Folate Moiety Research Articles

Magnetic particles with polymeric shells bearing lithocholic and folic acid moieties: Nano-warriors to fight colon cancer

In the study, we aimed to investigate the activity of nanoformulations containing 5-fluorouracil and polymer-magnetic hybrids bearing membrane-penetrating and ligand-receptor-recognizing agents against colorectal cancer cells. The formation and characterization of iron oxide particles covered with polymeric shells comprising lithocholic acid and folic acid moieties are presented. The efficiency of nanoformulations combined by the simple mixing of low doses of 5-fluorouracil with the obtained hybrids was demonstrated against DLD-1 and HT-29 colon cancer cells. The most pronounced cytotoxic potential against HT-29 cells was observed in the cases of particles based on block and randomly arranged copolymers functionalized by FA motifs with depletion of viable cells by approximately 50 % compared to control cells and cells treated by 5-FU applied in free form. In the case of the DLD-1 cell line, the percentage of viable DLD-1 cells decreased by about 30 to 40% after treatment with the block and randomly arranged copolymer decorated by FA-moiety, when compared to 5-FU at the free form and the untreated control. The induction of apoptosis associated with PS-translocation was determined to be the main mechanism of their cytotoxic effects. Moreover, the safety profiles of the nanoformulations were established through hemolysis assay and the analysis of the viability of human colorectal fibroblasts. It was indicated that all tested nanoparticles met the compatibility requirements at the in vitro level. It should be emphasized that in many cases, there was a significant improvement in the compatibility of hybrids with the FA motif compared to non-functionalized hybrids with the addition of 5-FU. These findings suggest that the presence of FA might modulate the toxicity of chemotherapeutic agents.

Development and Characterization of Quercetin-Loaded Polymeric Liposomes with Gelatin-Poly(ethylene glycol)-Folic Acid Coating to Increase Their Long-Circulating and Anticancer Activity.

Liposomes as drug-delivery systems have been researched and applied in multiple scientific reports and introduced as patented products with interesting therapeutic properties. Despite various advantages, this drug carrier faces major difficulties in its innate stability, cancer cell specificity, and control over the release of hydrophobic drugs, particularly quercetin, a naturally derived drug that carries many desirable characteristics for anticancer treatment. To improve the effectiveness of liposomes to deliver quercetin by tackling and mitigating the mentioned hurdles, we developed a strategy to establish the ability to passively target cancerous cells, as well as to increase the bioavailability of loaded drugs by incorporating poly(ethylene glycol), gelatin, and folic acid moieties to modify the liposomal system's surface. This research developed a chemically synthesized gelatin, poly(ethylene glycol), and folic acid as a single polymer to coat drug-loaded liposome systems. Liposomes were coated with gelatin-poly(ethylene glycol)-folic acid by electrostatic interaction, characterized by their size, morphology, ζ potential, drug loading efficiency, infrared structures, differential scanning calorimetry spectra, and drug-releasing profiles, and then evaluated for their cytotoxicity to MCF-7 breast cancer cells, as well as cellular uptake, analyzed by confocal imaging to further elaborate on the in vitro behavior of the coated liposome. The results indicated an unusual change in size with increased coating materials, followed by increased colloidal stability, ζ potential, and improved cytotoxicity to cancer cells, as shown by the cellular viability test with MCF-7. Cellular uptake also confirmed these results, providing data for the effects of biopolymer coating, while confirming that folic acid can increase the uptake of liposome by cancer cells. In consideration of such results, the modified gelatin-poly(ethylene glycol)-folic acid-coated liposome can be a potential system in delivering the assigned anticancer compound. This modified biopolymer showed excellent properties as a coating material and should be considered for further practical applications in the future.

