Glycol chitin/PAA hydrogel composite incorporated bio-functionalized PLGA microspheres intended for sustained release of anticancer drug through intratumoral injection.

A novel anti-hepatoma drug release hybrid system is prepared by using poly(acrylic acid) (PAA) and glycol chitin as substrate in combination with Paclitaxel (PTX)-loaded bio-biofunctionalized poly(lactic-co-glycolic acid) (PLGA) micro-particles, which is intended for cancer therapy through intratumoral injection. The rheological behavior of glycol chitin (7 wt%)/PAA illustrates that it has low gelling temperature (i.e. 17 °C at pH 7.56) which ensures that the formulation turns to gel at physiological condition. The gelling time of glycol chitin/PAA is 16 minutes at 25 °C and 3 minutes at 37 °C, which is convenient for doctors to inject the in-situ gel formulations into the tumor location of patient. The drug release behavior reveals that the system can dramatically postpone the drug release. The cell viability test indicates that the micro-particles with drug still have 62% inhibitory effect on hepatoma cells in the fourteenth day after combing with hydrogel. This system is a promising approach for cancer therapy through intratumoral injection of in-situ gel formulations to extend retention time at tumor sites.

Stimulation of wound healing by PU/hydrogel composites containing fibroblast growth factor-2.

In this study, polyurethane (PU)/hydrogel composites were fabricated for wound healing applications. The hydrogel is a copolymer of thermosensitive N-isopropyl acrylamide (NIPAAm) and acrylic acid (AAc). γ-ray irradiation was employed to simultaneously copolymerize NIPAAm with AAc and graft the hydrogel onto porous PU. Fibroblast growth factor-2 (FGF-2) was incorporated into the composite to facilitate wound healing. The physical properties of the composites were characterized, the in vitro release of FGF-2 was examined, and in vivo tests were conducted. The results indicate that the thermosensitive hydrogel can absorb most of the wound exudates due to its high water uptake ability. Due to its thermosensitive properties, the PU/hydrogel composite is easier to strip off than that of commercial wound dressing, which prevents additional injury to the wound when replacing the wound dressing. In vivo results show that the PU/hydrogel composite incorporating FGF-2 could accelerate wound healing and reduce scar formation.

Poly(acrylic acid)-chitosan-silica hydrogels carrying platelet gels for bone defect repair.

Most hydrogels derived from either natural or synthetic sources suffer from the lack of mechanical strength. In this study, high strength poly(acrylic acid)-chitosan-silica (PAA-Ch-Si) hydrogels were prepared by UV polymerization for tissue engineering applications. Compressive strength up to 42 MPa can be achieved by the formation of an interpenetrating network (IPN) structure between PAA and chitosan with nano-silica as the filler. The preliminary cell culture of osteoblast cells (7F2) on PAA-Ch-Si hydrogels indicates good biological safety. The growth factor (platelet glue) is fast and completely released from PAA-Ch-Si hydrogel scaffolds within 620 min. The scaffold starts to degrade after eight months in vitro. Histological examinations demonstrate that the hydrogel incorporated with growth factors and osteoblast cells can promote cell migration. All these results illustrate that PAA-Ch-Si hydrogels are beneficial for tissue engineering applications and can be used as scaffolds for bone defect repair.

A novel in-situ-gelling liquid suppository for site-targeting delivery of anti-colorectal cancer drugs.

In order to avoid anti-cancer drugs undergoing a first-pass effect and reduce their toxicity, and to solve conventional suppositories defects, we developed an in-situ-gelling and injectable Pluronic-poly(acrylic acid) (Pluronic-PAA) liquid suppository, which could gel fast in the physiological state and had suitable gel strength and bioadhesive force. The liquid suppositories were inserted into the rectum of rabbits without difficulty and leakage, and retained in the rectum for at least 6 h and while releasing the drug. The toxicity and cytotoxic tests indicated that Pluronic and PAA were non-toxic materials and could inhibit colon cancer cells when oxaliplatin was incorporated. C max and AUC0→12h values of oxaliplatin after rectal administration of a oxaliplatin suppository were higher than those for an oxaliplatin solution administered orally. These results suggest that an in-situ-gelling and injectable liquid suppository for humans can be further developed as a more convenient and effective rectal dosage form.

High pH tolerance of a chitosan-PAA nanosuspension for ophthalmic delivery of pilocarpine.

In this paper, nanoparticles composed of chitosan (CS) and poly(acrylic acid) (PAA) were prepared by template polymerization for use as ophthalmic drug carrier. Before the polymerization, hydrogen peroxide was used to cut down the molecular weight of chitosan to improve its solubility and tolerance of pH values in the physiological condition. We found that, as the hydrogen peroxide concentration increased up to 2 M, the reaction temperature was kept at 60 degrees C and depolymerization for 2 h, the molecular weight of chitosan was cut down to 4.1 x 10(4) and its pH tolerance was increased up to 7.1. The modified chitosan (MCS) is expected to tolerate in neutral condition without any precipitation. MCS-PAA nanoparticles for use as an ophthalmic drug carrier were successfully prepared using template polymerization of acrylic acid in the modified chitosan solution. The particle size of the nanoparticles was significantly affected by the pH value of the medium. Both in vitro and in vivo studies reveal that the prepared nanoparticles either modified or unmodified have the better ability in sustaining the release of pilocarpine than the simulated tear fluid and commercial eye drops.

