Hydrogen Bond-Mediated Supramolecular Polymeric Nanomedicine with pH/Light-Responsive Methotrexate Release and Synergistic Chemo-/Photothermal Therapy.

Complete cancer cure and healing are still difficult, owing to its complexity and heterogeneity. Integration of supramolecular forces, for example, hydrogen bonds (H-bonds), to anti-cancer nanomedicine affords new scaffolds for biomedical material decoration, featuring the advantages of dynamic property and easier processability. Here, we target the construction of H-bond-mediated supramolecular polymer micelles, loaded with a chemotherapeutic drug along with a photothermal agent for synergistic chemo-/photothermal therapies (CT/PTT). To do so, we design and synthesize an amphiphilic ABA-type triblock copolymer, bearing H-bonding moiety (barbiturate, Ba) within the middle hydrophobic B block. The presence of pendant Ba moieties within the hydrophobic core promotes the loading capability of methotrexate (MTX) and transportation stability, benefitting from the formation of specific Ba/MTX H-bonding interactions. IR780, a photothermal agent, concomitantly encapsulated via hydrophobic interactions, facilitates the development of a synergistic CT/PTT modalities, where MTX can be released on demand owing to the dissociation of Ba/MTX H-bonding interactions induced by elevated temperature. Such H-bonding nanomedicine possesses enhanced drug loading capacity and transport performance and can also trigger stimuli-responsive drug release in the tumor zone. We believe that H-bonded nanomedicines provide a fine toolbox that is conducive to attaining biomedical requirements with remarkable values in theranostics that are highly promising in clinical applications.

Design of ROS-Responsive Hyaluronic Acid-Methotrexate Conjugates for Synergistic Chemo-Photothermal Therapy for Cancer.

Combining chemotherapy with photothermal therapy (PTT) for cancer treatment could overcome the inherent limitations of both single-modality chemotherapy and PTT. However, the obstacle of accurate drug delivery to tumor sites based on chemo-photothermal remains challenging. This article describes development of a reactive oxygen species (ROS)-responsive hyaluronic acid-based nanoparticle to overcome these drawbacks. Herein, HA-TK-MTX (HTM) was synthesized by a ROS-responsive cleaved thioketal moiety linker (TK) of methotrexate (MTX) and hyaluronic acid (HA). Through hydrophobic interaction and π-π stacking interaction, a photothermal agent IR780 was integrated into the HTM, and the IR780/HTM nanoparticles (IHTM NPs) were obtained. The IHTM NPs show high photostability, excellent photothermal performance, remarkable tumor-targeting ability, and ROS sensibility. Due to the accurate drug delivery ability and superior chemo-photothermal treatment effect of IHTM NPs, the tumor inhibition rate reached 70.95% for 4T1 tumor-bearing mice. This work serves as a precedent for the chemo-photothermal therapy of cancer by rationally designing ROS-responsive nanoparticles.

Insight into the Sorption of 5-Fluorouracil and Methotrexate onto Soil-pH, Ionic Strength, and Co-Contaminant Influence.

Nowadays anticancer drugs (ADs), like other pharmaceuticals, are recognized as new emerging pollutants, meaning that they are not commonly monitored in the environment; however, they have great potential to enter the environment and cause adverse effects there. The current scientific literature highlights the problem of their presence in the aquatic environment by publishing more and more results on their analytics and ecotoxicological evaluation. In order to properly assess the risk associated with the presence of ADs in the environment, it is also necessary to investigate the processes that are important in understanding the environmental fate of these compounds. However, the state of knowledge on mobility of ADs in the environment is still very limited. Therefore, the main aim of our study was to investigate the sorption potential of two anticancer drugs, 5-fluorouracil (5-FU) and methotrexate (MTX), onto different soils. Special attention was paid to the determination of the influence of pH and ionic strength as well as presence of co-contaminants (cadmium (Cd2+) and another pharmaceutical-metoprolol (MET)) on the sorption of 5-FU and MTX onto soil. The obtained distribution coefficient values (Kd) ranged from 2.52 to 6.36 L·kg-1 and from 6.79 to 12.94 L·kg-1 for 5-FU and MTX, respectively. Investigated compounds may be classified as slightly or low mobile in the soil matrix (depending on soil). 5-FU may be recognized as more mobile in comparison to MET. It was proved that presence of other soil contaminants may strongly influence their mobility in soil structures. The investigated co-contaminant (MET) caused around 25-fold increased sorption of 5-FU, whereas diminished sorption of MTX. Moreover, the influence of environmental conditions such as pH and ionic strength on their sorption has been clearly demonstrated.