Resveratrol-loaded nanoplatform RSV@DTPF promote alveolar bone regeneration in OVX rat through remodeling bone-immune microenvironment

The reconstruction of alveolar bone defect is essential for periodontal regenerative therapy or subsequent prosthetic/implant therapy, particularly in individuals with systemic diseases, such as osteoporosis. ROS accumulation, coupled with aberrant macrophage polarization, is pivotal in the pathogenesis of osteoporosis and contributes to the disequilibrium between bone and the immune system. Consequently, therapeutic strategies targeting the immune microenvironment present a promising approach to the treatment of in situ alveolar bone regeneration in osteoporotic condition. Herein, we present a novel nano platform denoted as RSV@DTPF, designed to target macrophage and facilitate the controllable release of resveratrol in a ROS-responsive behavior. This approach aims to modulate the tampered immune microenvironment. The conjugated folate moiety selectively interacts with the folate receptors expressed on the macrophage surface, thereby augmenting cellular uptake. While the thioketal bond would break down when sensing a high level of intracellular ROS and release the encapsulated RSV. In vitro experiments suggested that designated nanoparticles could scavenge ROS effectively and restore the M1/M2 ratio in a lipopolysaccharide (LPS) -stimulated inflammation environment; The co-culture experiment provided evidence substantiating the adeptness of the modified immune milieu in fostering osteoblast differentiation, while concurrently impeding osteoclast maturation. Furthermore, through comprehensive imaging and histopathological evaluations, we elucidate the potential of RSV@DTPF in promoting osteogenesis within a periodontal defect model utilizing ovariectomized (OVX) rats. This in vivo study substantiates the advantageous impact of the nanoplatform on alveolar bone regeneration and its associated immunomodulatory effects. In summary, the RSV@DTPF nanoplatform exhibited the capacity to orchestrate immune microenvironmental shifts and enhance alveolar bone generation ability in osteoporosis and also could be expected to be applied in other biomedical fields associated with redox metabolism imbalance.

Mitochondria-Targeting Polyprodrugs to Overcome the Drug Resistance of Cancer Cells by Self-Amplified Oxidation-Triggered Drug Release.

The multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and is responsible for most cancer deaths. Developing efficient approaches to overcome MDR is still highly desirable for efficient chemotherapy of cancers. The delivery of targeted anticancer drugs that can interact with mitochondrial DNA is recognized as an effective strategy to reverse the MDR of cancers due to the relatively weak DNA-repairing capability in the mitochondria. Herein, we report on a polyprodrug that can sequentially target cancer cells and mitochondria using folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties, respectively. They were conjugated to the terminal groups of the amphiphilic block copolymer prodrugs composed of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin (DOX). After self-assembly into micelles with the suitable size (∼30 nm), which were termed as TF@CNM + DOX, and upon intravenous administration, the micelles can accumulate in tumor tissues. After FA-mediated endocytosis, the endosomal acidity (∼pH 5) can trigger the release of CNM from TF@CNM + DOX micelles, followed by enhanced accumulation into the mitochondria via the TPP target. This promotes the overproduction of reactive oxygen species (ROS), which can subsequently enhance the intracellular oxidative stress and trigger ROS-responsive release of DOX into the mitochondria. TF@CNM + DOX shows great potential to inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable side effects. Therefore, the tumor and mitochondria dual-targeting polyprodrug design represents an ideal strategy to treat MDR tumors through improvement of the intracellular oxidative level and ROS-responsive drug release.

Aptamer-programmable adeno-associated viral vectors as a novel platform for cell-specific gene transfer

Adeno-associated viruses (AAVs) are commonly used for invivo gene therapy. Nevertheless, the wide tropism that characterizes these vectors limits specific targeting to a particular cell type or tissue. Here, we developed new chemically modified AAV vectors (Nε-AAVs) displaying a single site substitution on the capsid surface for post-production vector engineering through biorthogonal copper-free click chemistry. We were able to identify AAV vectors that would tolerate the unnatural amino acid substitution on the capsid without disrupting their packaging efficiency. We functionalized the Nε-AAVs through conjugation with DNA (AS1411) or RNA (E3) aptamers or with a folic acid moiety (FA). E3-, AS1411-, and FA-AAVs showed on average a 3- to 9-fold increase in transduction compared with their non-conjugated counterparts in different cancer cell lines. Using specific competitors, we established ligand-specific transduction. Invivo studies confirmed the selective uptake of FA-AAV and AS1411-AAV without off-target transduction in peripheral organs. Overall, the high versatility of these novel Nε-AAVs might pave the way to tailoring gene therapy vectors toward specific types of cells both for exvivo and invivo applications.

Folate receptor-targeted near-infrared photodynamic therapy for folate receptor-overexpressing tumors.

