Folate Analogue Research Articles

Antifibrotic preventive effect of polyethylene glycol (PEG) 3350 in methotrexateinduced hepatoxicity model.

ABSTRACTPurpose:Liver damage caused by drugs and other chemicals accounts for about 5% of all cases. Methotrexate (MTX), a folic acid analogue, is a first-line synthetic antimetabolite agent routinely used in the treatment of rheumatoid arthritis and other autoimmune and chronic inflammatory diseases. Polyethylene glycol (PEG) has antioxidant activity. In this study, we evaluated biochemically and histopathologically the antifibrotic effect of PEG 3350 administered intraperitoneally to prevent methotrexate-induced liver damage in rats.Methods:A total of 30 male rats including 10 rats was given no drugs (normal group), and 20 rats received single-dose 20 mg/kg MTXfor induced liver injury in this study. MTX was given to 20 rats, which were divided in two groups. Group 1 rats was given PEG30 mg/kg/day (Merck) intraperitoneally, and Group 2 rats % 0.9 NaCl saline 1 mL/kg/day intraperitoneally daily for two weeks.Results:Transforming growth factor beta (TGF-β), plasma malondialdehyde (MDA), liver MDA, serum tumour necrosis factor alpha (TNF-α), alanine aminotransferase and plasma pentraxin-3 levels and, according to tissue histopathology, hepatocyte necrosis, fibrosis and cellular infiltration were significantly better in MTX+PEG group than in MTX+saline group.Conclusions:PEG 3350 is a hope for toxic hepatitis due to other causes, since liver damage occurs through oxidative stress and cell damage, similar to all toxic drugs.

Potential Process Control Issues with Pemetrexed.

Pemetrexed is a folate analog metabolic inhibitor used in treatment of locally advanced or metastatic nonsquamous non-small cell lung cancer and for mesothelioma. Intra-lot and inter-lot variability in the spectra of ALIMTA® was detected in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). One vial of 12 (8%) sampled from lot S20I013A appeared 3.0 multidimensional SDs from the other vials, suggesting that it represents a different material. Consequently, additional spectra from other lots were analyzed. Spectra of 147 vials from 23 lots in the spectral library contained 14 vials that were outside the main group (26.4 SDs using a subcluster detection test), suggesting that the 14 library vials (9.5% of the total) also contain differing materials.

Joseph R. Bertino: In Memoriam (1930–2021)

Joseph R. Bertino: In Memoriam (1930–2021)

Methotrexate Toxicity from Unintentional Dosing Errors: Calls to a Poison Center and Death Descriptions.

Methotrexate is a folate analog prescribed for varying disease with weekly administration as opposed to daily. Dosing errors can prove clinically significant and sometimes fatal. We performed a retrospective poison center review of methotrexate calls between 2009 and 2019. Of 111 human-related poison center calls, most patients taking methotrexate were women ages 41 to 80 years old and were prescribed methotrexate for rheumatoid arthritis. Eighty-eight (79%), and 41 (36%) were admitted to the hospital. Thirty-one (75%) of hospitalized patients received leukovorin treatment for their exposure. Two patients died from methotrexate dosing errors. Most methotrexate accidental ingestions reported to poison centers result from dose frequency errors. However, we note a higher incidence of unintentional therapeutic errors (79% vs 13.7%) than reported in the National Poison Data System in 2019. Patients are often hospitalized for lab monitoring, and many receive leucovorin. Most methotrexate calls to our poison center resulted from taking the drug more often than prescribed. Efforts may focus on patient education, physician or pharmacist monitoring during initiation, improved dispensing devices, or weekly drug dispensing.

