Targeted co-delivery of methotrexate and chloroquine via a pH/enzyme-responsive biocompatible polymeric nanohydrogel for colorectal cancer treatment.

Application of conventional chemotherapy regardless of its unique effectiveness have been gradually being edged aside due to limited targeting capability, lack of selectivity and chemotherapy-associated side effects. To this end, colon-targeted nanoparticles via combination therapy have shown great therapeutic potential against cancer. Herein, pH/enzyme-responsive biocompatible polymeric nanohydrogels based on poly(methacrylic acid) (PMAA) containing methotrexate (MTX) and chloroquine (CQ) were fabricated. PMAA-MTX-CQ exhibited high drug loading capacity of which MTX was 4.99% and was CQ 25.01% and displayed pH/enzyme-triggered drug release behavior. Higher CQ release rate (76%) under simulated acidic microenvironment of tumor tissue whereas 39% of CQ was released under normal physiological conditions. Intestinally, MTX release was facilitated in the presence of proteinase K enzyme. TEM image demonstrated spherical morphology with particle size of less than 50 nm. In vitro and in vivo toxicity assessments indicated that developed nanoplatforms possessed great biocompatibility. These nanohydrogels did not cause any adverse effects against Artemia Salina and HFF2 cells (around 100% cell viability) which highlight the safety of prepared nanohydrogels. There was no death in mice received different concentrations of nanohydrogel through oral administration and less than 5% hemolysis was found in red blood cells incubated with PMAA nanohydrogels. In vitro anti-cancer results showed that combination therapy based on PMAA-MTX-CQ can effectively suppress the growth of SW480 colon cancer cells (29% cell viability) compared to monotherapy. Altogether, these findings suggest that pH/enzyme-responsive PMAA-MTX-CQ could effectively inhibit cancer cell growth and progression via site-specific delivery of its cargo in a safe and controlled manner.

In vitro evaluation of anti-angiogenesis property of anti-VEGFR2 nanobody-conjugated H40-PEG carrier loaded with methotrexate.

Objectives: In this study, Boltorn® H40-PEG-MTX-anti-VEGFR2 nanobody was fabricated in which nanobody was selected for blocking the receptor, H40 as a nanocarrier for delivery of methotrexate (MTX) to the tumor cells, and polyethylene glycol (PEG) moieties for improving the blood circulation time and safety. Materials and Methods: The synthesis process of the nanosystem has been characterized by different analytical methods. Results: The prepared nanoplatform exhibited high drug loading capacity, excellent colloidal stability, and an average particle size of around 105 nm. MTX was successfully conjugated through ester bonds and its release profile clearly showed that the ester bond is in favor of releasing the drug in acidic pH (5.5). The cytotoxicity of the developed nanoplatform exhibited great anti-cancer activity against MCF7 and KDR293 (cells with overexpressed anti-VEGFR2 NB receptors) cell lines while no deleterious toxicity was observed for nanocarrier against HEK293 normal cells. Furthermore, both hemolysis and LD50 assay results confirmed the hemocompatibility and biocompatibility of the developed nanoplatform. Conclusion: The most striking result to derive from the data is that the designed nanoplatform could potentially inhibit cell migration and invasion and the anti-angiogenesis properties of the developed nanoplatform may serve as a promising nanosystem to suppress the formation of blood vessels around tumor cells and consequently inhibit tumor progression.

Recent advances in targeting malaria with nanotechnology-based drug carriers.

Malaria, as one of the most common human infectious diseases, remains the greatest global health concern, since approximately 3.5 billion people around the world, especially those in subtropical areas, are at the risk of being infected by malaria. Due to the emergence and spread of drug resistance to the current antimalarials, malaria-related mortality and incidence rates have recently increased. To overcome the aforementioned obstacles, nano-vehicles based on biodegradable, natural, and non-toxic polymers have been developed. Accordingly, these systems are considered as a potential drug vehicle, which due to their unique properties such as the excellent safety profile, good biocompatibility, tunable structure, diversity, and the presence of functional groups within the polymer structure, could facilitate covalent attachment of targeting moieties and antimalarials to the polymeric nano-vehicles. In this review, we highlighted some recent developments of liposomes as unique nanoscale drug delivery vehicles and several polymeric nanovehicles, including hydrogels, dendrimers, self-assembled micelles, and polymer-drug conjugates for the effective delivery of antimalarials.

Synthesis and Characterization of Biodegradable Semi-Interpenetrating Polymer Networks Based on Star-Shaped Copolymers of ɛ-Caprolactone and Lactide.

In this paper, the focus is on a new kind of biodegradable semi-interpenetrating polymer networks, which is derived from ɛ-caprolactone, lactide, 1,4-butane diisocyanate and ethylenediamine and also its potential has been investigated in soft tissue engineering applications. The polymers were characterized by nuclear magnetic resonance (NMR) spectrometry, Fourier transform infrared spectroscopy (FT-IR), differential thermal analysis (DTA), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). These experiments show that the polymers with the right composition and the expected molecular weight were achieved. Also, the in-vitro degradation of polymer network was examined in phosphate buffer solutions (pH 7.4) at 37 °C. Moreover, cell viability and adhesion tests were carried out with fibroblast cells by the MTT assay, which confirmed biocompatibility. Polyurethane materials have superior mechanical properties, so these biodegradable and biocompatible films demonstrate potential for future application as cell scaffolds in soft tissue engineering applications.

