We report on a novel type of triblock copolymer polymersomes with temperature-controlled permeability within the physiologically relevant temperature range of 37–42 °C for sustained delivery of anticancer drugs. These polymersomes combine characteristics of liposomes, such as biocompatibility, biodegradability, monodispersity, and stability at room temperature, with tunable size and thermal responsiveness provided by amphiphilic triblock copolymers. The temperature-sensitive poly(N-vinylcaprolactam) n -poly(dimethylsiloxane)65-poly(N-vinylcaprolactam) n (PVCL n -PDMS65-PVCL n ) copolymers with n = 10, 15, 19, 29, and 50 and polydispersity indexes less than 1.17 are synthesized by controlled RAFT polymerization. The copolymers are assembled into stable vesicles at room temperature when the ratio of PVCL to the total polymer mass is 0.36 < f < 0.52 with the polymersome diameter decreasing from 530 to 40 nm as the length of PVCL is increased from 10 to 19 monomer units. Importantly, the permeability of polymersomes loaded with the anticancer drug doxorubicin can be precisely controlled by PVCL length in the temperature range of 37–42 °C. Increasing the temperature above the lower critical solution temperature of PVCL results in either gradual vesicle shrinkage (n = 10 and n = 15) or reversible formation of beadlike aggregates with no size change (n = 19), both leading to sustained drug release. All temperature-triggered morphological changes are reversible and do not compromise the structural stability of the vesicles. Finally, concentration- and time-dependent cytotoxicity of drug-loaded polymersomes to human alveolar adenocarcinoma cells is demonstrated. Considering the high loading capacity (∼40%) and temperature responsiveness in the physiological range, these polymer vesicles have considerable potential as novel types of stimuli-responsive drug nanocarriers.
Type 1 diabetes is an autoimmune-mediated disease resulting in the destruction of insulin-secreting pancreatic β-cells. Transplantation of insulin-producing islets is a viable treatment to restore euglycemia in Type 1 diabetics, however, the clinical application remains limited due to the use of toxic immunosuppressive therapies to prevent immune-mediated rejection. We present a nanothin polymer material with dual antioxidant and immunosuppressive properties capable of modulating both innate and adaptive immune responses crucial for transplantation outcome. Through the use of hollow microparticles (capsules) comprising of hydrogen-bonded multilayers of natural polyphenol (tannic acid) with poly(N-vinylpyrrolidone) (TA/PVPON) and with poly(N-vinylcaprolactam) (TA/PVCL), pro-inflammatory reactive oxygen and nitrogen species are efficiently dissipated and the production of IFN-γ and TNF-α pro-inflammatory cytokines are attenuated by cognate antigen-stimulated autoreactive CD4+ T cells. Our results provide evidence that TA-containing capsules are efficacious in immunomodulation and may provide physical transplant protection and prevent diabetogenic autoreactive T cell responses. Future studies will determine if xeno- and allotransplantation with (TA/PVPON)- or (TA/PVCL)-coated pancreatic islets will decrease the risk of graft rejection due to attenuation of oxidative stress and IFN-γ, and restore euglycemia in Type 1 diabetics.
Despite the accessibility of ultrasound, the clinical potential of ultrasound-active theranostic agents has not been fully realized because it requires combining sufficient imaging contrast, high encapsulation efficiency, and ultrasound-triggered release in one entity. We report on theranostic polymer microcapsules composed of hydrogenbonded multilayers of tannic acid and poly(N-vinylpyrrolidone) that produce high imaging contrast and deliver the anticancer drug doxorubicin upon low-power diagnostic or high-power therapeutic ultrasound irradiation. These capsules exhibit excellent imaging contrast in both brightness and harmonic modes and show prolonged contrast over six months, unlike commercially available microbubbles. We also demonstrate low-dose gradual and high-dose fast release of doxorubicin from the capsules by diagnostic (~100 mW/cm2) and therapeutic (>10 W/cm2) ultrasound irradiation, respectively. We show that the imaging contrast of the capsules can be controlled by varying the number of layers, polymer type (relatively rigid tannic acid versus more flexible poly(methacrylic acid)), and polymer molecular weight. In vitro studies demonstrate that 50% doxorubicin release from ultrasound-treated capsules induces 97% cytotoxicity to MCF-7 human cancer cells, while no cytotoxicity is found without the treatment. Considering the strong ultrasound imaging contrast, high encapsulation efficiency, biocompatibility, and tunable drug release, these microcapsules can be used as theranostic agents for ultrasound-guided chemotherapy.