The Synergistic Effect of Hyperthermia and Chemotherapy in Magnetite Nanomedicine-Based Lung Cancer Treatment.

BACKGROUND: Lung cancer is the leading cause of cancer patient death in the world. There are many treatment options for lung cancer, including surgery, radiation therapy, chemotherapy, targeted therapy, and combined therapy. Despite significant progress has been made in the diagnosis and treatment of lung cancer during the past few decades, the prognosis is still unsatisfactory. PURPOSE: To resolve the problem of chemotherapy failure, we developed a magnetite-based nanomedicine for chemotherapy acting synergistically with loco-regional hyperthermia. METHODS: The targeting carrier consisted of a complex of superparamagnetic iron oxide (SPIO) and poly(sodium styrene sulfonate) (PSS) at the core and a layer-by-layer shell with cisplatin (CDDP), together with methotrexate - human serum albumin conjugate (MTX-HSA conjugate) for lung cancer-specific targeting, referred to hereafter as SPIO@PSS/CDDP/HSA-MTX nanoparticles (NPs). RESULTS: SPIO@PSS/CDDP/HSA-MTX NPs had good biocompatibility and stability in physiological solutions. Furthermore, SPIO@PSS/CDDP/HSA-MTX NPs exhibited a higher temperature increase rate than SPIO nanoparticles under irradiation by a radiofrequency (RF) generator. Therefore, SPIO@PSS/CDDP/HSA-MTX NPs could be used as a hyperthermia inducer under RF exposure after nanoparticles preferentially targeted and then accumulated at tumor sites. In addition, SPIO@PSS/CDDP/HSA-MTX NPs were developed to be used during combined chemotherapy and hyperthermia therapy, exhibiting a synergistic anticancer effect better than the effect of monotherapy. CONCLUSION: Both in vitro and in vivo results suggest that the designed SPIO@PSS/CDDP/HSA-MTX NPs are a powerful candidate nanoplatform for future antitumor treatment strategies.

Multimodal image-guided folic acid targeted Ag-based quantum dots for the combination of selective methotrexate delivery and photothermal therapy.

Multifunctional quantum dots (QDs) with photothermal therapy (PTT) potential loaded with an anticancer drug and labelled with a targeting agent can be highly effective nano-agents for tumour specific, image-guided PTT/chemo combination therapy of cancer. Ag-chalcogenides are promising QDs with good biocompatibility. Ag2S QDs are popular theranostic agents for imaging in near-infrared with PTT potential. However, theranostic applications of AgInS2 QDs emitting in the visible region and its PTT potential need to be explored. Here, we first present a simple synthesis of small, glutathione (GSH) coated AgInS2 QDs with peak emission at 634 nm, 21% quantum yield, and excellent long-term stability without an inorganic shell. Ag2S-GSH QDs emitting in the near-infrared region (peak emission = 822 nm) were also produced. Both QDs were tagged with folic acid (FA) and conjugated with methotrexate (MTX). About 3-fold higher internalization of FA-tagged QDs by folate-receptor (FR) overexpressing HeLa cells than HT29 and A549 cells was observed. Delivery of MTX by QD-FA-MTX reduced the IC50 of the drug from 10 µg/mL to 2.5-5 µg/mL. MTX release was triggered at acidic pH, which was further enhanced with local temperature increase created by laser irradiation. Irradiation of AgInS2-GSH QDs at 640 nm (300 mW) for 10 min, caused about 10 °C temperature increase but did not cause any thermal ablation of cells. On the other hand, Ag2S-GSH-FA based PTT effectively and selectively killed HeLa cells with 10 min 808 nm laser irradiation via mostly necrosis with an IC50 of 5 µg Ag/mL. Under the same conditions, IC50 of MTX was reduced to 0.21 µg/mL if Ag2S-GSH-FA.

