Synthesis and evaluation of injectable thermosensitive penta-block copolymer hydrogel (PNIPAAm-PCL-PEG-PCL-PNIPAAm) and star-shaped poly(CL─CO─LA)-b-PEG for wound healing applications.

BACKGROUND: Loss of skin integrity due to injury, burning, or illness makes the development of new treatment options necessary. Skin tissue engineering provides some solutions for these problems. OBJECTIVE: The potential of a biodegradable star-shaped copolymer [Poly(CL─CO─LA)-b-PEG] and penta-block copolymer hydrogel (PNIPAAm-PCL-PEG-PCL-PNIPAAm) was assessed for skin tissue engineering applications. METHODS: Two copolymers were synthesized for cellular culture scaffolds and their mechanical properties were compared. The resulting star-shaped copolymer and thermosensitive penta-block copolymer were characterized using Fourier transform infrared and nuclear magnetic resonance spectroscopy. The crystallizability of the two copolymers was analyzed using X-ray diffraction. The resulting thermosensitive penta-block copolymer was evaluated by differential thermal analysis, differential scanning calorimetry and thermogravimetric analysis. Scanning electron microscopy and in vitro degradation of the polymer network in phosphate buffer solutions (pH 7.4) at 37°C were also examined. The pore size of the gels was calculated with Image Analyzer software. Finally, the cytotoxic, morphological, and gene expression effects of copolymers on the skin fibroblast were evaluated. RESULTS: The experiments showed that the PNIPAAm-PCL-PEG-PCL-PNIPAAm polymer with the right composition and the expected molecular weight was achieved. The hydrogel had less crystallizability compared with its precursors. The resulting thermosensitive hydrogel had a three-dimensional structure with interconnected pores that mimicked the extracellular matrix. The control of the degradability rate can be possible by weight percent changes. The pore size correlated with the polymer concentration in aqueous solution and the pore sizes of the 20 wt% hydrogel were better for fibroblast cultivation than those of the 10 wt% hydrogel. Cell proliferation on the 20% gel was more than that of the 10% gel. The hydrogel not only preserved the viability and phenotypical morphology of the entrapped cells but also stimulated the initial cell-cell interactions and proliferation of fibroblasts. The hydrogel did not influence cell conformation and this property of the polymer underlined its safety. Cells seeded on this copolymer showed a normal and spear shape and formed a focal adhesion with the hydrogel surface. Notably, the hydrogel increased collagen I α1 and collagen III mRNAs expression. CONCLUSION: Due to the low molecular weight and poor mechanical strength of the star-shaped copolymer, it was not considered for fabrication of the scaffolds for wound healing. The biodegradable, biocompatible, injectable and thermosensitive PNIPAAm-PCL-PEG-PCL-PNIPAAm hydrogel in 20 wt% demonstrated a desirable potential for future application as a cell scaffold in skin tissue engineering and wound healing.

pH-sensitive curcumin conjugated micelles for tumor triggered drug delivery.

Development of new drugs are confronted with some barriers and challenges, since these projects are mainly expensive, complex, time consuming with lack of success, there is an urgent need to reformulate the current poorly water soluble anti-cancer drugs. In this study, a new type of polymer-curcumin conjugates based on glycidyl azide polymer (GAP) was developed for cancer therapy. The copolymer was used for delivery of curcumin (CUR) as an anticancer drug to cancer cells. Our method is based on the facile conjugation of CUR to amine-containing polymeric vehicles through imine linkage bonds, which could remain stable in normal physiological condition while readily dissociate by an acidic environment and make the prodrug active to liberate its payload CUR to inhibit cell growth. The results demonstrated that fabricated amphiphilic PDCs were self-assembled into nanosized micelles in aqueous solution and the micelles showed an average size of 180 nm with a good polydispersity index. Drug release studies demonstrated that this nano-conjugate is fairly stable at physiologic environments but prone to mild acidic conditions which would trigger the release of conjugated CUR. Moreover, the PDCs micelles exhibited excellent cytotoxicity effect on 4T1 mouse breast cancer cell line but no significant toxicity was observed for the copolymer. In addition, the copolymer did not display remarkable toxicity against A. salina even at high doses of copolymer. In addition, the synthesized PDCs exhibited hemolysis lowers than 6%. The safety of copolymers as a drug vehicle was also confirmed by LD50, since all mice which treated with 5000 mg/Kg (limited dose) were still alive after one week. Our findings revealed that these unique pH-sensitive PDCs may provide a promising approach for delivery of the anticancer drugs to cancer cells.[Formula: see text].

A robust polyfunctional Pd(II)-based magnetic amphiphilic nanocatalyst for the Suzuki-Miyaura coupling reaction.

