesoporous silica nanocarriers containing superparamagnetic iron oxide nanoparticle, 5-fluorouracil or oxaliplatin, and metformin as a radiosensitizer, significantly impact colorectal cancer radiation therapy

This study investigates the anticancer effects of SPION-based silica nanocarriers carrying 5-fluorouracil (5-FU) or oxaliplatin (OX), and metformin (MET) on colorectal cancer cells. Nanocarriers were equipped with pH-responsive gold gatekeepers for controlled release, PEGylation for longer circulation, and folic acid (FA) for targeted delivery. The effects were evaluated by investigating cell viability, cellular uptake, flow cytometry, and clonogenic assay in vitro. The efficacy of the system was also tested in vivo on C57BL/6 mice bearing HT-29 tumors, and potential side effects were evaluatedNanocarriers were synthesized with hydrodynamic diameters of 79.8 nm for 5-FU and 85.2 nm for OX; zeta potentials of −21 and –22 mV, respectively, and remained stable after 72 h. Encapsulation efficiencies were 85 % for 5-FU, 80 % for OX, and 83 % for MET, with loading capacities of 44 %, 38 %, and 41 %, respectively. Drug release in acidic buffer was 38.7 % for 5-FU, 32.8 % for OX, and 43.5 % for MET. MTT assay showed increased toxicity due to FA conjugation, while PEGylation reduced the hemolysis activity. Targeted nanocarriers demonstrated superior cellular uptake and tumor localization compared to non-targeted variants. The combination of 5-FU-MET and OX-MET nanocarriers with radiation therapy (RT) demonstrated the greatest effect on their antitumor activity, accompanied by minimal side effects indicating effective tumor targeting in vivo. MRI and CT imaging further supported these findings. This study underscores the synergistic impact of MET alongside RT on the inhibition of cancer cells and tumor growth for both targeted 5-FU and OX nanocarriers reflecting the significant radiosensitizing properties of MET.

Surface Engineered Osteoblast-Extracellular Vesicles Serve as an Efficient Carrier for Drug and Small RNA to Actively Target Osteosarcoma.

Osteosarcoma (OS) is a rare malignant tumor that affects soft tissue and has high rates of lung metastasis and mortality. The primary treatments for OS include preoperative chemotherapy, surgical resection of the lesion, and postoperative chemotherapy. However, OS chemotherapy presents critical challenges related to treatment toxicity and multiple drug resistance. To address these challenges, nanotechnology has developed nanosystems that release drugs directly to OS cells, reducing the drug's toxicity. Extracellular vesicles (EVs) are nanosized lipid-bilayer bound vesicles that act as cell-derived vehicles and drug delivery systems for several cancers. This study aims to utilize EVs for OS management by co-delivering Hdac1 siRNA and zoledronic acid (zol). The EVs' surface is modified with folic acid (FA) and their targeting ability is compared to that of native EVs. The results showed that the EVs' targeting ability depends on the parent cell source, and FA conjugation further enhanced it. Furthermore, EVs were used as the carrier for co-loading drug (zol) and small RNA (Hdac-1). This approach of using surface engineered EVs as carriers for cargo loading and delivery can be a promising strategy for osteosarcoma management.

Combinatorial Delivery of Docetaxel- and Erlotinib-Loaded Functionalized Nanostructured Lipid Carriers for the Treatment of Triple-Negative Breast Cancer Using Quality-by-Design Approach.

This study explored the combined administration of docetaxel (DOC) and erlotinib (ERL) using nanostructured lipid carriers (NLCs), with folic acid (FA) conjugation to enhance their synergistic anticancer efficacy against triple-negative breast cancer. NLCs were developed through hot melt homogenization-ultrasound dispersion, and optimized by a quality-by-design (QbD) approach using Plackett-Burman design and Box-Behnken design. Plots were generated based on maximum desirability. Spherical, nanosized dispersions (<200 nm) with zeta potential ranging from -16.4 to -14.15 mV were observed. These nanoformulations demonstrated ~95% entrapment efficiency with around 5% drug loading. Stability tests revealed that the NLCs remained stable for 6 months under storage conditions at 4 °C. In vitro release studies indicated sustained release over 24 h, following Higuchi and Korsmeyer-Peppas models for NLCs and FA NLCs, respectively. Additionally, an in vitro pH-stat lipolysis model exhibited a nearly fivefold increase in bioaccessibility compared to drug-loaded suspensions. The DOC-ERL-loaded formulations exhibited dose- and time-dependent cytotoxicity, revealing synergism at a 1:3 molar ratio in MDA-MB-231 and 4T1 cells, with combination indices of 0.35 and 0.37, respectively. Co-treatment with DOC-ERL-loaded FA NLCs demonstrated synergistic anticancer effects in various in vitro assays.