Optimization and Development of Methotrexate- and Resveratrol-Loaded Nanoemulsion Formulation Using Box-Behnken Design for Rheumatoid Arthritis.

Methotrexate (MTX) is the first line of choice for the management of rheumatoid arthritis (RA) and has been reported for its low bioavailability and side effects. Combination therapy has been widely investigated to overcome bioavailability issues and to reduce adverse effects associated with monotherapy. Various phytoconstituents such as resveratrol (RSV) and curcumin have been found to possess potent anti-inflammatory activity via downregulating the signaling of cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor alpha) and nuclear factor kappa B signaling. The prime objective of this study was to develop transdermal gel containing MTX-RSV loaded nanoemulsions (NEs) to overcome bioavailability issues and adverse effects of RA monotherapy. The NEs optimized by using Box-Behnken Design were incorporated within gel, and an in vitro skin permeation study performed on rat skin by using vertical Franz diffusion cells exhibited controlled drug release up to 48 h. Subsequently, anti-inflammatory and potential anti-arthritic activities of the combination in nanocarrier were assessed in rats and showed 78.76 ± 4.16% inhibition in inflammation and better anti-arthritic effects. Consequently, integration of dual delivery with nanotechnology can hopefully produce successful therapeutic options for rheumatic diseases.

Food-Derived Nanoscopic Drug Delivery Systems for Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a severe systemic inflammatory disease with no cure at present. Recent developments in the understanding of inflammation and nanomaterial science have led to increased applications of nanostructured drug delivery systems in the treatment of RA. The present review summarizes novel fabrications of nanoscale drug carriers using food components as either the delivered drugs or carrier structures, in order to achieve safe, effective and convenient drug administration. Polyphenols and flavonoids are among the most frequently carried anti-RA therapeutics in the nanosystems. Fatty substances, polysaccharides, and peptides/proteins can function as structuring agents of the nanocarriers. Frequently used nanostructures include nanoemulsions, nanocapsules, liposomes, and various nanoparticles. Using these nanostructures has improved drug solubility, absorption, biodistribution, stability, targeted accumulation, and release. Joint vectorization, i.e., using a combination of bioactive molecules, can bring elevated therapeutic outcomes. Utilization of anti-arthritic chemicals that can self-assemble into nanostructures is a promising research orientation in this field.

Self-recognizing and stimulus-responsive carrier-free metal-coordinated nanotheranostics for magnetic resonance/photoacoustic/fluorescence imaging-guided synergistic photo-chemotherapy.

Carrier-free nanotheranostics directly assembled by using clinically used photosensitizers and chemotherapeutic drugs are a promising alternative to tumor theranostics. However, the weak interaction-driven assembly still suffers from low structural stability against disintegration, lack of targeting specificity, and poor stimulus-responsive property. Moreover, almost all exogenous ligands possess no therapeutic effect. Enlightened by the concept of metal-organic frameworks, we developed a novel self-recognizing metal-coordinated nanotheranostic agent by the coordination-driven co-assembly of photosensitizer indocyanine green (ICG) and chemo-drug methotrexate (MTX, also served as a specific "targeting ligand" towards folate receptors), in which ferric (FeIII) ions acted as a bridge to tightly associate ICG with MTX. Such carrier-free metal-coordinated nanotheranostics with high dual-drug payload (∼94 wt%) not only possessed excellent structural and physiological stability, but also exhibited prolonged blood circulation. In addition, the nanotheranostics could achieve the targeted on-demand drug release by both stimuli of internal lysosomal acidity and external near-infrared laser. More importantly, the nanotheranostics could self-recognize the cancer cells and selectively target the tumors, and therefore they decreased toxicity to normal tissues and organs. Consequently, the nanotheranostics showed strongly synergistic potency for tumor photo-chemotherapy under the precise guidance of magnetic resonance/photoacoustic/fluorescence imaging, thereby achieving highly effective tumor curing efficiency. Considering that ICG and bi-functional MTX are approved by the Food and Drug Administration, and FeIII ions have high biosafety, the self-recognizing and stimulus-responsive carrier-free metal-coordinated nanotheranostics may hold potential applications in tumor theranostics.