METHOTREXATE-INDUCED PNEUMONITIS

TOPIC: Lung Pathology TYPE: Fellow Case Reports INTRODUCTION: Methotrexate is an analogue of folic acid that inhibits cellular proliferation by inducing an intracellular deficiency of folate coenzymes. Lung toxicity, while rare, often occurs after weeks to months of low dose oral methotrexate therapy. CASE PRESENTATION: A 46 year old male with a history of T cell lymphoma status post chemotherapy on POMP maintenance therapy and pleurX catheter for malignant pleural effusion presented to the ED with fever for 4 days. Associated symptoms were dry cough, chills, and fatigue. He denied drug allergies.BP 153/84, HR 135, SpO2 98% on room air, and temperature 101.5F. WBC was 3.2 and COVID PCR was negative. Broad spectrum antibiotics were initiated. CT thorax showed upper lobe predominant ground-glass opacities suggestive of a multifocal pneumonia or drug reaction. He became hypoxic requiring 3L of oxygen and underwent bronchoscopy. Transbronchial biopsy revealed lung parenchyma with isolated giant cells and loosely formed granulomas consistent with hypersensitivity pneumonia. Left upper lobe broncho-alveolar lavage had lymphocytic predominance and elevated CD4:CD8 ratio (4.7), all supporting the diagnosis of methotrexate pneumonitis. Empiric treatment for PJP and Prednisone were started. Viral, bacterial, fungal studies and PJP stain were negative. Antibiotics were stopped and steroids were continued for 2 weeks. His symptoms improved and fevers subsided. As an outpatient, repeat CT thorax and PFTs were ordered and he continues to improve clinically. DISCUSSION: There is a set of criteria to establish the diagnosis. Major criteria includes: 1. hypersensitivity pneumonitis by histopathology without pathogenic organisms 2. imaging with diffuse ground-glass or consolidative opacities 3. negative blood cultures (if febrile) and initial sputum cultures (if produced). Minor criteria includes: 1. dyspnea for <8 weeks 2. nonproductive cough 3. SpO2< 90% on room air at initial evaluation 4. DLCO < 70% of predicted for age and 5. WBC < 15k. Methotrexate pneumonitis is definite if major criteria 1 or 2 and major criterion 3 are present with three of the five minor criteria and probable if major criteria 2 and 3 plus two of the five minor criteria are present (1). Our patient met all major criteria and four minor criteria. CONCLUSIONS: Although rare with a prevalence of 0.3-11.6% (1,3), methotrexate pneumonitis has a mortality rate of 13-17.6% (2,4). Patients should be advised about the possibility of lung toxicity. Some data suggests patients should be screened for lung disease prior to medication initiation (5) and clinicians should be cautious using the drug in patients with underlying lung disease (6). REFERENCE #1: Salehi, Mashal et al. "Methotrexate-induced Hypersensitivity Pneumonitis appearing after 30 years of use: a case report." Journal of medical case reports vol. 11,1 174. 28 Jun. 2017, doi:10.1186/s13256-017-1333-0 DISCLOSURES: No relevant relationships by Bianca Dominguez, source=Web Response No relevant relationships by Gurjot Garcha, source=Web Response No relevant relationships by Wael Nasser, source=Web Response No relevant relationships by Olatunji Otegbeye, source=Web Response

Photodegradation of methotrexate in aqueous solution: degradation kinetics and identification of transformation products.

Methotrexate is an antineoplastic folate analog of high environmental concern, due to its low biodegradability and toxicological properties. This study focused on its photodegradation under two irradiation conditions, aiming to be representative of environment (300-450 nm) and drinking water treatment (254 nm). The photodegradation experiments were conducted at two pH, to vary the methotrexate ionization state and to produce a large variety of transformation products (TPs). The degradation kinetics determined through LC-UV monitoring were contrasted according to pH and irradiation wavelength. However, the quantum yields were independent of ionization state at 254 nm and the changes in kinetics at higher wavelengths were attributed to a change in the degradation mechanism. The TPs formed during the reactions were identified by UHPLC-MS/MS, using both the positive and negative modes. Among the eleven proposed structures, five were described as methotrexate TPs for the first time. The TPs result from N-demethylation, glutamic acid oxidation, and C-N cleavage, all of them leading to further degraded photoproducts presenting modified or lost glutamic acid part. This was made possible thanks to the negative mode, which allowed the exploration of the glutamic acid moiety modifications. Cytotoxicity assessment on A549 cancer cells demonstrated that all photoproducts formed at pH 7 were less toxic than the parent compound.

