Boronic-targeted albumin-shell oily-core nanocapsules for synergistic aromatase inhibitor/herbal breast cancer therapy.

Multi-modality strategies of albumin-mediated drug accumulation in tumor, boronate-based active tumor targeting and synergistic cancer therapy were combined together for effective treatment of breast cancer. Herein we report the development of albumin-shell oily-core nanocapsules (NCs), loaded with novel combination of hydrophobic drugs, exemestane (EXE) and hesperetin (HES), for targeted breast cancer therapy. This protein-lipid nanohybrid carrier was successfully fabricated using a simple protein-coating method based on the electrostatic adsorption of negatively charged albumin shell onto the oily core containing cationic surfactant. While EXE was directly encapsulated into the oily core, HES was pre-formulated in the form of phospholipid complex before solubilization in oily phase. In addition to albumin-mediated binding to albondin and SPARC, phenylboronic acid was chemically coupled to the albumin shell to confer additional tumor targeting. The targeted nanocarrier (TNC) demonstrated enhanced internalization into MCF-7 breast cancer cells resulting in synergistic cytotoxic activity with a combination index (CI) of 0.662 and dose reduction index (DRI) of 8.22 and 1.84 for EXE and HES, respectively. In vivo, TNC displayed superior anti-cancer activity in tumor-bearing mice compared to their non-targeted counterparts and the free drug combination. A significant reduction of both tumor volume (7-folds) and Ki67 expression (3-folds) was obtained by the targeted nanocarriers compared to positive control. Overall, the boronic-targeted albumin NCs offer a promising platform for hydrophobic drug combination against cancer therapy.

Open-Label, Crossover Study to Determine the Pharmacokinetics of Fluticasone Furoate and Batefenterol When Administered Alone, in Combination, or Concurrently.

The study aim was to investigate the pharmacokinetics of single high doses and repeated therapeutic doses of fluticasone furoate (FF) and batefenterol (BAT; a bifunctional muscarinic antagonist and ß2 -agonist) administered in combination (BAT/FF) or as monotherapy. In this open-label, 6-period, crossover study of 48 subjects, the treatment sequences were (1) single high-dose BAT/FF 900/300 µg followed by repeated therapeutic doses of BAT/FF 300/100 µg (once daily for 7 days); (2) single high-dose BAT 900 µg administered concurrently with FF 300 µg; (3) single high-dose BAT 900 µg followed by repeated therapeutic-dose BAT 300 µg; (4) single high-dose FF 300 µg followed by repeated therapeutic-dose FF 100 µg; (5) single high-dose FF 300 µg (magnesium stearate); and (6) single high-dose FF/vilanterol 300/75 µg. Plasma FF area under the plasma drug concentration-time curve (AUC) was reduced after single high-dose BAT/FF versus FF alone (ratio of geometric least squares means: 0.79; 90% confidence interval: 0.75-0.83). After repeat dosing, FF AUC at the lower therapeutic dosage was similar for BAT/FF and FF (primary endpoint; AUC geometric least squares means: 1.03). Adverse events were minor, the most common being cough. These data support the feasibility of developing BAT/inhaled corticosteroid triple therapy in a single inhaler.

Pharmacokinetic and pharmacodynamic evaluation of the suitability of using fluticasone and an acute rat lung inflammation model to differentiate lung versus systemic efficacy.

Inhaled corticosteroids (ICSs) are often prescribed as the first line therapy for pulmonary diseases such as asthma. The biggest concern of using steroid therapy is the systemic side effects at high dose. To reduce the side effects, the pharmaceutical industry has been putting effort to generate new drugs with maximized topical efficacy. One of the key challenges is to differentiate efficacy from local versus systemic contribution in preclinical animal models. Fluticasone with various formulations was used as a model compound to explore the possibilities to demonstrate lung targeted efficacy by intratracheally instillation in the lipopolysaccharide induced inflammation rat model. Fluticasone formulations contained various surfactant concentrations and particle sizes to achieve lung retention and lower systemic exposure. Neutrophil infiltration in broncoalveolar lavage fluid and cytokine production in whole blood were measured to assess pulmonary efficacy versus systemic efficacy. PK/PD characterization of fluticasone with various formulations in the rat inflammation model provided an integrated approach in preclinical to evaluate lung targeted efficacy for ICS. Our study concluded that the combination of the rat LPS model and fluticasone is not suitable to use for establishing potency and dose requirement for new drug candidate designed for topical only efficacy.

The presence of emphysema does not affect the systemic bioactivity of inhaled fluticasone in severe chronic obstructive pulmonary disease.