Design and construction of multifunctional hyperbranched polymers coated magnetite nanoparticles for both targeting magnetic resonance imaging and cancer therapy.

Magnetic drug targeting is a drug delivery strategy that can be used to improve the therapeutic efficiency on tumor cells and reduce the side effects on normal cells and tissues. The aim in this study is designing a novel multifunctional drug delivery system based on superparamagnetic nanoparticles for cancer therapy. Magnetic nanoparticles were synthesized by coprecipitation of iron oxide followed by coating with poly citric acid (PCA) dendritic macromolecules via bulk polymerization strategy. It was further surface-functionalized with poly(ethylene glycol) (PEG) and then to achieve tumor cell targeting property, folic acid was further incorporated to the surface of prepared carriers via a facile coupling reaction between the hydroxyl end group of the PEG and the carboxyl group of folic acid. The so prepared nanocarriers (Fe3O4@PCA-PEG-FA) were characterized by X-ray diffraction, TEM, TGA, FT-IR, DLS and VSM techniques. The room temperature VSM measurements showed that magnetic particles were superparamagnetic. Transmission electron microscopy and dynamic light scattering were also performed which revealed that size of nanocarriers was lying in the range of 10-49nm. Quercetin loading and release profiles of prepared nanocarriers showed that up to 83% of loaded drug was released in 250h. Fluorescent microscopy showed that the cellular uptake by folate receptor-overexpressing HeLa cells of the quercetin-loaded Fe3O4@PCA-PEG-FA nanoparticles was higher than that of non-folate conjugated nanoparticles. Thus, folate conjugation significantly increased nanoparticle cytotoxicity. Also, T2-weighted MRI images of Fe3O4@PCA-PEG-FA nanoparticles showed that the magnetic resonance signal is enhanced significantly with increasing nanoparticle concentration in water and they also served as MRI contrast agents with relaxivities of 3.4mM-1s-1 (r1) and 99.8mM-1s-1 (r2). The results indicate that this multifunctional nanocarrier is a significant breakthrough in developing a drug delivery vehicle that combines drug targeting as well as sensing and therapy at the same time.

pH-responsive unimolecular micelles self-assembled from amphiphilic hyperbranched block copolymer for efficient intracellular release of poorly water-soluble anticancer drugs.

Novel unimolecular micelles from amphiphilic hyperbranched block copolymer H40-poly(ε-caprolactone)-b-poly(acrylic acid)-b'-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate (i.e., H40-PCL-b-PAA-b'-MPEG/PEG-FA (HCAE-FA)) as new multifunctional nanocarriers to pH-induced accelerated release and tumor-targeted delivery of poorly water-soluble anticancer drugs were developed. The hydrophobic core of the unimolecular micelle was hyperbranched polyester (H40-poly(ε-caprolactone) (H40-PCL)). The inner hydrophilic layer was composed of PAA segments, while the outer hydrophilic shell was composed of PEG segments. This copolymer formed unimolecular micelles in the aqueous solution with a mean particle size of 33 nm, as determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). To study the feasibility of micelles as a potential nanocarrier for targeted drug delivery, we encapsulated a hydrophobic anticancer drug, paclitaxel (PTX), in the hydrophobic core, and the loading content was determined by UV-vis analysis to be 10.35 wt.%. In vitro release studies demonstrated that the drug-loaded delivery system is relatively stable at physiologic conditions but susceptible to acidic environments which would trigger the release of encapsulated drugs. Flow cytometry and fluorescent microscope studies revealed that the cellular binding of the FA-conjugated micelles against HeLa cells was higher than that of the neat micelles (without FA). The in vitro cytotoxicity studies showed that the PTX transported by these micelles was higher than that by the commercial PTX formulation Tarvexol®. All of these results show that these unique unimolecular micelles may offer a very promising approach for targeted cancer therapy.

Ultrasound-promoted synthesis of novel spirooxindolo/spiroacenaphthen dicyano pyrrolidines and pyrrolizidines through regioselective azomethine ylide cycloaddition reaction.

Novel dicyano functionalised spiropyrrolidine and spiropyrrolizidine were synthesized from the reaction of various arylidenemalononitrile Knöevenagel adducts with non-stabilized azomethine ylides generated from isatin/acenaphthenequinone and sarcosine/N-phenylglycine/proline. The reactions were carried out under both conventional heating and ultrasonic irradiation conditions. In general, improvement in rates and yields were observed when the reactions were carried out under sonication compared with classical conditions. The regio and stereochemistry of the products was established by single crystal X-ray structure and spectroscopic techniques.

1'-Methyl-2-oxo-5'-phenyl-spiro-[indoline-3,3'-pyrrolidine]-4',4'-dicarbo-nitrile.

The title spiro-compound, C(20)H(16)N(4)O, crystallizes with four independent mol-ecules in the asymmetric unit. In all of them, the oxindole unit is planar, the r.m.s. deviations ranging from 0.07 to 0.08 Å, while the pyrrolinyl ring adopts an envelope conformation (with the N atom representing the flap). In the crystal, adjacent mol-ecules are linked by N-H⋯N and N-H⋯O hydrogen bonds.