Updates in the Treatment of Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of rare hematologic malignancies accounting for less than 10% of non-Hodgkin lymphomas. The 2016 classification of World Health Organization recognized 29 different entities of PTCLs. These subgroups are characterized by different molecular and genetic patterns. For nearly 30 years, little improvement in the treatment of PTCLs has been noticed due to the paucity of randomized trials and anthracycline-based chemotherapy remains the mainstay of first-line treatment. In front-line setting, ECHELON-2, the first randomized controlled Phase III clinical trial, recently met its primary endpoint of PFS demonstrating the superiority of BV containing regimen when compared to standard CHOP in patients with CD30 positive PTCLs. The role of therapeutic intensifications such as autologous or allogenic stem cell transplantations remains controversial in first-line setting and in relapsed/refractory disease due to the lack of studies clearly addressing this question and the recently published negative studies. PTCLs are often refractory to first-line chemotherapy and tend to relapse after an initial response. New agents have been approved for relapsed/refractory disease such as Histone deacetylase inhibitors, folate analogue metabolic inhibitor or CD30 antibody drug conjugated. Despite an acceptable response to these agents, progression-free survival remains very poor. New strategies such as combinations of different agents have been evaluated in order to improve outcomes. Innovative drugs in the fields of epigenetics, immunomodulation within the tumor microenvironment, and direct targeting of tumor cells to CD30 and T-cell receptor abnormalities open new perspectives to improve the treatment of PTCLs.

MYC as a candidate upstream controller involved in TYMS gene expression and 5-FU/folate treatment efficacy in colorectal cancer.

e15512 Background: One of the target enzymes of 5-fluorouracil (5-FU)-based therapies is thymidylate synthase (TS) encoded by the TYMS gene. To enhance the effect of 5-FU, a folate analogue is often provided as part of the treatment. In this context, it has previously been shown in the ISO-CC-005 clinical study that TYMS gene expression can be predictive of response to 5-FU + folate analogue Arfolitixorin. Methods: To better understand the role of TYMS expression as a predictor of response to 5-FU + folate-based therapies and identify potential mechanisms and biomarkers of sensitivity/resistance, we leveraged data from the publicly available cancer genome atlas database (TCGA). We combined this information with a knowledgebase of causal biological relationships extracted from peer reviewed publications, to identify other relevant genes and candidate upstream controllers directly or indirectly related to TYMS expression and 5-FU + folate efficacy. Results: In TCGA subjects suffering from colorectal cancer (CRC) (stage IV tumors, treated with FOLFOX/FOLFIRI (n = 38)), lower TYMS expression was associated with a better overall survival (OS). This is consistent with what has been observed in the ISO-CC-005 study. Applying our causal biology knowledgebase to both genes identified as correlated to TYMS expression in TCGA CRC tumors and other published sets of genes associated with FOLFOX or FOLFIRI efficacy, we identified overlap with a MYCN signature. Notably MYC has been shown to directly activate TYMS expression. Thus, the MYC family is a compelling candidate upstream controller of these genes. We scored TCGA CRC tumors for inferred MYC activity, using this MYCN gene signature, and evaluated the inferred activity with respect to OS. In stage IV tumors, higher inferred MYC activity appears to be associated with worse OS. To further characterize this inferred MYC activity, we employed a transcriptomics-based cell deconvolution estimation of immune cell population proportions in the TCGA CRC cohort. We found inferred MYC activity inversely correlated with immune cell proportions overall, specifically strongest with those of pDCs and classical monocytes. Conclusions: MYC activation, a known transcriptional regulator of TYMS, has been identified as a potentially relevant common upstream controller of a group of genes involved in 5-FU + folate analogue efficacy. Here we have also observed a similar relationship to OS between TYMS and inferred MYC activity in Stage IV CRC. MYC family activity (and activated protein forms), genes of the MYCN signature, or the identified immune cell proportions are all potential biomarker candidates to explore as factors in 5-FU + folate analogue efficacy.

