Hyperthermia-mediated local drug delivery by a bubble-generating liposomal system for tumor-specific chemotherapy.

As is widely suspected, lysolipid dissociation from liposomes contributes to the intravenous instability of ThermoDox (lysolipid liposomes), thereby impeding its antitumor efficacy. This work evaluates the feasibility of a thermoresponsive bubble-generating liposomal system without lysolipids for tumor-specific chemotherapy. The key component in this liposomal formulation is its encapsulated ammonium bicarbonate (ABC), which is used to actively load doxorubicin (DOX) into liposomes and trigger a drug release when heated locally. Incubating ABC liposomes with whole blood results in a significantly smaller decrease in the retention of encapsulated DOX than that by lysolipid liposomes, indicating superior plasma stability. Biodistribution analysis results indicate that the ABC formulation circulates longer than its lysolipid counterpart. Following the injection of ABC liposome suspension into mice with tumors heated locally, decomposition of the ABC encapsulated in liposomes facilitates the immediate thermal activation of CO2 bubble generation, subsequently increasing the intratumoral DOX accumulation. Consequently, the antitumor efficacy of the ABC liposomes is superior to that of their lysolipid counterparts. Results of this study demonstrate that this thermoresponsive bubble-generating liposomal system is a highly promising carrier for tumor-specific chemotherapy, especially for local drug delivery mediated at hyperthermic temperatures.

EGRF conjugated PEGylated nanographene oxide for targeted chemotherapy and photothermal therapy.

Low accumulation of chemotherapeutic agent in tumor tissue and multidrug resistance (MDR) present a major obstacle to curing cancer treatment. Therefore, how to combine several therapeutics in one system is a key issue to overcome the problem. Here, we demonstrate epidermal growth factor receptor (EGFR) antibody-conjugated PEGylated nanographene oxide (PEG-NGO) to carry epirubicin (EPI) for tumor targeting and triple-therapeutics (growth signal blocking, chemotherapy, photothermal therapy) in tumor treatment. This synergistic targeted treatment simultaneously enhances the local drug concentration (6.3-fold) and performs the ultra-efficient tumor suppression to significantly prolong the mice survival (over the course of 50 days).

Areca-nut extract modulates antigen-specific immunity and augments inflammation in ovalbumin-sensitized mice.

Areca-nut chewing has been linked to oral cancer and many other diseases, in which immune deterioration and tissue inflammation are plausibly involved. Recent studies reported that areca-nut extract (ANE) affected the functionality of lymphocytes and neutrophils in vitro. In the present study, we investigated the immunomodulatory effect of ANE in vivo. Ovalbumin (OVA)-sensitized mice were daily administered with ANE (5-50 mg/kg) for 10 doses by intraperitoneal injection from days 1 to 5 and from 8 to 12. The mice were systemically sensitized with OVA on day 3, and their footpads were challenged with OVA to induce delayed-type hypersensitivity (DTH) reactions on day 13. The serum level of OVA-specific IgM and IgG(1) was significantly attenuated by 5 and 25 mg/kg of ANE, whereas OVA-specific IgG(2a) was markedly enhanced by 50 mg/kg of ANE. The production of interferon (IFN)-γ by splenocytes reexposed to OVA in culture was markedly augmented by ANE (25 and 50 mg/kg). In addition, ANE (25 and 50 mg/kg) demonstrated an enhancing effect on DTH reactions, including the tissue swelling, the infiltration of CD3(+) and F4/80(+) cells, and the expression of IFN-γ and tumor necrosis factor (TNF)-α in the footpads challenged with OVA. The phagocytic activity and TNF-α production by the splenic CD11b(+) cells were also enhanced in ANE-treated groups. Taken together, these results demonstrated that ANE modulated antigen-specific immune responses and promoted inflammatory reactions in vivo, which may contribute to immune deregulation associated with areca-related diseases.

Diosgenin, a steroidal sapogenin, enhances antigen-specific IgG2a and interferon-gamma expression in ovalbumin-sensitized BALB/c mice.

The effect of diosgenin, the most abundant sapogenin in Chinese yam, on humoral immunity was investigated. Ovalbumin (OVA)-sensitized and challenged BALB/c mice were administered daily with diosgenin for 34 days. The production of OVA-specific serum IgG2a was significantly enhanced by diosgenin treatment, whereas total IgE and OVA-specific IgG1, IgG2a and IgM were unaffected. In parallel with the enhancement of IgG2a, OVA-induced IFN-gamma secretion and mRNA expression were markedly elevated in splenocytes of diosgenin-treated mice, whereas IL-4 expression was unaltered. Furthermore, the expression of T-bet, but not of GATA-3, in splenocytes was up-regulated by diosgenin administration. However, diosgenin treatment did not modulate IL-4 mRNA expression and inflammatory cell infiltration in the lung of OVA-sensitized and challenged mice. Collectively, these data suggest that diosgenin regulates the systemic immune response towards the Th1 direction in response to OVA sensitization. The present study provides evidence to show that intake of diosgenin modulates certain aspects of acquired immunity, including the enhancement of antigen-specific IgG2a and IFN-gamma expression, which may be mediated through the up-regulation of Th1 differentiation.

Biodistribution study of [(123)I] ADAM in mice: correlation with whole body autoradiography.

Iodine-123 labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([(123)I] ADAM) has been suggested as a promising serotonin transporter (SERT) imaging agent. Much research has been accomplished, mainly focusing on the SERT binding sites in the central nervous system (CNS). However, the biodistribution of [(123)I] ADAM using whole body autoradiography (WBAR) has never been previously described, to the best of our knowledge. In this study, we assayed the biodistribution of [(123)I] ADAM in tissues/organs removed from mice, and measured their radioactivity with a scintillation counter (SC). The results showed that the liver has the highest uptake. On the other hand, the WBAR clearly demonstrated that [(123)I] ADAM was bound to SERT-rich sites including those in the brain stem, lung, adrenal glands and intestinal mucosa. This radiotracer also accumulated in the liver, kidney, and thyroid. The results from both methods were compared; each has its own complementary role in the biodistribution studies. The SC method revealed the total amount of radiotracer accumulation in each organ, and the WBAR demonstrated more anatomical details of the radiotracer's distribution. The whole body distribution results of the radioligand using both methods explore the usage of this novel radioligand for most possible SERT binding sites, not only in the CNS but also in the peripheral nervous system and neuroendocrine tissues. These findings suggest that [(123)I] ADAM is a potentially useful imaging agent for SERT.