Photodynamic therapy (PDT) is a minimally invasive form of cancer therapy, and the development of a novel photosensitizer (PS) with optimal properties is important for enhancing PDT efficacy. Folate receptor (FR) membrane protein is frequently overexpressed in 40% of human cancer and a good candidate for tumor-specific targeting. Specific active targeting of PS to FR can be achieved by conjugation with the folate moiety. A folate-linked, near-infrared (NIR)-sensitive probe, folate-Si-rhodamine-1 (FolateSiR-1), was previously developed and is expected to be applicable to NIR-PDT. To investigate the therapeutic efficacy of NIR-PDT induced by FolateSiR-1, a FR-targeted PS, in preclinical cancer models. FolateSiR-1 was developed by conjugating a folate moiety to the Si-rhodamine derivative through a negatively charged tripeptide linker. FR expression in the designated cell lines was examined by western blotting (WB). The selective binding of FolateSiR-1 to FR was confirmed in FR overexpressing KB cells (FR+) and tumors by fluorescence microscopy and in vivo fluorescence imaging. Low FR expressing OVCAR-3 and A4 cell lines were used as negative controls (FR-). The NIR light (635 ± 3 nm)-induced phototoxic effect of FolateSiR-1 was evaluated by cell viability imaging assays. The time-dependent distribution of FolateSiR-1 and its specific accumulation in KB tumors was determined using in vivo longitudinal fluorescence imaging. The PDT effect of FolateSiR-1 was evaluated in KB tumor-bearing mice divided into four experimental groups: (1) FolateSiR-1 (100 μmol/L) alone; (2) FolateSiR-1 (100 μmol/L) followed by NIR irradiation (50 J/cm2); (3) NIR irradiation (50 J/cm2) alone; and (4) no treatment. Tumor volume measurement and immunohistochemical (IHC) and histological examinations of the tumors were performed to analyze the effect of PDT. High FR expression was observed in the KB cells by WB, but not in the OVCAR-3 and A4 cells. Substantial FR-specific binding of FolateSiR-1 was observed by in vitro and in vivo fluorescence imaging. Cell viability imaging assays showed that NIR-PDT induced cell death in KB cells. In vivo longitudinal fluorescence imaging showed rapid peak accumulation of FolateSiR-1 in the KB tumors 2 h after injection. In vivo PDT conducted at this time point caused tumor growth delay. The relative tumor volumes in the PDT group were significantly reduced compared to those in the other groups [5.81 ± 1.74 (NIR-PDT) vs 12.24 ± 2.48 (Folate-SiR-1), vs 11.84 ± 3.67 (IR), vs 12.98 ± 2.78 (Untreated), at Day 16, P < 0.05]. IHC analysis revealed reduced proliferation marker Ki-67-positive cells in the PDT treated tumors, and hematoxylin-eosin staining revealed features of necrotic- and apoptotic cell death. FolateSiR-1 has potential for use in PDT, and FR-targeted NIR-PDT may open a new effective strategy for the treatment of FR-overexpressing tumors.

Folic Acid Enables Targeting Delivery of Lipodiscs by Circumventing IgM-Mediated Opsonization.

Folic acid (FA) is one of the most widely utilized small-molecule ligands for cancer targeted drug delivery. Natural IgM was recently found to avidly absorb on the surface of FA-functionalized liposomes (FA-sLip), negatively regulating the in vivo performance by efficiently activating complement. Herein, FA-functionalized lipodiscs (FA-Disc) were constructed to successfully circumvent IgM-mediated opsonization and retained binding activity with folate receptors in vivo. The FA moiety along with the bound IgM was restricted to the highly curved rim of lipodiscs, leading to IgM incapability of presenting the membrane-bound conformation to trigger complement activation. The C1q docking, C3 binding, and C5a release were blocked and accelerated blood clearance phenomenon was mitigated of FA-Disc. FA-Disc retained folate binding activity and could effectively target folate receptor positive tumors in vivo. The present study provides a useful solution to avoid the negative regulation by IgM and achieve FA-enabled targeting by exploring disc-shaped nanocarriers.