Chitosan coated biocompatible zeolitic imidazolate framework ZIF-90 for targeted delivery of anticancer drug methotrexate

In this work, using zeolitic imidazolate framework (ZIF) as carrier, a new biocompatible anti-cancer drug delivery system CS@MTX@ZIF-90 (CMZ) was efficiently synthesized by one-pot method. Methotrexate (MTX), an anticancer drug as folic acid analogue was loaded into ZIF-90 through Schiff base reaction between amino group in MTX and aldehyde group of imidazole-2-carboxaldehyde ligand with drug loading amount about 250 ​mg/g. As a pH-sensitive biomaterial, chitosan (CS) was modificated by the outer layer of the particles to improve the pH responsiveness of the composite CMZ during the drug release process. By releasing a large amount of MTX under acidic conditions (the pH environment around tumor cells), and releasing a substantially lower amount of MTX at a normal environment, CMZ exhibited a pH-responsive and target-selective behavior. In addition, in vitro cytotoxicity and anticancer activity results showed that CMZ can inhibit the growth of liver cancer HepG2 cells, prostate cancer DU145 ​cells and gastric cancer SGC7901 ​cells, with only negligible toxicity to normal EC304 ​cells. Based upon the results of corresponding experiments, CMZ exhibited high MTX drug loading, cancer-targeted release and good biocompatibility, which can be used as a good candidate for anticancer drug delivery system.

Unusual Presentation of Ectopic Pregnancy Treated by Medical Management

Implantation of the fertilized ovum outside the uterine cavity is called ectopic pregnancy. It is associated with adverse outcome if not treated earlier. The fate of ectopic pregnancy depends on many factors. Important among them being site and duration of ectopic pregnancy. The main serious outcome is rupture. If the ectopic pregnancy ruptures and the patient survives this catastrophe, the ectopic mass gets organized and presents as pelvic mass with pain. Methotrexate is a folic acid analog that inhibits dihydrofolate reductase and thereby prevents synthesis of DNA. It affects actively growing cells including trophoblastic tissues, malignant cells, bone marrow, intestinal mucosa and respiratory epithelium. Medical management of ectopic pregnancies with methotrexate is safe and effective, therapy can be considered for patients with confirmed ectopic pregnancy who are hemodynamic ally stable with no evidence of rupture. It should be used with caution and severe toxicity should be kept in mind. Key words: Ectopic Pregnancy; Methotrexate; Medical management.

Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight.

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.

Long-term safety of combination treatment with methotrexate and tumor necrosis factor (TNF)-α antagonists versus TNF-α antagonists alone in psoriatic patients.

Methotrexate, a folic acid analog, is the conventional systemic anti-psoriatic agent most commonly chosen for combination with biologics in the treatment of psoriasis. Real-world long-term safety data of this combination versus biologic treatment alone in dermatological practice are sparse. Here, we present results of a comparative retrospective study of laboratory dynamics and adverse events in psoriatic patients receiving a tumor necrosis factor (TNF)-α antagonist (adalimumab or etanercept) with and without concomitant methotrexate (176 treatment courses, mean duration of 629days). Co-treatment with methotrexate significantly (P<0.05) correlated with a decrease of leukocyte, neutrophil and erythrocyte counts and an increase of glutamate pyruvate transaminase (GPT) (Pearson correlation, n>148). The relative risk for a Common Terminology Criteria for Adverse Events (CTCAE) grade 1-2 laboratory adverse event was significantly elevated to 1.11 for anemia and 1.16 for a GPT increase if the patients received concomitant methotrexate at the time the laboratory test was performed. Combination treatment was given for equal or more than 30% of the time (MTX≥30% ) during 12% of the treatment courses. During these treatment courses, dynamics of leukocyte (-8.1%), neutrophil (-8.1%), erythrocyte (-3.2%) counts and GPT (+16.9%) from baseline to average under treatment were significantly more pronounced. CTCAE grade 3-4 laboratory adverse events occurred in 9.5% and 5.2% of treatment courses with and without MTX≥30% , respectively (p=0.70), and affected transaminases in 90% of the cases. Methotrexate was discontinued due to CTCAE grade 3-4 laboratory adverse events in 4.25% of the treatment courses with MTX of 30% or more. Elevated baseline γ-glutamyl transferase levels significantly predicted the occurrence of CTCAE grade 3-4 laboratory adverse events and should trigger investigations for pre-existing liver disease or alcohol abuse. In conclusion, our comparative data supplement previous short-term studies and support a tolerable long-term safety profile of the combination treatment. However, given the additional toxicities and low evidence for benefits, alternative options such as biologic monotherapy or switching to a different biologic should be considered in a dermatological setting.