Role of folate-conjugated glycol-chitosan nanoparticles in modulating the activated macrophages to ameliorate inflammatory arthritis: in vitro and in vivo activities.

Activated macrophages are the primary targets in rheumatoid arthritis (RA) management. So, we report efficacious, dual-functional Methotrexate (MTX) loaded folate-conjugated pH-responsive glycol-chitosan nanoparticles (MFGCN) prepared by nano-precipitation and zero-order cross-linking reaction for targeting inflamed arthritic tissue. Physical characterization by DLS, SEM and TEM indicated a spherical, smooth morphology with a diameter ~ 300 nm. 1H NMR and FTIR indicated folic acid conjugation to GC by zero-order cross-linkers. In vitro release kinetics in PBS showed pH-responsive and sustained release behaviour of MFGCN. Enhanced cellular uptake and cytotoxicity of MFGCN in LPS(+)RAW and activated peritoneal macrophages (Mϕ) were observed when compared to LPS(-)RAW cells. MFGCN-induced mitochondrial membrane potential (MMP) perturbations indicated apoptosis. Oxidative stress was evident by significant increase in ROS and RNS, 4 h post incubation with MFGCN. Negligible hemolysis by FGCN and MFGCN on rat RBC's indicated biocompatibility. In vivo biodistribution of MFGCN in adjuvant-induced arthritis (AIA) rats indicated RA targetability. Prolonged blood circulation coupled with higher concentrations of 99mTc-MFGCN at the arthritic site was observed post 24 h of injection. The gamma scintigraphic image confirmed accumulation of radiolabelled MFGCN in arthritic paw when compared to the non-inflamed paw, confirming the selective uptake of 99mTc-MFGCN by folate-overexpressing macrophages in the arthritic synovium thereby proving its targeted efficacy and theranostic potential. In AIA rats, MFGCN lowers arthritic signs, improves antioxidant response and decreases pro-inflammatory cytokines, suggesting its potential in targeting activated macrophages of synovium. Graphical abstract.

Co-encapsulating CoFe2O4 and MTX for hyperthermia.

Magnetic manotheranostics can be a fascinating charm to diagnose a tumour with MRI, and treatment through hyperthermia. This study aims to synthesise and characterise magnetically responsive polymer colloids (MRPCs). Healthy tissue damage done by chemotherapy session could be minimised by MRPCs. For the colloidal formulation of MRPCs, the oil in water emulsion technique was employed with the aid of sonication and stirring. The organic phase of emulsion contained methotrexate (MTX) drug, Eudragit E100 and CoFe2O4 (synthesised by co-precipitation) in ethanol, and the aqueous phase contained tween 80 in deionised water. The emulsion was optimised by studying/adjusting two different parameters, i.e. the concentration of constituents and sonication cycles. Multiple formulations were produced at sonication amplitude of 60% at 20 kHz, followed by centrifugation and lyophilisation. Characterisation of MRPCs was done for morphology, size measurement (23-25 nm), surface charge (∼15.12), coercivity (∼1549.6 G), magnetisation (2.6 emu) and retentivity (1.34 emu). Drug release in simulating physiological environment (pH = 7.4), was observed for up to 48 h, and, to determine the best release kinetic mechanism results were compared with kinetic models. Magnetic hyperthermia studies showed that MRPCs achieved an acceptable temperature of 42°C, for hyperthermia treatments in cancer patients.