Herein, a robust Pd(II)-based polyfunctional magnetic amphiphilic artificial metalloenzyme was prepared by anchoring a Pd(2,2'-dipyridylamine)Cl2 bearing hydrophilic monomethyl ether poly(ethylene glycol) (mPEG) chains on the surface of amino-functionalized silica-coated magnetic nanoparticles. The 2,2'-dipyridylamine (dpa) has shown excellent complexation properties for Pd(II) and it could be easily anchored onto functionalized magnetic support by the bridging nitrogen atom. Moreover, the bridging nitrogen atom at the proximity of Pd(II) catalytic center could play an important role in dynamic suppramolecular interactions with substrates. The leaching, air and moisture resistant [Pd(dpa)Cl2] complex endow the dynamic and robust structure to the designed artificial enzyme. Moreover, the water dispersibility of designed artificial metalloenzyme raised from mPEG chains and the magnetic nanoparticles core which could function as protein mimics endow it other necessary characters of artificial enzymes. The prepared artificial metalloenzyme displayed remarkable activity in Suzuki-Miyaura cross-coupling reaction employing low-palladium loading under mild conditions, with the exceptionally high turnover frequency, clean reaction profile, easy work-up procedure, good to excellent products yields and short reaction times. The designed air- and moisture-stable artificial metalloenzyme could recycle more than fifteen times with easy separation procedure in aqueous solution under aerobic conditions without any noticeable loss in activity.

pH-Sensitive Magnetite Nanoparticles Modified with Hyperbranched Polymers and Folic Acid for Targeted Imaging and Therapy.

OBJECTIVE: A novel pH-sensitive superparamagnetic drug delivery system was developed based on quercetin loaded hyperbranched polyamidoamine-b-polyethylene glycol-folic acid-modified Fe3O4 nanoparticles (Fe3O4@PAMAM-b-PEG-FA). METHODS: The nanoparticles exhibit excellent water dispersity with well-defined size distribution (around 51.8 nm) and strong magnetisability. In vitro release studies demonstrated that the quercetinloaded Fe3O4@PAMAM-b-PEG-FA nanoparticles are stable at normal physiologic conditions (pH 7.4 and 37°C) but sensitive to acidic conditions (pH 5.6 and 37°C), which led to the rapid release of the loaded drug. RESULTS: Fluorescent microscopy results indicated that the Fe3O4@PAMAM-b-PEG-FA nanoparticles could be efficiently accumulated in tumor tissue compared with non-folate conjugated nanoparticles. Also, in comparison with free quercetin, the quercetin loaded Fe3O4@PAMAM-b-PEG-FA exerts higher cytotoxicity. Furthermore, this magnetic nanocarrier showed high MRI sensitivity, even in its lower iron content. CONCLUSION: The results indicated that the prepared nanoparticles are an effective chemotherapy and diagnosis system to inhibit proliferation and monitor the progression of tumor cells, respectively.

Folate-decorated thermoresponsive micelles based on star-shaped amphiphilic block copolymers for efficient intracellular release of anticancer drugs.

In this study, a new type of folate-decorated thermoresponsive micelles based on the star-shaped amphiphilic block copolymer 4s[poly(ε-caprolactone)-b-2s(poly(N-isopropylacrylamide-co-acrylamide)-b'-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate)] (i.e., 4s[PCL-b-2s(P(NIPAAm-co-AAm)-b'-MPEG/PEG-FA)] (PCIAE-FA)), were developed for the tumor-targeted delivery and temperature-induced controlled release of hydrophobic anticancer drugs. These amphiphilic star copolymers are capable of self-assembling into spherical micelles in aqueous solution with an average diameter of 91 nm. The lower critical solution temperature (LCST) of micelles was around 39.7 °C. The anticancer drug, paclitaxel (PTX), was encapsulated into the micelles. In vitro release studies demonstrated that the drug-loaded delivery system (PTX-PCIAE-FA) is relatively stable at physiologic conditions but susceptible to temperatures above LCST which would trigger the release of encapsulated drugs. The cytotoxicity studies showed that the PTX transported by these micelles was higher than that by the commercial PTX formulation Tarvexol(®). The efficacy of this thermoresponsive drug delivery system was also evaluated at temperatures above the LCST; the results demonstrated that the cellular uptake and the cytotoxicity of PTX-loaded micelles increase prominently. These results indicate that these thermoresponsive micelles may offer a very promising carrier to improve the delivery efficiency and cancer specificity of hydrophobic chemotherapeutic drugs.

Ultrasound-assisted one-pot, three-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones.

Triethylamine was found to be an efficient catalyst for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones by one-pot reaction of phthalhydrazide, aromatic aldehydes, and malononitrile or ethyl cyanoacetate in ethanol under ultrasonic irradiation. The advantages of this method are the use of an inexpensive and readily available catalyst, easy workup, improved yields, and the use of ethanol as a solvent that is considered to be relatively environmentally benign.