Pemetrexed - First-Line Therapy for Non-Squamous Non-Small Cell Lung Cancer: A Review of Patent Literature.

Pemetrexed is a folate analogue metabolic inhibitor for mammalian cells. Pemetrexed is toxic to several cancer cells by interfering with their new biosynthesis of nucleotides, thus causing cell apoptosis. Presently, Pemetrexed is given to patients with Non-Small Cell Lung Cancer (NSCLC). This review focuses on the recent patents of Pemetrexed. This assessment includes patents grouped in segments like crystalline form patent, composition related patents, product patents, as well as a method of treatment. The aim of this review is to simplify inventors with existing patents in a single place. Data were searched from several available databases, including paid databases which include Orbit® and SciFinder®. Free databases include Worldwide Espacenet® (EPO), Patentscope® (WIPO), InPASS (Indian patent database) and Google Patents. Some new polymorph and composition-related inventions of Pemetrexed have been recently patented as its orange-book listed patents will soon expire in May 2022. Further, because of the problem of oxidation through the development and continuing storage of Pemetrexed composition, several excipients are experimented with within these patents to stabilize the same. Nevertheless, there is a need for further development of an improved composition of Pemetrexed with improved characteristics. Wide research has been conducted on different processes for preparing Pemetrexed and formulation thereof. Such type of active research may clear the track for the generic companies in the United States, producing the formulation at low prices and providing universal health care at economical prices.

Interaction of nobiletin with methotrexate ameliorates 7-OH methotrexate-induced nephrotoxicity through endoplasmic reticulum stress-dependent PERK/CHOP signaling pathway

Drug-induced nephrotoxicity is a frequent adverse event that contributes to acute kidney injury with tubular and/or glomerular lesions. Methotrexate (MTX) is a folate analog used against a myriad of malignancies and autoimmune diseases. Unfortunately, ambiguous renal toxicology limits its safe clinical usage. Based on our previous studies, 7−OH MTX as an overlooked oxidative metabolite of MTX was proposed to be the main culprit responsible for nephrotoxicity, while nobiletin, a naturally occurring polymethoxylated flavonoid screened from our prepared total phenolic extracts of Citrus aurantium L. (TPE-CA), was employed as a therapeutic agent for drug-drug interactions. According to the present study, nobiletin can ameliorate the renal accumulation of 7−OH MTX through the interaction with aldehyde oxidase. RNA-seq analysis revealed that 7−OH MTX was mainly related to protein processing in endoplasmic reticulum (ER) stress, with the PERK/CHOP pathway selected as the most significant for metabolic nephrotoxicity. Meanwhile, the cross-linked proteins and conducted signals were investigated by western blotting and further verified by GSK inhibition analyses. These results indicated that nobiletin protected renal function from MTX-induced nephrotoxicity by modulating metabolism and ameliorated the metabolic toxicity of 7−OH MTX on ER stress-induced PERK/CHOP conduction by maintaining Ca2+ homeostasis and reducing the production of reactive oxygen species.