Neem gum based pH responsive hydrogel matrix: A new pharmaceutical excipient for the sustained release of anticancer drug.

The present research work was aimed to synthesize neem gum-based site-specific drug delivery device for anticancer drug methotrexate at different pH condition. The hydrogel-based drug delivery device was synthesized by optimizing reaction parameters using a factorial design approach response surface method. This model comprised of various sets of reactions with varying concentrations of solvent, crosslinker, initiator and monomer under microwave radiation. Characterization of the candidate hydrogel was done using UV-visible spectrophotometer, FTIR, SEM, Raman, and XRD techniques. The release profile of the hydrogels network was studied through a methotrexate under different pH conditions. The drug encapsulation capacity was found to be around 93% and 90% in pH 7.4 and 6.8. Drug release through the synthesized hydrogel matrix was found to show non-Fickian behaviour at each medium. The hydrogel network showed less release in pH 6.8 than pH 7.4, suggesting that hydrogels may be suitable drug carriers for release of anticancer drug delivery system. Hemolysis testing was also done to check the compatibility of the synthesized drug delivery device with the four different blood samples. Hemolysis was found to be less than 1% in the case of all blood groups, which indicates that the synthesized candidate polymers are biocompatible with all blood groups.

Solvent-Induced Protein Precipitation for Drug Target Discovery on the Proteomic Scale.

High-throughput drug discovery is highly dependent on the targets available to accelerate the process of candidates screening. Traditional chemical proteomics approaches for the screening of drug targets usually require the immobilization/modification of the drug molecules to pull down the interacting proteins. Recently, energetics-based proteomics methods provide an alternative way to study drug-protein interaction by using complex cell lysate directly without any modification of the drugs. In this study, we developed a novel energetics-based proteomics strategy, the solvent-induced protein precipitation (SIP) approach, to profile the interaction of drugs with their target proteins by using quantitative proteomics. The method is easy to use for any laboratory with the common chemical reagents of acetone, ethanol, and acetic acid. The SIP approach was able to identify the well-known protein targets of methotrexate, SNS-032, and a pan-kinase inhibitor of staurosporine in cell lysate. We further applied this approach to discover the off-targets of geldanamycin. Three known protein targets of the HSP90 family were successfully identified, and several potential off-targets including NADH dehydrogenase subunits NDUFV1 and NDUFAB1 were identified for the first time, and the NDUFV1 was validated by using Western blotting. In addition, this approach was capable of evaluating the affinity of the drug-target interaction. The data collectively proved that our approach provides a powerful platform for drug target discovery.

Methotrexate and Curcumin co-encapsulated PLGA nanoparticles as a potential breast cancer therapeutic system: In vitro and in vivo evaluation.

Nanoparticulate delivery systems have been noticed for chemotherapeutical delivery due to their ability in controlling the drug release and reducing the side effect. These systems could also be used to deliver two drugs or more simultaneously, inhibiting the development of resistant cancerous cells. Methotrexate (MTX), one of the most frequently used chemotherapeutic agent, and Curcumin (CUR), a natural chemopreventive compound, have shown promising results in treatment or controlling the progression of cancer. The aim of this study is to prepare and evaluate polymeric nanoparticles for co-delivery of MTX and CUR. The PLGA nanoparticles were prepared and characterized in respect of their particles size, morphology, drug encapsulation efficiencies, release patterns, cell cytotoxicity, and in vivo efficacy. Altering MTX and CUR amounts leads to particle size of 142.3 ±â€¯4.07 nm with MTX encapsulation efficiency of 71.32 ±â€¯7.8% and CUR encapsulation efficiency of 85.64 ±â€¯6.3%. These particles showed significantly higher cytotoxicity in comparison with free MTX or CUR or even their solo-loaded formulations. The in vivo results showed the synergic effect of MTX and CUR co-delivery on inhibiting the progression of breast cancer. Considering the appropriate in vitro properties of acquired nanoparticles for controlled drug delivery and the satisfactory in vivo efficacy results, it seems that the prepared formulation is a promising candidate for further in vivo studies.