Abstract 1077: Stability and safety evaluation of ELU001, a targeted C’Dot drug conjugate for the potential treatment of folate receptor alpha-overexpressing cancers

Abstract While several antibody-drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors ADCs remain limited in their therapeutic efficacy due to long circulatory half-life and limited tumor penetration. Ultra-small (sub-10nm) C’Dot-drug-conjugates (CDCs) directly address this, exhibiting deep penetration and retention in solid tumor models, with limited systemic exposure following rapid renal clearance. CDCs can also achieve greater potency by delivering over 10x more payload and by binding to tumor cells with a higher avidity allowing effective killing of tumors with broader range of moderate to high expression of target antigens. ELU001 is a CDC that targets folate receptor alpha (FRα) overexpressing tumors via folic acid moieties on its surface and delivers an average of 21 exatecan topoisomerase-1 inhibitor molecules as its payload. FRα is overexpressed on a variety of tumors including ovarian, endometrial, triple negative breast and non-small cell lung, but is minimally expressed on normal tissues making it an attractive tumor-associated antigen for targeted drug delivery. ELU001 is highly stable in plasma and elicits antitumor efficacy in a variety of cell line and PDX-derived tumor models both in vitro and in vivo. In 15-day repeat dose toxicology and toxicokinetic studies performed in Wistar Han rats and Beagle dogs, ELU001 was well tolerated at up to 0.87 mg/kg/day in rats and 0.174 mg/kg/day in dogs based upon conjugated exatecan concentration when administered on a QWx3 schedule via a 1-hour infusion. Observed dose-related toxicities for both species were limited to the bone marrow and GI tract - the same organs as those observed when free payload (exatecan) was administered suggesting that the delivery of exatecan conjugated to the CDC did not broaden the tissue toxicity profile. Observed toxicities were recovered or substantially reduced by the end of a two-week recovery period. No drug-related hepatic, renal, pulmonary or ocular toxicities were observed and there were no drug-related deaths in the repeat dose toxicity study. TK parameters, estimated in the 15-day GLP studies revealed similar plasma exposure values in males and females for ELU001, Total Exatecan (conjugated and released) and Released Exatecan for rats and dogs, respectively. ELU001 exhibited an average circulatory half-life ranging from approximately 15 to 20 hrs in rats and 24 to 29 hrs in dogs with no accumulation of ELU001, Total Exatecan or Free Exatecan observed from day 1 to day 15. Based upon AUC0-last (hr*ng/ml) released payload levels in the circulation were less than approximately 0.3% and 0.1% of the total payload levels in the rat and the dog respectively. No ELU001 anti-drug antibodies were induced in either species. In summary, ELU001 has a favorable nonclinical safety/TK profile and is currently under evaluation in a clinical safety study - NCT05001282. Citation Format: Gregory P. Adams, Kai Ma, Feng Chen, Marion Scocca, Aranapakam Venkatesan, Cathy Reddick, Mary Hilgart, Thomas Gardinier, Fei Wu, Melik Turker, Peiming Chen, Tin Khor, Vaibhav Patel, Eliel Bayever. Stability and safety evaluation of ELU001, a targeted C’Dot drug conjugate for the potential treatment of folate receptor alpha-overexpressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1077.

Tumor site-specific PEG detachment and active tumor homing of therapeutic PEGylated chitosan/folate-decorated polydopamine nanoparticles to augment antitumor efficacy of photothermal/chemo combination therapy

To effectively promote tumor-targeted delivery of photothermal/chemo combined therapy for boosted antitumor efficacy, the versatile photothermal hybrid polymeric nanoparticles capable of detaching poly(ethylene glycol) (PEG) segments and exposing tumor-targeting folate (FA) moieties in response to tumor extracellular acidity (pHe) are developed to selectively deliver doxorubicin (DOX), a chemotherapy drug, to the tumor sites. Through one-pot co-deposition of dopamine molecules with acidity-responsive benzoic imine-containing PEGylated chitosan (BI-PC) adducts, the hybrid BI-PC/polydopamine (PDA) nanoparticles were attained as DOX vehicles and characterized to have a spherical structure composed of a PDA core surrounded by hydrophilic BI-PC shells. The DOX@BI-PC/PDA nanoparticles not only showed prominent colloidal stability in serum-containing environment and photothermal conversion efficiency, but also exhibited acidity/photothermal-activated drug release. The PEG detachment and FA exposure of FA-DOX@BI-PC/PDA nanoparticles in weak acidic environment appreciably promoted their uptake by FA receptor-overexpressed CT-26 colon cancer cells, thus largely augmenting anticancer potency based on the photothermal/chemo therapy. Importantly, the pHe-responsive FA-DOX@BI-PC/PDA nanoparticles markedly accumulated in CT-26 tumor sites in vivo and inhibited tumor growth without significant systemic toxicity upon the near infrared (NIR)-triggered hyperthermia integrated with DOX chemotherapy. This work presents a practical strategy for improved antitumor potency of photothermal/chemo combination therapy.

