Effect of oil structure on cyclodextrin-based Pickering emulsions for bupivacaine topical application.

Cyclodextrins (CDs) coupled with oils forms an insoluble inclusion complex that is able to adsorb to the interface between oils and aqueous phases; it thereby stabilizes Pickering emulsions. Three types of oils (triglyceride, linear chain oil, and ring-structured oil) were chosen to work with CDs to prepare bupivacaine (BPC)-encapsulated Pickering emulsions. We also investigated the relationship between oils and CDs; as well as their influences on stability, drug-releasing capability and skin permeability. Particle sizes and microstructures were determined by dynamic light scattering and scanning electron microscopy, respectively. In vitro drug release studies and in vitro skin permeation studies were evaluated by using Franz diffusion model. Particle sizes of all Pickering emulsions were larger than 1µm, and the morphology was spherical and covered with rough surfaces. BPC was released over an extended period, and the releasing ratios from Pickering emulsions were only 12.2%-23.1% after 48h. In skin permeation studies, compared with other formulations, a formula involved with ring-structured oil allowed the highest permeation amount through skin. However, after 24h of exposure, formulation operated with linear chain oil showed the highest skin-retaining amount. These results suggest that Pickering emulsions could regulate the target site of skin depending on various types of oil used.

A liposomal formulation able to incorporate a high content of Paclitaxel and exert promising anticancer effect.

A liposome formulation for paclitaxel was developed in this study. The liposomes, composed of naturally unsaturated and hydrogenated phosphatidylcholines, with significant phase transition temperature difference, were prepared and characterized. The liposomes exhibited a high content of paclitaxel, which was incorporated within the segregated microdomains coexisting on phospholipid bilayer of liposomes. As much as 15% paclitaxel to phospholipid molar ratio were attained without precipitates observed during preparation. In addition, the liposomes remained stable in liquid form at 4°C for at least 6 months. The special composition of liposomal membrane which could reduce paclitaxel aggregation could account for such a capacity and stability. The cytotoxicity of prepared paclitaxel liposomes on the colon cancer C-26 cell culture was comparable to Taxol. Acute toxicity test revealed that LD(50) for intravenous bolus injection in mice exceeded by 40 mg/kg. In antitumor efficacy study, the prepared liposomal paclitaxel demonstrated the increase in the efficacy against human cancer in animal model. Taken together, the novel formulated liposomes can incorporate high content of paclitaxel, remaining stable for long-term storage. These animal data also demonstrate that the liposomal paclitaxel is promising for further clinical use.

Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: Implications for increasing therapeutic gain in cancer radiotherapy.

Radiotherapy is an effective treatment for head and neck, skin, anogenital, and breast cancers. However, radiation-induced skin morbidity limits the therapeutic benefits. A low-toxicity approach to selectively reduce skin morbidity without compromising tumor killing by radiotherapy is needed. We found that the antitumor agents known as histone deacetylase (HDAC) inhibitors (phenylbutyrate, trichostatin A, and valproic acid) could suppress cutaneous radiation syndrome. The effects of HDAC inhibitors in promoting the healing of wounds caused by radiation and in decreasing later skin fibrosis and tumorigenesis were correlated with suppression of the aberrant expression of radiation-induced transforming growth factor beta and tumor necrosis factor alpha. Our findings implicate that the inhibition of HDAC may provide a novel strategy to increase the therapeutic gain in cancer radiotherapy by not only inhibiting tumor growth but also protecting normal tissues.

A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by progressive destruction of the affected joints. The pathophysiology results from genetic susceptibility and autoimmune phenomena, leading to tissue inflammation and synovial hyperplasia termed pannus, which irreversibly destroys cartilage and bone. The current treatment options, which suppress immune responses or ameliorate inflammation, do not halt the destructive process. We found that the histone deacetylase (HDAC) inhibitors (phenylbutyrate and trichostatin A) causing histone hyperacetylation to modulate multiple gene expression not only induced the expression of p21(Cip1) and p16(INK4) in synovial cells but also inhibited the expression of tumor necrosis factor-alpha in affected tissues in adjuvant arthritis, an animal model of RA. Based on the observations that joint swelling is reduced, subintimal mononuclear cell infiltration is decreased, synovial hyperplasia is inhibited, pannus formation is suppressed, and no cartilage or bone destruction is seen, the HDAC inhibitors may represent a new class of compounds for the treatment of RA by simultaneously, coordinately, synergistically, or epigenetically modulating multiple molecular targets in the pathogenesis of RA.