Effects of oral estrogen on aortic ROS-generating and -scavenging enzymes and atherosclerosis in apoE-deficient mice.

The effect of hormone replacement therapy (HRT) on cardiovascular diseases remains controversial. Studies conducted on postmenopausal women indicate that oral HRT increases risk factors that may counteract the atheroprotective effect of estrogen. However, the effects of estrogen on atherosclerosis have been examined using subcutaneous estrogen in most animal studies, which points to the need for evaluating the effect of oral estrogen. Reactive oxygen species (ROS) have emerged as critical factors in the pathogenesis of atherosclerosis. This study examined the effect of long-term oral estrogen treatment on aortic oxidative stress and atherosclerosis in female apoE(-/-) mice to mimic HRT in humans. Ovariectomized apoE(-/-) mice were given 6 microg/day of oral 17beta-estradiol (E(2)) or control vehicle for 12 weeks. Estrogen treatment reduced atherosclerotic lesions by 38% (E(2): 0.20 +/- 0.01 mm(2)/section; control vehicle: 0.32 +/- 0.02 mm(2)/section) and intima by 32% (E(2): 0.44 +/- 0.02 mm(2)/section; control vehicle: 0.65 +/- 0.04 mm(2)/section) in the aortic root. Serum levels of total and low-density lipoprotein cholesterol were significantly decreased after estrogen treatment. Aortic superoxide anion levels and the expression of NAD(P)H oxidase subunit p22(phox) markedly decreased, and two ROS scavenging enzymes, Cu/ZnSOD and MnSOD, were upregulated after estrogen treatment. Estrogen at physiological concentration inhibited tumor necrosis factor-alpha-stimulated NAD(P)H oxidase activity in both cultured smooth muscle cells and peritoneal macrophages. These results showed that long-term oral estrogen treatment reduces ROS levels and atherosclerosis progression in apoE(-/-) mice. Oral estrogen alters ROS-generating and -scavenging enzyme expression, suggesting that anti-oxidative actions in the vessel wall contribute to atheroprotective effects of estrogen.

High strength and low friction of a PAA-alginate-silica hydrogel as potential material for artificial soft tissues.

In this study, a series of poly(acrylic) acid (PAA)-based hydrogels was prepared by UV polymerization. Hydrogels with an interpenetrating network structure were formed by combining PAA and alginate (Alg) solutions. The incorporation of nano-silica into these gel solutions significantly increased their compressive strength and fracture toughness but lowered their cross-linking density and friction coefficient. The prepared hydrogels were considerably hydrophilic for water content greater than 98%, which is in accordance with the nature of soft tissues such as cartilage. The preliminary cell culture of adipose stem cells (ADSCs) on PAA-Alg-Si hydrogels results in good biological safety. These features suggest that the PAA-Alg-Si hydrogels prepared in this study can be used as artificial soft tissues.

Pilocarpine-loaded chitosan-PAA nanosuspension for ophthalmic delivery.

Chitosan-poly(acrylic acid) (CS-PAA) nanoparticles, to be used as ophthalmic drug carrier, were successfully prepared using template polymerization of acrylic acid (AA) in a chitosan solution. When the polymerization was done at 70 degrees C for 45 min with a CS/AA weight ratio of 1:1, the surface structure of the prepared nanoparticles was most stable with the smallest mean diameter (92.0 +/- 7.5 nm) and a stable zeta potential (25.5 +/- 2.6 mV) in a buffer solution (pH 4.5). The size of the nanoparticles dramatically increased with the pH value of the medium. Both in vitro and in vivo studies revealed that the prepared nanoparticle suspension was better at sustaining the release of pilocarpine than either simulated tear fluid or commercial eye drops.

Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model.

Substantial evidence suggests that inflammatory cytokines, immune cells, and angiogenesis are important for endometriosis. In this study, we investigated the role of the sequential events in the development of endometriosis in a mouse model. Uterine tissue was transplanted into the peritoneum of ovariectomized mice and then supplemented with estrogen or vehicle. On different days after transplantation, cell proliferation, angiogenesis, and infiltrated immune cells in ectopic tissue were examined using immunochemical staining. Many disintegrated blood vessels but no bromodeoxyuridine-positive cells in ectopic tissue were observed in the estrogen-treated group on posttransplantation d 1 and 2. On d 4-7, bromodeoxyuridine-positive cells were detected in the blood vessels of ectopic tissue, indicating that angiogenesis was initiated in this stage. Angiogenesis also occurred in ectopic tissue in the vehicle-treated group. Profound infiltration of neutrophils in ectopic tissue occurred on d 1-4, when the number of neutrophils and levels of macrophage inflammatory protein (MIP)-1alpha and MIP-2 chemokines in peritoneal fluids also reached their peak. Peritoneal macrophage numbers did not change, but secretions of TNFalpha, IL-6, MIP-1alpha, and MIP-2 from macrophages isolated on d 2 were higher than on d 0. In vitro studies showed that peritoneal neutrophils and macrophages secreted vascular endothelial growth factor, which was up-regulated by TNFalpha and IL-6. Our results suggest that neutrophils and macrophages may promote angiogenesis in the early stage of endometriosis and that chemokines and cytokines amplify the angiogenic signal for the growth of endometriotic tissue.