A strategy of “adding fuel to the flames” enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy

Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of “adding fuel to the flames” for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (i.e., DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H2S, Cu2+, and Fe2+ in the acidic tumor microenvironment (TME). The hydrogen peroxide (H2O2) levels and acidity within tumor cells enhanced by the released H2S induce acceleration of Fenton (Fe2+) and Fenton-like (Cu2+) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of “fuel”, intensifying catalytic effect (“flame”) in tumor cells through the sustainable Fenton chemistry (i.e., “add fuel to the flames”). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe–S) proteins, and elevates intracellular oxidative stress by releasing free Fe3+. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.

Catalytically Self‐Supplied Oxygen to Alleviate Hypoxia for Treatment of Acute Kidney Injury

AbstractOvercoming hypoxia is an urgent clinical challenge in acute kidney injury (AKI) treatment. Specifically, hypoxia upregulates xanthine oxidase (XO) expression and induces reactive oxygen species (ROS) generation, which exacerbates renal injury. Herein, a therapeutic strategy of self‐supply oxygen for highly efficient AKI therapy is developed, in which the biocompatible CeO2 nanorods modified by poly(ethylene glycol)‐folic acid conjugate (CeFA) catalytically convert ROS into oxygen and effectively relieve hypoxia in injured renal tissues. Modification with poly(ethylene glycol)‐folic acid conjugate allows the catalysts to be accumulated in injured renal tissues, and the high activity of CeFA guaranteed long‐lasting endogenous ROS decomposition to continuously supply oxygen. This resulted in the relief of renal hypoxia, which inhibits XO expression, reduces ROS generation and thereafter essentially alleviates kidney injury. Moreover, CeFA significantly reduces lipopolysaccharide‐induced ROS injury and reverses hypoxia in the murine AKI model, where the levels of kidney function indicators remain normal, and inflammation is alleviated without negative effects. This study offers a promising strategy for relieving hypoxia and protecting the kidney from AKI. This methodology is anticipated to provide a valuable approach for treating other oxygen‐dependent diseases and events, such as tumors and stroke.

Synthesis of 1, 2, 3-triazole linked 5 fluorouracil - carbon dots -folate conjugates for target specific anticancer activity and cell imaging applications

This work provides a unique strategy to anchor the individual properties of fluorophores, pharmacophores and receptors in a single platform using a copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC). Notably, this approach counters the long-term dispute associated with the target-specific drug delivery of 5 fluorouracil and its intracellular tracing. Significantly, the luminescence property of the carbon dots (CDs) and the anticancer activity of the 5 fluorouracil drug are well preserved, even after their structural modification. The resulting nano-hybrid conjugate shows good thermal stability, photo-stability and can selectively guide the drug molecule toward cancer cells and remain nontoxic to noncancerous (hFB) cells. The conjugation of folic acid to the nanohybrid surface promoted the folate receptor-facilitated endocytosis to the folate-positive (HeLa) cell lines over the folate-negative (MCF-7) cells, which enhanced cellular uptake and corresponding better cell apoptosis results. Around 18.2% of cell apoptosis (late + early) values were recorded for the folate-conjugated formulation compared to the folate-less formulation (12.3%) and pure 5 FU drug (7.9%) by a flow cytometry study. Cell cycle analysis confirmed that the populations of HeLa cells in the S phase were around 18.20% and 29.8% for the folate-less formulation and the folate-conjugated formulation, indicating all the formulations can hinder the DNA replication and thymidylate synthesis by introducing cell cycle arrest in the S phase, just like the pure 5 FU drug. Also, the location of the drug molecule can be simultaneously traced because of the luminescent nature of the CDs. Therefore, the developed system has potential in target-specific drug delivery and long-term drug molecule tracking applications.

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.