Efficient gene transfection to lung cancer cells via Folate-PEI-Sorbitol gene transporter.

Lung cancer is known to be one of the fatal diseases in the world and is experiencing treatment difficulties. Many treatments have been discovered and implemented, but death rate of patients with lung cancer continues to remain high. Current treatments for cancer such as chemotherapy, immunotherapy, and radiotherapy have shown considerable results, yet they are accompanied by side effects. One effective method for reducing the cytotoxicity of these treatments is via the use of a nanoparticle-mediated siRNA delivery strategy with selective silencing effects and non-viral vectors. In this study, a folate (FA) moiety ligand-conjugated poly(sorbitol-co-PEI)-based gene transporter was designed by combining low-molecular weight polyethyleneimine (LMW PEI) and D-sorbitol with FA to form FPS. Since folate receptors are commonly overexpressed in various cancer cells, folate-conjugated nanoparticles may be more effectively delivered to selective cancer cells. Additionally, siOPA1 was used to induce apoptosis through mitochondrial fusion. The OPA1 protein stability level is important for maintaining normal mitochondrial cristae structure and function, conserving the inner membrane structure, and protecting cells from apoptosis. Consequently, when FPS/siOPA1 was used for lung cancer in-vitro and in-vivo, it improved cell viability and cellular uptake.

Synthesis, characterization, and biological activities of folic acid conjugates with polyvinyl alcohol, chitosan, and cellulose

AbstractPolyvinyl alcohol (PVA), chitosan (CS), and cellulose (CL) are promising polymers for chemical functionalization and biomedical applications. This study aimed to synthesize folic acid (FA) conjugates with PVA, CS, and CL via chloroacetyl chloride, 2‐bromopropionyl bromide, and epichlorohydrin to enhance it biomedical applications. The functionalized polymer conjugates were characterized by FT‐IR, 1H‐NMR, GPC, and TGA techniques. FT‐IR and 1H‐NMR revealed the main functional groups (OH, NH, C═O, C═N), the aromatic CH and NH protons of FA moieties. TGA illustrated two stages of decompositions of all‐polymer conjugates. FA showed no antifungal activity, while two of the newly grafted polymer conjugates (chitosan bromopropionate‐grafted FA and cellulose chloroacetate‐grafted FA) illustrated antifungal activity against both Aspergillus fumigatus and Candida albicans. Polymer conjugates; poly(vinyl chloroacetate)‐grafted FA and chitosan‐EPCH‐grafted FA revealed good antifungal effect on C. albicans and A. fumigatus, respectively. Most FA polymer conjugates showed significant antitumor activity against EAC‐bearing mice. Among these conjugates, chitosan chloroacetate‐grafted FA (P‐2A) showed the highest antitumor effect against EAC‐bearing mice via reduction in total tumor volume. Thus, these conjugates provided enhanced antifungal and antitumor activities as compared with FA itself. These conjugates may act as promising biologically active carrier systems for other applications such as drug delivery.

PH and ultrasound dual-responsive drug delivery system based on PEG–folate-functionalized Iron-based metal–organic framework for targeted doxorubicin delivery