Development of Topical Gel of Methotrexate Incorporated Ethosomes and Salicylic Acid for the Treatment of Psoriasis.

BACKGROUND: There is an unmet need for optimized drug delivery system of psoriasis therapy because of various issues like adverse reaction, permeation problem associated with convention treatment (oral and topical) available for psoriasis. OBJECTIVE: The goal was to develop an ethosomal gel of methotrexate (MTX)-incorporated ethosomes and salicylic acid (SA) and to evaluate and study its ethosomal gel potential in Imiquimod-induced psoriasis animal model to treat symptoms of psoriasis. METHODS: MTX-SA ethosomal gel was prepared by the cold method given by Touitou et al. and optimized by comparing it with MTX ethosomal gel and drug solution. Particle size, zeta potential, entrapment efficiency, and ex-vivo study were selected as the critical quality checking attributes. Psoriatic Area and Severity Index (PASI) score & histopathological examination were done for checking Antipsoriatic potential of MTX-SA ethosomal gel by using the imiquimod-induced psoriasis model. RESULTS: Optimized MTX-SA exhibited a particle size of 376.04 ± 3.47nm, EE(Entrapment efficiency) of 91.77 ± 0.02%. At the end of 24h, MTX-SA ethosomal gel exhibited a slow and prolonged release of MTX (26.13 ± 1.61% versus 6.97 ± 0.06%) compared to MTX drug solution. It also attributes of 43% retention study as compared to drug solution (13%). Besides, it essentially decreased the PASI score with the recuperation of normalcy of the mice's skin, while the MTX-SA gel displayed indications of gentle hyper and parakeratosis toward the completion of investigation when contrasted with the blank gel. CONCLUSION: The developed MTX-SA ethosomal gel formulation can be a promising alternative to existing MTX formulation in topically treating psoriasis.

A Non-innocent Magnesium Organoclay-Based Drug Vehicle for Improving the Cancer Therapy Effect of Methotrexate.

A synthetic, dispersible magnesium aminoclay (MgAC) was synthesized in the present study. Besides, structural and spectroscopic detections were conducted to investigate the MgAC nanoclay. With a poor aqueous solubility, methotrexate (MTX) has been applied as a valid antitumor agent in recent years. In our research, an unobtrusive sol-gel process was carried out to manufacture the MgAC-MTX nanohybrids through entrapment of MTX over MgAC in situ. The final product was capable of desquamating and thus dispersed in water, equably. In comparison with rough MTX, the MgAC-MTX nanocomposite with a preferable treatment efficacy against MCF-7 cells was mainly attributed to the preeminent enhanced aqueous solubility, controlled release and the increased cellular uptake capacity. Moreover, with excellent anticancer function and hypotoxicity as vindicated in vivo, the MgAC-MTX nanohybrid was supposed to own the potency in the application of malignant tumors cure as a valid nanomedicine. It turned out that, by virtue of its high bioavailability, the MgAC-MTX nanohybrids with high bioavailability is deserving of further study for the treatment of cancers.

Preparation and in vitro evaluation of radiolabeled HA-PLGA nanoparticles as novel MTX delivery system for local treatment of rheumatoid arthritis.