A Review of Clinical Applications and Side Effects of Methotrexate in Ophthalmology.

Methotrexate (MTX) is a folate analog widely used against a range of diseases including malignancies and autoimmune disorders. Its high effectiveness-price ratio also won extensive application in ophthalmology. On the other hand, although MTX has an excellent pharmacological efficacy, MTX associated side effects in clinical use, which vary from patient to patient, are nonnegligible. There is no comparatively systematic review on MTX associated side effects and its risk factors. This review aimed to reveal novel clinical approaches of MTX and its adverse effects in order to provide a reference for ophthalmic scholars in clinical application of MTX.

Preclinical evaluation of the anti-tumor activity of pralatrexate in high-risk neuroblastoma cells.

Introduction: Pralatrexate is a folate analogue inhibitor of dihydrofolate reductase exhibiting high affinity for reduced folate carrier-1 with antineoplastic and immunosuppressive activities, similar to methotrexate. Despite advances in multi-modality treatment strategies, the survival rates for children with high-risk neuroblastoma have failed to improve. Therefore, the intense research continues in order to identify the ideal novel agent or combination of chemotherapy drugs to treat high-risk neuroblastoma.Materials and Methods: Four human neuroblastoma cell lines were used to determine IC50 values of select chemotherapy agents. Antiproliferative effects of pralatrexate were assessed by adherent and non-adherent colony formation assays. Cell cycle arrest and apoptosis were measured by flow cytometry and immunoblotting. PDX tissue culture was used to assess ex vivo efficacy.Results: Treatment with pralatrexate in all four neuroblastoma cell lines blocked cell growth in 2D and 3D culture conditions in a time-dependent manner. The potency of pralatrexate was ten-fold stronger than methotrexate, as measured by IC50. Pralatrexate-induced apoptosis was confirmed by caspase-3 activation and PARP cleavage. MYCN and SLC19A1 mRNA expressions were decreased with pralatrexate in MYCN-amplified neuroblastoma cells.Conclusions: Pralatrexate demonstrated effective inhibition of cell growth and viability. The higher potency of pralatrexate compared to methotrexate, a drug with high levels of toxicity, suggests pralatrexate may be a safer alternative to methotrexate as an effective chemotherapeutic agent in the treatment of patients with high-risk neuroblastoma.

Development of a Pemetrexed/Folic Acid Nanoformulation: Synthesis, Characterization, and Efficacy in a Murine Colorectal Cancer Model.

The folate analogue pemetrexed (PEM) is an approved therapeutic for non-small cell lung cancer and malignant pleural mesothelioma with the potential for broader application in combination therapies. Here, we report the development of a nanoformulation of PEM and its efficacy against the CT26 murine colorectal cancer cell line in vitro and in vivo. Utilizing layer-by-layer deposition, we integrate PEM, along with folic acid (FA), onto a fluorescent polystyrene nanoparticle (NP) substrate. The final nanoformulation (PEM/FA-NP) has a size of ∼40 nm and a zeta potential of approximately −20 mV. Cell uptake studies indicated increased uptake in vitro for the PEM/FA-NP compared to the uncoated NP, likely due to the presence of PEM and FA. Viability studies were performed to determine the potency of the PEM/FA-NP formulation against CT26 cells. Syngeneic CT26 tumors in BALB/c mice showed reduced growth when treated once daily (2.1 mg/kg PEM) for 3 days with PEM/FA-NP versus the vehicle (uncoated) control, with no observable signs of systemic toxicity associated with the nanoformulation. Although the current study size is limited (n = 4 animals for each group), the overall performance and biocompatibility of the PEM/FA-NP observed suggest that further optimization and larger-scale studies may be warranted for this novel formulation.