In recent years, the use of metal–organic frameworks (MOFs) as drug nanocarriers has gained attention because of their extraordinary physical and chemical properties. In this work, dual-responsive iron-based MOFs were synthesized via the microwave-assisted method using FeCl 3 .6 (H 2 O) as the metal cluster and 2-aminoterephthalic acid (NH 2 -BDC) as the organic linker (namely NH 2 -Fe-BDC) and loaded with the anti-cancer drug doxorubicin (DOX). The DOX-loaded MOFs were further functionalized with polyethylene glycol-folate (PEG–FA), yielding PEG–FA-NH 2 -Fe-BDC. The folate moiety is used to specifically target several cancers overexpressing the folate receptor (FR). These nanoparticles were characterized using Fourier-Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Thermogravimetric Analysis (TGA), and Dynamic Light Scattering (DLS). The FTIR confirmed the PEG–FA conjugation to the MOFs, while the XRD patterns confirmed the crystallinity of the nanoparticles. TGA results demonstrated the thermal stability of the MOFs. Moreover, the DLS analysis showed that regular MOFs had a particle diameter of 577 nm, while the PEG–FA-functionalized MOF had a particle diameter of 461 nm, which demonstrates the improved colloidal stability of the functionalized MOF. The DOX encapsulation efficiency was determined to be approximately 97%, while the encapsulation capacity was around 14.5 wt%. Furthermore, the in-vitro release profiles were studied under different pH values (5.3 and 7.4) with and without low-frequency ultrasound (LFUS, at 40 kHz). The results confirmed the sonosensitivity of the nanovehicles, with US-triggered release efficiency reaching up to 90% after 280 min (at a pH of 5.3). The MTT study revealed that these nanocarriers are non-toxic at lower concentrations. Their toxicity increases at higher concentrations. Furthermore, the cellular uptake was investigated via flow cytometry, and the results showed that the conjugation of the PEG-FA moiety to the MOF’s surface significantly enhanced uptake by cancer cells. Accordingly, this study showed the pH/US dual-responsive capability of NH 2 -Fe-BDC and PEG–FA-NH 2 -Fe-BDC.

Tuning ligand number to enhance selectivity of paclitaxel liposomes towards ovarian cancer

Although several anticancer drugs are currently available to tackle the growing menace of cancer, their efficacy is severely hampered due to their non-selectivity and associated toxicity to the healthy cells. The prime hurdles in the fabrication of efficient and targeted cancer therapy are improving the selectivity of these drugs towards cancerous cells while reducing their toxicity to the healthy cells. Thus, the current study aims to develop a liposomal system with an optimized number of folate moiety anchored on its surface (480/liposome) to selectively target the ovarian tumor cells in vivo. The pharmacokinetics of the folate anchored liposome indicated a 16.61-fold increase in the area under the curve along with an increased mean retention time of 12.41 h, as compared to the marketed formulation. In vivo biochemical assays indicated a significant reduction in reactive oxygen species generation, which could ultimately lead to a decrease in tumor incidence. Antitumor efficacy study on an ovarian tumor model showed an improved targeting potential of the optimized liposome with a 6.7-fold reduction in tumor volume and 1.56-fold reduction in tumor weight compared to the marketed formulation. This was achieved along with more than 75% survival without any significant drop in body weight. The findings collectively suggest the potential of rationalizing and optimizing the ligand number anchored on the liposomal surface can help in explicitly targeting the ovarian tumor in vivo. Thus, optimizing the ligand number could serve as an important protocol for designing target-based delivery systems concerning targeting ligands.

Efficient Design to Monitor the Site‐specific Sustained Release of a Non‐Emissive Anticancer Drug

A pH-responsive smart nanocarrier with significant components was synthesized by conjugating the non-emissive anticancer drug methyl orange and polyethylene glycol derived folate moiety to the backbone of polynorbornene. Complete synthesis procedure and characterization methods of three monomers included in the work: norbornene-derived Chlorambucil (Monomer 1), norbornene grafted with polyethylene glycol, and folic acid (Monomer 2) and norbornene attached methyl orange (Monomer 3) connected to the norbornene backbone through ester linkage were clearly discussed. Finally, the random copolymer CHO PEG FOL METH was synthesized by ring-opening metathesis polymerization (ROMP) using Grubbs' second-generation catalyst. Advanced polymer chromatography (APC) was used to find the final polymer's molecular weight and polydispersity index (PDI). Dynamic light scattering, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were utilized to explore the prodrug's size and morphology. Release experiments of the anticancer drug, Chlorambucil and the coloring agent, methyl orange, were performed at different pH and time. Cell viability assay was carried out for determining the rate of survived cells, followed by the treatment of our final polymer named CHO PEG FOL METH.