A dynamic study of VEGF-A siDOX-EVs trafficking through the in-vitro insert co-culture blood-brain barrier model by digital holographic microscopy.

Modeling the blood-brain barrier has long been a challenge for pharmacological studies. Up to the present, numerous attempts have been devoted to recapitulating the endothelial barrier in vitro to assess drug delivery vehicles' efficiency for brain disorders. In the current work, we presented a new approach for analyzing the morphometric parameters of the cells of an insert co-culture blood-brain barrier model using rat brain astrocytes, rat brain microvascular endothelial cells, and rat brain pericytes. This analytical approach could aid in getting further information on drug trafficking through the blood-brain barrier and its impact on the brain indirectly. In the current work, we cultured rat brain astrocytes, rat brain microvascular endothelial cells, and rat brain pericytes and then used an insert well to culture the cells in contact with each other to model the blood-brain barrier. Then, the morphometric parameters of the porous membrane of the insert well, as well as each cell type were imaged by digital holographic microscopy before and after cell seeding. At last, we performed folate conjugation on the surface of the EVs we have previously tested for glioma therapy in our previous work called VEGF-A siDOX-EVs and checked how the trafficking of EVs improves after folate conjugation as a clathrin-mediated delivery setup. the trafficking and passage of EVs were assessed by flowcytometry and morphometric analysis of the digital holographic microscopy holograms. Our results indicated that EVs successfully entered through the proposed endothelial barrier assessed by flow cytometry analysis and furthermore, folate conjugation significantly improved EV passage through the blood-brain barrier. Moreover, our results indicated that the VEGF-A siDOX-EVs insert cytotoxic impact on the cells of the bottom of the culture plate. folate-conjugation on the surface of EVs improves their trafficking through the blood-brain barrier and by using digital holographic microscopy analysis, we could directly assess the morphometric changes of the blood-brain barrier cells for pharmacological purposes as an easy, label-free, and real-time analysis.

Folic acid receptor conjugated mesoporous CaCO3 nanoformulation for the therapeutic potential against lung carcinoma

The folic acid conjugation with the nanocarrier system possess enhanced targeting of lung cancer cells due to the folate receptors present in the lung cancer cells. This work plan focused on the development of a mesoporous CaCO3 nanoformulation system for the targeted delivery of citronellyl acetate for lung cancer therapy. CaCO3 nanoparticles were obtained from the marine conch waste and the citronellyl acetate an acetic ester derivative of citronellol reported for its anticancer potential were used for the present study. Here the citronellyl acetate loaded CaCO3 formulation was surface conjugated with folic acid as an extension of our previous work. The physiochemical and material characterizations of folic acid conjugated nanoformulation confirms the loading of citronellyl acetate within CaCO3 nanoparticles and surface conjugation with folic acid. The folic receptor conjugated CaCO3 nanoformulation attained anticancer potential against H460 non-small cell lung cancer cell lines with the IC50 value at 102.09 ± 0.25 μg/mL. In addition, the receptor-conjugated nanoformulation withstands its biocompatibility level in the in-vitro and in-vivo toxicity evaluation models. The findings of this study suggest that, CaCO3 nanoformulation surface conjugated with folic acid can serve as a progressive drug delivery system for lung cancer therapy.

Targeted delivery and apoptosis induction of CDK-4/6 inhibitor loaded folic acid decorated lipid-polymer hybrid nanoparticles in breast cancer cells

Targeted drug delivery is an advanced approach for active targeting of tumor that can enhance the concentration of the drug at the site of action and reduce the off-target toxicity and non-specific effects of the drug. Folate receptors (FR) are membrane-bound surface proteins, over-expressed in numerous solid tumors, folate and folate conjugates bind to FR with higher affinity. In the present investigation, we fabricated Folic acid (FA) decorated Palbociclib loaded lipid-polymer hybrid nanoparticles (FA-PLPHNPs) using quality by design (QbD) approach and evaluated its anti-cancer activity in folate receptor-positive breast cancer cell lines. 1HNMR, ATR-FTIR spectroscopic techniques confirmed the formation of DSPE-PEG-FA ligand. The optimized FA-PLPHNPs formulation exhibited 143.36 ± 5.24 nm, 0.172 ± 0.004, −16.84 ± 0.27 mV, and 93.12 ± 0.43 % of particle size, PDI, zeta potential and % entrapment efficiency, respectively. The FA-PLPHNPs exhibited an approximately 9, 11-fold reduction in IC50 values than free Palbociclib in MCF-7 and MDA-MB-231 cells at 48 h. The role of FA in targeting breast cancer was studied by means of a receptor-blocking assay, and concluded that FA-PLPHNPs were internalized into MCF-7 and MDA-MB-231 cells by folate receptor-mediated endocytosis. FA-PLPHNPs showed higher anti-cancer efficiency and caused enhanced reactive oxygen species generation, apoptosis (Acridine orange/ ethidium bromide dual staining and Annexin V/PI staining), reduced cell migration, and colony formation. Thus, the fabricated Palbociclib-loaded FA-conjugated lipid polymer hybrid nanoparticles could act as a potential nanocarrier for the treatment of breast cancer.

