Nanoemulsions have been developed for the oral delivery of poorly bioavailable phenolic compounds that are sensitive to intestinal glucuronidation. However, little is known about the contribution of UDP-glucuronosyltransferase (UGT) inhibitory excipients in nanoemulsions toward the inhibition of intestinal glucuronidation and the consequent enhanced bioavailability. In this study, Labrasol but not poloxamer 188 (F68) was found to inhibit the glucuronidation of resveratrol (RES), a model phenolic compound, in an inhibition assay with rat microsomes. Subsequently, two nanoemulsions, Lab-N and F68-N, were prepared with similar particle size distribution, zeta potentials, and entrapment efficiency by coemulsifying with Labrasol or F68, respectively. Although Lab-N exhibited inferior or comparable profiles of in vitro release, cellular uptake in Caco-2 cells, and lymphatic transport in rats to F68-N, the in vitro absorption study with everted sacs suggested that Labrasol containing formulations significantly and dose-dependently increased the transport of RES relative to free RES or F68-N by decreasing the amount of permeated metabolite, RES-3-glucuronide (RES-G). The in vivo pharmacokinetic experiments indicated that Lab-N exhibited increments in the maximum plasma concentration and the bioavailability of RES by 1098% and 560%, respectively, and significant decreases in those of RES-G, compared to F68-N. The overall results demonstrated that the improved oral bioavailability of RES by Lab-N was mainly attributable to the inhibition of intestinal glucuronidation by the presence of UGT inhibitory excipient.

Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.

Background: The management of cancer-related anorexia/cachexia syndrome (CACS) is a great challenge in clinical practice. To date, practice guidelines for the prevention and treatment of CACS are lacking. The authors conducted a randomized study to confirm the effectiveness and safety of treatment of CACS utilizing megestrol acetate (MA) plus thalidomide. Methods: One hundred and two candidates with CACS were randomly assigned to two treatment groups (trial group and control group): the trial group received MA (160 mg po, bid) plus thalidomide (50 mg po, bid), while the control group received MA (160 mg po, bid) alone. Treatment duration was 8 weeks. Results: Analysis of the trial group demonstrated a significant increase from baseline in body weight (<0.01), quality of life (p = 0.02), appetite (p = 0.01), and grip strength (p = 0.01), and a significant decrease in fatigue, Glasgow Prognostic Score (p = 0.05), Eastern Cooperative Oncology Group performance status (p = 0.03), IL-6 (p < 0.01), and tumor necrosis factor-α (p = 0.02). In contrast, in the control group, endpoints with a significant improvement from baseline included body weight (p < 0.02) and appetite (p = 0.02). The mean changes in the endpoints from baseline in the trial group were significantly greater compared with the control group: in the primary endpoints, body weight (p = 0.05), fatigue (p < 0.01) and quality of life (p = 0.01), and in the secondary endpoints, grip strength (p = 0.05), Glasgow Prognostic Score (p = 0.02), Eastern Cooperative Oncology Group performance status (p = 0.02), IL-6 (p < 0.01) and tumor necrosis factor-α (p = 0.01). Toxicity was found to be relatively negligible in both groups. Conclusion: A combination regimen of MA and thalidomide is more effective than MA alone in the treatment of CACS.

Capecitabine is a novel fluoropyrimidine carbamate, which has a broader spectrum of antitumor activity than other fluoropyrimidines, such as 5-FU, DFUR, or UFT; it has proved effective over a wide dose range. Recent research has suggested that frequent administration of lower doses of certain chemotherapeutic drugs might enhance their antiangiogenic effect. The present study investigated the antiangiogenic effect of capecitabine on breast cancer. In order to augment its efficacy, we combined capecitabine chemotherapy with ginsenoside Rg3. Our results indicate that a metronomic regimen of capecitabine inhibited angiogenesis in breast cancer, and its antiangiogenic effects may be further enhanced by the concurrent administration of ginsenoside Rg3. As an antiangiogenic method, this regimen presented better antitumor effects, less toxicity, and reduced susceptibility to drug resistance.

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NCT01754935; results.