AIMS: To assess the systemic bioactivity of fluticasone proprionate (FP) 2000 micro g daily on sensitive adrenal and bone markers in severe chronic obstructive pulmonary disease (COPD) patients with or without significant emphysema. METHODS: Ten patients without emphysema (COPD group: age 55 years, FEV(1) 51% predicted and DL(CO) 83% predicted) and 10 patients with emphysema (COPDE group: age 59 years, FEV(1) 43% predicted and DL(CO) 49% predicted) received FP 2000 micro g daily via a spacer for 2 weeks. There was a 1-week washout period prior to FP treatment where patients were given salmeterol and oxitropium, after stopping their usual inhaled corticosteroids for the duration of the study. Measurements including overnight 10 h urinary cortisol excretion corrected for creatinine (OUCC) and serum osteocalcin concentrations were performed at baseline following washout and after 2 weeks of FP. RESULTS: Values for OUCC and serum osteocalcin concentrations pre- and post-FP were not significantly different between the COPD and COPDE groups. There was significant suppression of OUCC (nmol mmol(-1)) by FP treatment within the COPD group (P = 0.03): 7.86 vs 4.64 (95% CI on the difference 0.47, 5.98), and within the COPDE group (P = 0.006): 7.13 vs 4.27 (95% CI on the difference: 1.03, 4.69). Likewise, there was significant suppression of osteocalcin concentration (nmol l(-1)) by FP treatment within the COPD group (P = 0.04): 7.24 vs 6.34 (95% CI on the difference: 0.01, 1.78), and within the COPDE group (P = 0.03): 6.92 vs 5.72 (95% CI on the difference: 0.12, 2.29). CONCLUSIONS: Severe COPD patients who are receiving high dose FP are susceptible to the development of systemic adverse effects, irrespective of the presence of emphysema.

Exemestane and aromatase inhibitors in the management of advanced breast cancer.

In metastatic breast cancer, orally-active, potent, selective third-generation nonsteroidal inhibitors and steroidal inactivators have shown superiority over tamoxifen, a selective oestrogen receptor modulator. In advanced breast cancer, aromatase inhibitors and inactivators are becoming established as the standard of care over tamoxifen in postmenopausal female breast cancer patients when hormonal therapy is indicated for first-line treatment. Emerging research evidence and ongoing clinical investigations look likely to further extend the use of these potent agents across several additional treatment settings in the management of breast cancer. Several multi-centre studies are underway examining the role of novel hormonal therapy in the adjuvant treatment of early breast cancer and other investigations will explore possible future applications of these potent antiaromatase agents, including breast cancer prevention.

Aerosol characterization of nebulized intranasal glucocorticoid formulations.

Inhaled glucocorticoids (GCs) are the mainstay of long-term therapy for asthma. The lack of suitable preparations in the United States has induced clinicians to use intranasal (IN) GC formulations as "nebulizer suspensions" for off-label therapy. However, no data are available regarding aerosol production and characteristics. The aim of this study was to characterize drug outputs and aerodynamic profiles of four nebulized IN GC formulations with further analysis of flunisolide (Flu), and to test the influence of different delivery system/formulation combinations. The aerodynamic profiles and drug outputs were determined by impaction and chemical analysis. The solution output was determined by the gravimetric technique. Triamcinole acetonide (TAA), fluticasone propionate (Flut), beclomethasone dipropionate (Bec), and Flu (550, 500, 840, and 250 microg, respectively) diluted to 4 mL with saline solution were tested with the Sidestream (SID) and Aero-Tech II (AT2) nebulizers. Subsequently, Flu was tested with four additional nebulizers (Pari LC + [PARI] Acorn II, Hudson T Up-draft II, and Raindrop). All the aerosols were heterodisperse and had a particle size range optimal for peripheral airway deposition (1.85 to 3.67 microm). Flu had the highest drug output in the respirable range (22.8 and 20.3 microg/min with the AT and SID, respectively). Flu was 5-11 times more efficiently nebulized than the other formulations tested. No differences were detected in the solution outputs (0.25 to 0.3 mL/min). In subsequent testing of Flu, the PARI, AT, and SID showed the best performances. The LC+ achieved the highest drug and solution output (27.4 microg/min and 0.89 mL/min, respectively). In conclusion, Flu showed the best aerosol performance characteristics. These data do not endorse the off-label utilization of nebulized IN GC, but underscores the importance of in vitro testing before selecting any formulation/nebulizer combinations for clinical use.