Folic Acid-Conjugated Fe-Au-Based Nanoparticles for Dual Detection of Breast Cancer Cells by Magnetic Resonance Imaging and Computed Tomography

Purpose: We synthesized folic acid-conjugated Fe3O4/Au-pralidoxime chloride Nanoparticles (Fe2O3/Au@PAM NPs) for use as dual-modal contrast agents for Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) in the diagnosis of breast cancer.&#x0D; Materials and Methods: Fe2O3/Au@PAM NPs labeled or not to folic acid were synthesized and analyzed by dynamic light scattering, transmission electron microscopy, and vibrating sample magnetometry. The ability of these NPs to create image contrast was also investigated in silico and in vitro (in MCF-7 breast cancer cells and A549 lung cancer cells) with CT and MRI.&#x0D; Results: Dynamic light scattering and transmission electron microscopy revealed that the Fe2O3/Au@PAM NPs were nearly spherical. The average diameter of Fe2O3/Au NPs increased from 11.6 nm to 98 nm after folic acid conjugation. The saturation magnetization values of Fe2O3/Au@PAM NPs with and without folic acid conjugation were 25.56 and 32.6 emu/g, respectively. Conjugation of folic acid to NPs greatly improved their uptake by cancer cells. The additional coating of NPs with FA reduced the T2 relaxation time and signal intensity for MRI. Folic acid-labeled MCF-7 cells had a radiodensity measurement of 208 Hunsfield Units (HU) compared to 95 HU for A549 cells. For breast cancer cells, NPs labeled with folic acid significantly improved the X-ray absorption coefficient as a sign of active cellular uptake compared to NPs without labeling.&#x0D; Conclusion: Folic acid-labeled Fe2O3/Au@PAM NPs can serve as dual CT/MRI contrast agents and improve the sensitivities of both modalities for the detection of cancer cells.

Folic acid-conjugated cancer drug curcumin-loaded albumin nanoparticles: Investigation of curcumin release kinetics

The aim of this study is to design a drug delivery system in which both the carrier material and the flavonoid anticancer, chemopreventive and chemotherapeutic active substance to be loaded into this material are biologically sourced soft material. In this study, bovine serum albumin nanoparticles (BSANPs) were synthesized using “Desolvation Method”. Characterization studies were carried out by performing SEM, TEM, FT-IR, XRD, TGA, DSC and Zetasizer analyses. The most suitable BSA concentration was determined to be 25 mg/ml, and the size of BSANPs was measured at 156.9 nm with a PDI value of 0.078 in a medium with pH adjusted to 10 after 24 h of cross-linking. The optimum ratio of distilled water (solvent) to ethanol (non-solvent) for desolvation was found to be 1:2. The maximum CUR encapsulation efficiency and capacity of BSANPs were obtained as 90.2 % and 44.22 %, respectively, at a cross-linking time of 24 h using 15 mg of CUR and 110 μl of glutaraldehyde. The cumulative CUR release percentage from CUR-BSANPs containing 0.5, 1.0 and 1.5 mg CUR was determined to be 51.6 %, 67.3 % and 56.2 %, respectively, after 72–168 h in pH 5.6 PBS buffer. The conjugation of folic acid to CUR-BSANPs slightly reduced the release rate and the cumulative percentage release of CUR, but still provided a sustained and controlled release of CUR. In order to analyze the CUR release kinetic mechanism, the fit of CUR release profiles to zero order, first order, Higuchi, Hixson-Crowell and Korsmeyer-Peppas models was examined. The values of kinetic constants for each model were calculated.