Radiosynovectomy is a technique used to decrease inflammation of the synovial tissue by intraarticular injection of a ß-emitting radionuclide, such as 177Lu, which is suitable for radiotherapy due to its decay characteristics. Drug-encapsulating nanoparticles based on poly lactic­co­glycolic acid (PLGA) polymer are a suitable option to treat several arthritic diseases, used as anti-inflammatory drugs transporters of such as methotrexate (MTX), which has been widely used in the arthritis treatment (RA), and hyaluronic acid (HA), which specifically binds the CD44 and hyaluronan receptors overexpressed on the inflamed synovial tissue cells. The 1,4,7,10­Tetraazacyclododecane­1,4,7,10­tetraacetic acid (DOTA) was used as complexing agent of Lutetium-177 for radiotherapy porpoises. The aim of this research was to synthesize 177Lu-DOTA-HA-PLGA(MTX) as a novel, smart drug delivery system with target-specific recognition, potentially useful in radiosynovectomy for local treatment of rheumatoid arthritis. The polymeric nanoparticle system was prepared and chemically characterized. The MTX encapsulation and radiolabelling were performed with suitable characteristics for its in vitro evaluation. The HA-PLGA(MTX) nanoparticle mean diameter was 167.6 nm ±â€¯57.4 with a monomodal and narrow distribution. Spectroscopic techniques demonstrated the effective conjugation of HA and chelating agent DOTA to the polymeric nanosystem. The MTX encapsulation was 95.2% and the loading efficiency was 6%. The radiochemical purity was 96 ±â€¯2%, determined by ITLC. Conclusion: 177Lu-DOTA-HA-PLGA(MTX) was prepared as a biocompatible polymeric PLGA nanoparticle conjugated to HA for specific targeting. The therapeutic nanosystem is based on bi-modal mechanisms using MTX as a disease-modifying antirheumatic drug (DMARD) and 177Lu as a radiotherapeutic component. The 177Lu-DOTA-HA-PLGA(MTX) nanoparticles showed properties suitable for radiosynovectomy and further specific targeted anti-rheumatic therapy.

Design and development of bioinspired calcium phosphate nanoparticles of MTX: pharmacodynamic and pharmacokinetic evaluation.

The aim of this investigation is the management of rheumatoid arthritis (RA) by developing methotrexate-loaded calcium phosphate nanoparticles (MTX-CAP-NP) and to evaluate pharmacokinetic and pharmacodynamic behavior in adjuvant induced arthritis model. The nanoparticles were synthesized by wet precipitation method and optimized by Box-Behnken experimental design. MTX-CAP-NPs were characterized by TEM, FTIR, DSC and XRD studies. The particle size, zeta potential and entrapment efficiency of the optimized nanoparticles were found to be 204.90 ± 64 nm, -11.58 ± 4.80 mV, and 88.33 ± 3.74%, respectively. TEM, FTIR, DSC and XRD studies revealed that the developed nanoparticles were nearly spherical in shape and the crystalline structure of CAP-NP was not changed after MTX loading. The pharmacokinetic studies revealed that MTX-CAP-NP enhanced bioavailability of MTX by 2.6-fold when compared to marketed formulation (FOLITRAX-10). Under pharmacodynamic evaluation, arthritic assessment, radiography and histopathology studies revealed that CAP has ability to regenerate cartilage and bone therefore, together with MTX, MTX-CAP-NPs have shown significant reduction in disease progression. The overall work demonstrated that the developed nanodelivery system was well tolerated and more effective than the marketed formulation.

A novel gold nanorods-based pH-sensitive thiol-ended triblock copolymer for chemo-photothermo therapy of cancer cells.

Currently an effective strategy in nanomedicine for cancer therapy is the combination of photothermal therapy with chemotherapy. Because combination cancer therapy improve the therapy efficiency by synergistic effects and overcoming drug resistance as compared to monotherapy possesses. According to these facts, gold nanorods-cored biodegradable micelles were prepared by coating gold nanorods (AuNRs) with synthesized pH-sensitive thiol-ended amphiphilic triblock copolymer (PAA-b-PDMAEMAQ-b-PCL-SH). The synthesized AuNRs@polymer was loaded with methotrexate (MTX) as an anticancer drug through electrostatic interactions to afford AuNRs@polymer-MTX. The success of the coating was investigated by means of atomic force microscopy (AFM), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, as well as dynamic light scattering (DLS), and zeta potential measurements. MTX-loading capacity, and pH triggered in vitro drug release behavior of the synthesized nanocomposites were also investigated. In vitro cytotoxic effects was comprehensively evaluated among free MTX, AuNRs@polymer, and AuNRs@polymer-MTX, with or without NIR light irradiation (1064 nm, 125 mJ/pulse, and 4 min) to improve curative effect of AuNRs@polymer-MTX led by the combination of photothermal therapy and chemotherapy.