Folic acid-modified methotrexate-conjugated gold nanoparticles as nano-sized trojans for drug delivery to folate receptor-positive cancer cells

Methotrexate (MTX), an analog of folic acid (FA), is a drug widely used in cancer treatment. To prevent its potential toxicity and enhance therapeutic efficacy, targeted drug delivery systems, especially nanotechnology–folate platforms, are a central strategy. Gold nanoparticles (AuNPs) are promising candidates to be used as drug delivery systems because of their small particle sizes and their inertness for the body. In this study, glutathione (GSH)-coated FA-modified spherical AuNPs (5.6 nm) were successfully synthesized, and the anticancer activity of novel MTX-loaded (MTX/Au-GSH-FA) NPs (11 nm) was examined. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results showed that MTX/AuNPs possess spherical morphology, nanoscaled particle size, narrow size distribution, and good stability. In vitro studies showed that cytotoxicity of MTX/Au-GSH-FA to folate receptor-positive (FR+) human brain (U-87 MG) and cervical (HeLa) cancer cells enhanced significantly (∼3 and ∼10 fold, respectively) compared to free MTX while there was no significant effect in FR−negative human cell lines A549 (lung carcinoma), PC3 (prostate carcinoma), HEK-293 (healthy embryonic kidney). Moreover, the receptor specificity of the conjugate was shown by fluorescent microscopic imaging. In conclusion, these results indicate that the synthesized novel MTX/Au-GSH-FA NP complex seems to be a good candidate for effective and targeted delivery in FR+ cancer therapy.

NanoGold-core dendrimeric seeds for combined chemo-, photothermal-, and photodynamic therapy of cancer

This article reports the development of nanoGold Core Dendrimeric seeds (nGCD) for combined chemo-, photothermal- and photodynamic therapies of breast cancer. The tethering of nGCD with Methotrexate (MTTX, a folate analogue) enhanced the cancer cell specific receptor-targeted uptake of nGCD. Docking study supported MTTX as a α-folate receptor ligand analogue. The IR780 (photodynamic bioactive) doping in nGCD (nGCD-MTTX-IR780) resulted in a architect that exhibited NIR laser responsive potent photothermal conversion efficiency, high reactive oxygen species generation and high cytotoxicity in vitro, as well as high stability and hemocompatibility. The NIR laser was also found to control the drug release pattern in a pH dependent manner. The developed architect showed promising result with diverse applications in cancer therapy and theragnosis.

The incidence, risk factors and outcomes of chemotherapy related acute kidney injury in China.

e24161 Background: Nephrotoxicity of chemotherapeutic agents remains a significant complication limiting the efficacy of the treatment. However, comprehensive data on the epidemiology and outcomes of chemotherapy related acute kidney Injury in China is lacking. Methods: We conducted a nationwide cohort study of hospitalized patients from 25 general and children’s hospitals in China during 2013-2015. Patient-level data were obtained from the electronic hospitalization information system, prescription database and laboratory databases of all cancer patients who received chemotherapy and had at least two serum creatinine tests within any 7-day window during the hospitalization. AKI was defined and staged according to Kidney Disease Improving Global Outcomes criteria. The incidence of AKI in patients with various type of cancer and chemotherapeutic agents was examined. The outcomes of AKI, including in-hospital mortality, death after discharge, kidney recovery, and length of stay, were also assessed. Results: A total of 23,232 cancer patients, including 3,120 children ( &lt; 18 years old), 16,310 adult (19-65 years old) and 3,802 elderly patients ( &gt; 65 years old), were analyzed. Platinum compounds and pyrimidine analogues were the most common used chemotherapy agents for cancer patients. The overall incidence of AKI was 4.9%. Patients with urinary system malignancy (12.3%), hematological malignancy (10.2%) and nerve motor system malignancy (4.1%) have the highest incidence of HA-AKI. The top three types of chemotherapy drugs with the highest incidence of AKI were Purine analogues (30.1%), folic acid analogues (15.3%) and combinations of antineoplastic agents (14.1%). The nephrotoxicity of chemotherapy drugs was different among age groups. AKI is associated with a higher risk of in-hospital mortality and death after discharge. Conclusions: The risk of AKI in cancer patients varied in different age group, type of cancer and chemotherapeutic agents.