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.

MIgM-mediated splenic marginal zone B cells targeting of folic acid for immunological evasion

Folic acid is a fully oxidized synthetic folate with high bioavailability and stability which has been extensively prescribed to prevent congenital disabilities. Here we revealed the immunosuppressive effect of folic acid by targeting splenic marginal zone B (MZB) cells. Folic acid demonstrates avid binding with the Fc domain of immunoglobulin M (IgM), targeting IgM positive MZB cells in vivo to destabilize IgM-B cell receptor (BCR) complex and block immune responses. The induced anergy of MZB cells by folic acid provides an immunological escaping window for antigens. Covalent conjugation of folic acid with therapeutic proteins and antibodies induces immunological evasion to mitigate the production of anti-drug antibodies, which is a major obstacle to the long-term treatment of biologics by reducing curative effects and/or causing adverse reactions. Folic acid acts as a safe and effective immunosuppressant via IgM-mediated MZB cells targeting to boost the clinical outcomes of biologics by inhibiting the production of anti-drug antibodies, and also holds the potential to treat other indications that adverse immune responses need to be transiently shut off.

Thermo-Responsive Hydrogels Encapsulating Targeted Core-Shell Nanoparticles as Injectable Drug Delivery Systems.

As therapeutic agents that allow for minimally invasive administration, injectable biomaterials stand out as effective tools with tunable properties. Furthermore, hydrogels with responsive features present potential platforms for delivering therapeutics to desired sites in the body. Herein, temperature-responsive hydrogel scaffolds with embedded targeted nanoparticles were utilized to achieve controlled drug delivery via local drug administration. Poly(N-isopropylacrylamide) (pNIPAM) hydrogels, prepared with an ethylene-glycol-based cross-linker, demonstrated thermo-sensitive gelation ability upon injection into environments at body temperature. This hydrogel network was engineered to provide a slow and controlled drug release profile by being incorporated with curcumin-loaded nanoparticles bearing high encapsulation efficiency. A core (alginate)-shell (chitosan) nanoparticle design was preferred to ensure the stability of the drug molecules encapsulated in the core and to provide slower drug release. Nanoparticle-embedded hydrogels were shown to release curcumin at least four times slower compared to the free nanoparticle itself and to possess high water uptake capacity and more mechanically stable viscoelastic behavior. Moreover, this therapy has the potential to specifically address tumor tissues over-expressing folate receptors like ovaries, as the nanoparticles target the receptors by folic acid conjugation to the periphery. Together with its temperature-driven injectability, it can be concluded that this hydrogel scaffold with drug-loaded and embedded folate-targeting nanoparticles would provide effective therapy for tumor tissues accessible via minimally invasive routes and be beneficial for post-operative drug administration after tumor resection.

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.

Folate-conjugated near-infrared fluorescent perfluorocarbon nanoemulsions as theranostics for activated macrophage COX-2 inhibition

Activated macrophages play a critical role in the orchestration of inflammation and inflammatory pain in several chronic diseases. We present here the first perfluorocarbon nanoemulsion (PFC NE) that is designed to preferentially target activated macrophages and can deliver up to three payloads (two fluorescent dyes and a COX-2 inhibitor). Folate receptors are overexpressed on activated macrophages. Therefore, we introduced a folate-PEG-cholesterol conjugate into the formulation. The incorporation of folate conjugate did not require changes in processing parameters and did not change the droplet size or fluorescent properties of the PFC NE. The uptake of folate-conjugated PFC NE was higher in activated macrophages than in resting macrophages. Flow cytometry showed that the uptake of folate-conjugated PFC NE occurred by both phagocytosis and receptor-mediated endocytosis. Furthermore, folate-conjugated PFC NE inhibited the release of proinflammatory cytokines (TNF-α and IL-6) more effectively than nonmodified PFC NE, while drug loading and COX-2 inhibition were comparable. The PFC NEs reported here were successfully produced on multiple scales, from 25 to 200 mL, and by using two distinct processors (microfluidizers: M110S and LM20). Therefore, folate-conjugated PFC NEs are viable anti-inflammatory theranostic nanosystems for macrophage drug delivery and imaging.