Iron-gold alloy nanoparticles serve as a cornerstone in hyperthermia-mediated controlled drug release for cancer therapy.

INTRODUCTION: The efficacy of a chemotherapy drug in cancer therapy is highly determined by the ability to control the rate and extent of its release in vivo. However, the lack of techniques to accurately control drug release drastically limits the potency of a chemotherapy drug. MATERIALS AND METHODS: Here, we present a novel strategy to precisely monitor drug release under magnetic stimulation. Methotrexate (MTX), an anticancer drug, was covalently functionalized onto iron-gold alloy magnetic nanoparticles (Fe-Au alloy nanoparticles or NFAs) through 2-aminoethanethiol grafting and the ability of this drug-nanoparticle conjugate (NFA-MTX) in limiting HepG2 (liver carcinoma) cell growth was studied. Well-dispersed NFAs were prepared through pyrolysis. RESULTS AND DISCUSSION: Transmission electron microscopy revealed the average nanoparticle size to be 7.22±2.6 nm, while X-ray diffraction showed distinct 2θ peaks for iron and gold, confirming the presence of iron and gold nanoparticles. Inductively coupled plasma mass spectrometry revealed that the amount of NFA-MTX conjugate ingested by HepG2 cancer cells was 1.5 times higher than that ingested by L929 fibroblasts, thereby proving a higher selective ingestion by cancer cells compared to normal cells. Fourier-transform infrared spectroscopy revealed the breakage of Au-S bonds by the heat generated under magnetic field stimulation to release MTX from the NFA-MTX conjugate, triggering a 95% decrease in cellular viability at 100 µg/mL. CONCLUSION: The ability of NFA-MTX to dissociate under the influence of an applied magnetic field provides a new strategy to induce cancer cell death via hyperthermia. Applications in drug delivery, drug development, and cancer research are expected.

Hyaluronic Acid-Methotrexate Conjugates Coated Magnetic Polydopamine Nanoparticles for Multimodal Imaging-Guided Multistage Targeted Chemo-Photothermal Therapy.

Combination cancer therapy with various kinds of therapeutic approaches could improve the effectiveness of treatment while reducing side effects. Herein, we elaborately developed a theranostics nanoplatform based on magnetic polydopamine (MPDA) coated with hyaluronic acid-methotrexate conjugates (MPDA@HA-MTX) for chemo-photothermal treatment (PTT). In this nanoplatform, Fe3O4 served as the core was applied as contrast agent for T2-weighted magnetic resonance imaging (MRI) and early phase magnet targeting. Meanwhile, PDA was used as a versatile shell for effective loading of chemotherapeutic doxorubicin (DOX) to achieve controlled release and PTT simultaneously. Moreover, HA-MTX conjugates could offer later-phase specific cellular dual-targeting ability during the therapy. Both in vitro and in vivo studies demonstrated that DOX-loaded MPDA@HA-MTX (MPDA/DOX@HA-MTX) exhibited the preferential tumor accumulation, enhanced specificity to target tumor cells, pH-/laser-responsive release, and high tumor cell-killing efficiency. By combined chemo-PTT under the guidance of fluorescence/MR imaging, the tumors in mice were completely eliminated after treatment, indicating that MPDA@HA-MTX nanoparticles have great potential as a novel drug-loading platform for imaging-guided multistage targeted chemo-photothermal combination therapy.