Design and synthesis of highly fluorescent and stable fullerene nanoparticles as probes for folic acid detection and targeted cancer cell imaging

Rational design and construction of fullerene derivatives play significant roles in the development of applications for sensing, marking and imaging in biomedical fields. In the present work, a novel type of C60 fluorescent nanoparticle (C60 FNP) was synthesized by a combination of thiol–ene chemistry and modification with folic acid (FA). The as-prepared C60 FNPs exhibited intense blue luminescence with a relatively high quantum yield of 26%, which is higher than that of any other reported fluorescent fullerene-based nanomaterial. Moreover, they revealed superior photobleaching resistance under constant UV lamp illumination for 5 h and excellent photostablity after 9 months of storage in water. Due to the mutual hydrogen bond interaction, the obtained C60 FNPs were capable of acting as a sensitive and specific probe for FA detection and quantification, with a liner range of 0 to 80 μM and a detection limit of 0.24 μM. Satisfactory recoveries (95.4%–105.2%) were obtained from a series of actual samples, further confirming the feasibility of this nanoprobe. Additionally, taking advantage of the FA moiety, the C60 FNPs had easy access to penetrate into cancer cells with higher expression levels of folate receptors, thereby achieving the function of targeted cellular imaging.

Iron oxide and gold bimetallic radiosensitizers for synchronous tumor chemoradiation therapy in 4T1 breast cancer murine model.

The development of highly integrated multifunctional nanomaterials with a superadditive therapeutic effect and good safety is an urgent but challenging task in cancer therapy research. The present study aims to design a nanoplatform that offers the opportunity to enhance antitumor activity while minimizing side effects. Given the Au-mediated X-ray radiation enhancement and the ability of Fe-based nanomaterials to create reactive oxygen species (ROS) and DNA damage, we anticipated that bimetallic Fe3O4-Au heterodimer would bring strong radiosensitizing capacity. Fe3O4-Au heterodimer surface was covered with bovine serum albumin (BSA) to achieve good surface functionality, stability and prolonged blood circulation. Folic acid (FA) moieties were added to the nanoformulation to increase tumor-homing, specificity and uptake. Finally, curcumin (CUR) was incorporated into the nanoparticle to function as a natural anticancer agent. The integration of all these components has yielded a single nanoplatform, Fe3O4-Au-BSA-FA-CUR, capable of successfully fulfilling the mission of superadditive cancer therapy to avoid the risks of organ removal surgery. The efficacy of the proposed nanoplatform was investigated in vitro and in vivo. High radiosensitizing ability, X-ray-induced ROS generation and DNA damage, and good biocompatibility were demonstrated through in vitro experiments. Also, the administration of Fe3O4-Au-BSA-FA-CUR with X-ray irradiation completely eradicated the tumor without any mortality and toxicity in healthy tissues in vivo. Our results highlight the potential of CUR-loaded Fe3O4-Au-BSA-FA heteronanostructure to enable synergistic localized radiochemotherapy and open up a new door to attractive possibilities that warrant further exploration.

Biofunctionalization of Water-Soluble poly(Phenylene Ethynylene)s.

We report the use of amide coupling chemistry to covalently link five different biofunctional groups onto an anionic water-soluble poly(phenylene ethynylene) (PPE) polymer. Two of the biofunctionalized PPEs are used in prototype applications, including pH sensing and flow cytometry labeling. The PPE is functionalized with carboxylate (R-CO2-) and sulfonate (R-SO3-) ionic groups. By using an activated ester, the amine-functionalized groups are covalently linked to the PPE polymer via amide linkages. The reaction chemistry is optimized using biotin-ethylene diamine, making it possible to control the loading of the biotin functionality on the PPE chains. Using the optimized approach, a family of five PPEs were prepared that contain biotin, rhodamine, cholesterol, mannose, or folic acid moieties appended to the polymer backbones. The rhodamine- and biotin-modified PPEs were further applied for pH response and flow cytometry applications. The reported approach can be utilized for other classes of water-soluble conjugated polymers, allowing facile development of a variety of new functionalized water-soluble conjugated polymers for a range of applications including sensing, bioimaging, and flow cytometry analysis.