Shape and responsiveness of nanoengineered delivery carriers are crucial characteristics for rapid and efficient delivery of therapeutics. We report on a novel type of micrometer-sized hydrogel particles of controlled shape with dual pH- and redox-sensitivity for intracellular delivery of anticancer drugs. The cubical and spherical poly(methacrylic acid) (PMAA) networks with disulfide links are obtained by cross-linking PMAA with cystamine within hydrogen-bonded multilayers of PMAA/poly(vinylpyrrolidone) (PMAA/PVPON) on sacrificial mesoporous templates. The pH-triggered hydrogel swelling/shrinkage not only affords effective doxorubicin entrapment but also efficient endosomal/lysosomal escape, and redox-triggered degradation provides drug release into the cytosolic space. The hydrogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione, which should ensure a rapid renal clearance in vivo. Particle shape is found to affect internalization at the initial step of cell-particle interactions. Drug-loaded spherical particles are found to be 12% more cytotoxic than the corresponding cubes within the first 10 h of cell incubation suggesting more rapid internalization of spheres. Both doxorubicin-loaded hydrogel cubes and spheres demonstrate 50% and 90% cytotoxicity when incubated with HeLa cancer cells for 24 and 48 h, respectively. The presented approach integrates the advantages of pH-sensitivity, enzymatic degradation, and shape-regulated internalization for novel types of "intelligent" three-dimensional networks with programmable behavior for use in controlled delivery of therapeutics.
Aim: To investigate whether high glucose stimulates the expression of inflammatory cytokines and the possible mechanisms involved. Methods: ELISA and real-time PCR were used to determine the expression of the inflammatory factors, and a chemiluminescence assay was used to measure the production of reactive oxygen species (ROS). Results: Compared to low glucose (10 mmol/L), treatment with high glucose (35 mmol/L) increased the secretion of tumor necrosis factor (TNF)α and monocyte chemotactic protein-1 (MCP-1), but not interleukin (IL)-1β and IL-6, in a time-dependent manner in primary cultured rat microglia. The mRNA expression of TNFα and MCP-1 also increased in response to high glucose. This upregulation was specific to high glucose because it was not observed in the osmotic control. High-glucose treatment stimulated the formation of ROS. Furthermore, treatment with the ROS scavenger NAC significantly reduced the high glucose-induced TNFα and MCP-1 secretion. In addition, the nuclear factor kappa B (NF-κB) inhibitors MG132 and PDTC completely blocked the high glucose-induced TNFα and MCP-1 secretion. Conclusion: We found that high glucose induces TNFα and MCP-1 secretion as well as mRNA expression in rat microglia in vitro, and this effect is mediated by the ROS and NF-κB pathways.Keywords: high glucose; microglia; tumor necrosis factor α; monocyte chemotactic protein-1; reactive oxygen species; NF-кB Acta Pharmacologica Sinica (2011) 32: 188-193; doi: 10.1038/aps.2010 Original Article * To whom correspondence should be addressed. [10][11][12] . An increased level of glucose in the brain induced by hyperglycemia leads to neuronal apoptosis and impaired cognition [9,[12][13][14][15] . However, the effect of hyperglycemia on the activation of microglia and the role of inflammation in the pathogenesis of diabetic encephalopathy is still unclear. We previously reported that high glucose can activate microglia and significantly increase the secretion and mRNA expression of growth-regulated oncogene (GRO), a member of the IL-8 family, in rat microglia in vitro [16] . This finding suggests that in the central nervous system of patients with diabetes mellitus, high concentrations of glucose may induce microglial activation and the secretion of IL-8, thus contributing to the development of diabetic encephalopathy. In this study, we investigated the effect of high glucose on the inflammatory function of microglia. We found that compared with low glucose (10 mmol/L), high glucose (35 mmol/L) increased the secretion and mRNA expression of TNFα and monocyte chemoattract protein-1 (MCP-1) in rat microglia in vitro. Reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) pathways were involved in this process. However, there were no effects of high glucose on the secretion of IL-1β and IL-6. Materials and methods ReagentsThe OX-42 antibody was purchased from Serotec (Oxford, UK). The MCP-1 antibody was purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). The glial fibrillary acidic protein (GFAP) antibody...
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