A Mixed Thermosensitive Hydrogel System for Sustained Delivery of Tacrolimus for Immunosuppressive Therapy.

Tacrolimus is an immunosuppressive agent for acute rejection after allotransplantation. However, the low aqueous solubility of tacrolimus poses difficulties in formulating an injection dosage. Polypeptide thermosensitive hydrogels can maintain a sustained release depot to deliver tacrolimus. The copolymers, which consist of poloxamer and poly(l-alanine) with l-lysine segments at both ends (P-Lys-Ala-PLX), are able to carry tacrolimus in an in situ gelled form with acceptable biocompatibility, biodegradability, and low gelling concentrations from 3 to 7 wt %. By adding Pluronic F-127 to formulate a mixed hydrogel system, the drug release rate can be adjusted to maintain suitable drug levels in animals with transplants. Under this formulation, the in vitro release of tacrolimus was stable for more than 100 days, while in vivo release of tacrolimus in mouse model showed that rejection from skin allotransplantation was prevented for at least three weeks with one single administration. Using these mixed hydrogel systems for sustaining delivery of tacrolimus demonstrates advancement in immunosuppressive therapy.

Gold nanorod-encapsulated biodegradable polymeric matrix for combined photothermal and chemo-cancer therapy.

PURPOSE: A biocompatible nanocomplex system co-encapsulated with gold nanorods (AuNRs) and doxorubicin (DOX) was investigated for its potentials on the combined photothermal- and chemotherapy. MATERIALS AND METHODS: Hydrophobic AuNRs were synthesized by the hexadecyltrimethyl-ammonium bromide (CTAB)-mediated seed growth method, and then, they received two-step surface modifications of polyethylene glycol (PEG) and dodecane. The AuNR/DOX/poly(lactic-co-glycolic acid) (PLGA) nanocomplexes were prepared by emulsifying DOX, AuNR, and PLGA into aqueous polyvinyl alcohol solution by sonication. Human serum albumin (HSA) was used to coat the nanocomplexes to afford HSA/AuNR/DOX-PLGA (HADP). Size and surface potential of the HADP nanocomplexes were determined by using a Zetasizer. Cytotoxicity and cellular uptake of the HADP were analyzed by using MTT assay and flow cytometry, respectively. In vitro anticancer effects of the HADP were studied on various cancer cell lines. To assess the therapeutic efficacy, CT26 tumor-bearing mice were intravenously administered with HADP nanocomplexes and laser treatments, followed by monitoring of the tumor growth and body weight. RESULTS: Size and surface potential of the HADP nanocomplexes were 245.8 nm and -8.6 mV, respectively. Strong photothermal effects were verified on the AuNR-loaded PLGA nanoparticles (NPs) in vitro. Rapid and repeated drug release from the HADP nanocomplexes was successfully achieved by near-infrared (NIR) irradiations. HSA significantly promoted cellular uptake of the HADP nanocomplexes to murine colon cancer cells as demonstrated by cell imaging and flow cytometric studies. By combining photothermal and chemotherapy, the HADP nanocomplexes exhibited strong synergistic anticancer effects in vitro and in vivo. CONCLUSION: An NIR-triggered drug release system by encapsulating hydrophobic AuNR and DOX inside the PLGA NPs has been successfully prepared in this study. The HADP NPs show promising combined photothermal- and chemotherapeutic effects without inducing undesired side effects on a murine colon cancer animal model.

Lipopolysaccharide Attenuates Induction of Proallergic Cytokines, Thymic Stromal Lymphopoietin, and Interleukin 33 in Respiratory Epithelial Cells Stimulated with PolyI:C and Human Parechovirus.