In Vitro Studies of Prednisolone Loaded PLGA Nanoparticles-Surface Functionalized With Folic Acid on Glioma and Macrophage Cell Lines

Background: Glucocorticoids are employed for their anti-inflammatory effects in treatingglioma, whose cells are known to overexpress the folate receptors. Some glucocorticoids haveshown inhibitory effects, but the efficacy of prednisolone when delivered via folate receptormediateduptake, has not been attempted. The study aimed to assess the efficacy of targeteddelivery of prednisolone on glioma cell lines like C6 and U87 via the folate receptors. Methods: Targeted delivery of prednisolone was achieved by initially conjugating folic acid (FA)to the di-block copolymer of polylactic acid (PLA) – polyethylene glycol (PEG). This moietycarrying di-block copolymer was incorporated on the surface of the drug-loaded poly lactic-coglycolicacid (PLGA) nanoparticle (NP) by employing the Interfacial Activity Assisted SurfaceFunctionalization (IAASF) technique. The NPs were evaluated for size, zeta potential, and drugloading. It was characterized using particle size analyser, SEM, 1H-NMR, and XRD. cell uptake,cytotoxicity, and anti-inflammatory activities were studied for various formulations. Results: The cytotoxicity assay indicated a high cell growth inhibitory effect of drug encapsulatedNPs with FA moiety as compared to free drug and NPs without the moiety for an incubationperiod of three, five, and six days. The growth-inhibitory effect of the free drug was short-lived,whereas FA functionalized NPs showed higher uptake and sustained inhibitory effect, and werealso able to significantly control the release of pro-inflammatory cytokines like tumour necrosisfactor-alpha (TNF-α) and nitric oxide (NO). Conclusion: Uptake, attenuation of pro-inflammatory signals, and the inhibitory effect ofprednisolone on the cells were more effective when targeted with the FA moiety on the surfaceof NPs as compared to free drug and NPs without the moiety.

Synthesize of Folic acid functionalized dendritic fibrous nano-silica and its application as an efficient nanocatalyst for access to direct amidation of carboxylic acids with amines

A new nanomaterial based on folic acid functionalized dendritic fibrous nano-silica (FA-KCC-1-NH2) was synthesized and used as a recyclable solid acid and heterogeneous nanocatalyst towards efficient amidation of a variety of carboxylic acids with amines in toluene under reflux conditions. KCC-1 porous nanomaterials were produced utilizing a hydrothermal technique and in the next functionalized with folic acid moieties to yield KCC-1-NH-FA nanocatalyst. The structure of KCC-1, KCC-1-NH2 and KCC-1-NH-FA nanoparticles were investigated by FESEM, DLS, zeta potential and TEM, instrumental techniques. Also, the pore size of KCC-1-NH-FA nanoparticles were moreover investigated with BET where results revealed that the surface of this nanocomposite was expanded. The synthesized KCC-1-NH-FA nanoparticles showed effective catalytic activity in amidation of carboxylic acids with amines affording in high yields (76-89%) and short period of times. Moreover, other advantages of present method are easy workup, no need to use of chromatographic column and excellent recyclability of catalyst without significant loss in its catalytic activity which gives economic rewards.

PEGylated-folic acid–modified black phosphorus quantum dots as near-infrared agents for dual-modality imaging-guided selective cancer cell destruction

Abstract Biological systems have high transparence to 700–1100-nm near-infrared (NIR) light. Black phosphorus quantum dots (BPQDs) have high optical absorbance in this spectrum. This optical property of BPQDs integrates both diagnostic and therapeutic functions together in an all-in-one processing system in cancer theranostic approaches. In the present study, BPQDs were synthesized and functionalized by targeting moieties (PEG-NH2-FA) and were further loaded with anticancer drugs (doxorubicin) for photodynamic–photothermal–chemotherapy. The precise killing of cancer cells was achieved by linking BPQDs with folate moiety (folic acid), internalizing BPQDs inside cancer cells with folate receptors and NIR triggering, without affecting the receptor-free cells. These in vitro experiments confirm that the agent exhibited an efficient photokilling effect and a light-triggered and heat-induced drug delivery at the precise tumor sites. Furthermore, the nanoplatform has good biocompatibility and effectively obliterates tumors in nude mice, showing no noticeable damages to noncancer tissues. Importantly, this nanoplatform can inhibit tumor growth through visualized synergistic treatment and photoacoustic and photothermal imaging. The present design of versatile nanoplatforms can allow for the adjustment of nanoplatforms for good treatment efficacy and multiplexed imaging, providing an innovation for targeted tumor treatment.