Epidemiological studies based on the "hygiene hypothesis" declare that the level of childhood exposure to environmental microbial products is inversely related to the incidence of allergic diseases in later life. Multiple types of immune cell-mediated immune regulation networks support the hygiene hypothesis. Epithelial cells are the first line of response to microbial products in the environment and bridge the innate and adaptive immune systems; however, their role in the hygiene hypothesis is unknown. To demonstrate the hygiene hypothesis in airway epithelial cells, we examined the effect of lipopolysaccharide (LPS; toll-like receptor 4 ligand) on the expression of the proallergic cytokines thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL33) in H292 cells (pulmonary mucoepidermoid carcinoma cells). Stimulation with the TLR ligand polyI:C and human parechovirus type 1 (HPeV1) but not LPS-induced TSLP and IL33 through interferon regulatory factor 3 (IRF3) and NF-κB activity, which was further validated by using inhibitors (dexamethasone and Bay 11-7082) and short hairpin RNA-mediated gene knockdown. Importantly, polyI:C and HPeV1-stimulated TSLP and IL33 induction was reduced by LPS treatment by attenuating TANK-binding kinase 1, IRF3, and NF-κB activation. Interestingly, the basal mRNA levels of TLR signaling proteins were downregulated with long-term LPS treatment of H292 cells, which suggests that such long-term exposure modulates the expression of innate immunity signaling molecules in airway epithelial cells to mitigate the allergic response. In contrast to the effects of LPS treatment, the alarmin high-mobility group protein B1 acts in synergy with polyI:C to promote TSLP and IL33 expression. Our data support part of the hygiene hypothesis in airway epithelia cells in vitro. In addition to therapeutic targeting of TSLP and IL33, local application of non-pathogenic LPS may be a rational strategy to prevent allergies.

Colchicine derivative as a potential anti-glioma compound.

Colchicine, an anti-microtubule and antimitotic drug, is a common therapeutically agent for gout, which is thought to have potential anti-tumor effects. Owing to concerns of colchicines poisoning, the development of derivatives with low dose efficacy and less side effects is of obvious interest. In this study, we characterized the inhibitory effects of a colchicine derivative named AD1 on the cell proliferation of human malignant glioblastoma (MG) cell lines, U87MG and U373MG. We found that 50 % of U87MG and U373MG cells were reduced in the cultures after exposure to AD1 for 24 h at 10 and 50 nM, respectively. Moreover, α-tubulin immunostaining indicated that AD1 induced the disruption of the microtubule polymerization in glioma cells with apoptotic features including membrane budding/blebbing or fragmented nuclei. Increased levels of reactive oxygen species (ROS) were also detected in AD1-treated U87MG and U373MG cells compared to that observed in the control culture. Moreover, examination of microtubule-associated protein 1A/1B-light chain 3 (LC3I)/LC3II conversion and acridine orange staining for autophagic vesicles, combined with flow cytometry, showed that treatment with AD1 induced the autophagic pathway in U87MG and U373MG cells. Furthermore, we found that the intermittent intravenous administration of AD1 suppressed glioma growth in rat brain receiving intracerebral injection with rat C6 glioma cells. Taken together, our findings reveal that treatment with AD1 at nanomolar scales can reduce glioma cell viability effectively, with the occurrence of a rise in ROS and cellular autophagy. In conjunction with the observations from in vivo study, the colchicine derivative AD1 has chemotherapeutic potential to suppress glioma progression.

Precompression quality-control algorithm for JPEG 2000.

In this paper, a precompression quality-control algorithm is proposed. It can greatly reduce computational power of the embedded block coding (EBC) and memory requirement to buffer bit streams. By using the propagation property and the randomness property of the EBC algorithm, rate and distortion of coding passes is approximately predicted. Thus, the truncation points are chosen before actual coding by the entropy coder. Therefore, the computational power, which is measured with the number of contexts to be processed, is greatly reduced since most of the computations are skipped. The memory requirement, which is measured with the amount required to buffer bit streams, is also reduced since the skipped contexts do not generate bit streams. Experimental results show that the proposed algorithm reduces the computational power of the EBC by 80% on average at 0.8 bpp compared with the conventional postcompression rate-distortion optimization algorithm. Moreover, the memory requirement is also reduced by 90%. The average PSNR degrades only about 0.1-0.3 dB, on average.