Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery.

The therapeutic potential of small nucleic acids such as small interfering RNA (siRNA) to treat lung diseases has been successfully demonstrated in many in vivo studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation. In this study, spray freeze drying was employed to prepare dry powder of small nucleic acids. Mannitol and herring sperm DNA were used as bulking agent and model of small nucleic acid therapeutics, respectively. Formulations containing different solute concentration and DNA concentration were produced. The scanning electron microscope (SEM) images showed that the porosity of the particles increased as the solute concentration decreased. Powders prepared with solute concentration of 5% w/v were found to maintain a balance between porosity and robustness. Increasing concentration of DNA improved the aerosol performance of the formulation. The dry powder formulation containing 2% w/w DNA had a median diameter of 12.5 µm, and the aerosol performance study using next generation impactor (NGI) showed an emitted fraction (EF) and fine particle fraction (FPF) of 91% and 28% respectively. This formulation (5% w/v solute concentration and 2% w/w nucleic acid) was adopted subsequently to produce siRNA powder. The gel retardation and liquid chromatography assays showed that the siRNA remained intact after spray freeze drying even in the absence of delivery vector. The siRNA powder formulation exhibited a high EF of 92.4% and a modest FPF of around 20%. Further exploration of this technology to optimise inhaled siRNA powder formulation is warranted.

Inhaled powder formulation of naked siRNA using spray drying technology with l-leucine as dispersion enhancer.

Pulmonary delivery of short interfering RNA (siRNA) has been widely studied in both animal and clinical studies to treat various respiratory diseases by gene silencing through RNA interference. Some of these studies showed that the administration of naked siRNA (without the use of any delivery vectors) could achieve satisfactory gene silencing effect, a unique feature to pulmonary delivery. Liquid aerosols were mostly used with very limited studies on the use of powder aerosols for siRNA. In this study, siRNA was co-spray dried with mannitol and l-leucine, the latter being a dispersion enhancer. To the best of our knowledge, this is the first time that siRNA in its naked form was formulated into an inhalable dry powder using spray drying technology. The aerosol performance of the powder was evaluated by Next Generation Impactor (NGI). The presence of l-leucine in the formulation could improve the aerosolization of siRNA-containing powders. Results from the X-ray photoelectron spectroscopy (XPS) suggested that l-leucine was enriched on the particle surface and promote powder dispersion. Among the different siRNA formulations being examined, the one that contained 50% w/w of l-leucine exhibited the best aerodynamic performance, with a high emitted fraction (EF) of around 80% and a modest fine particle fraction (FPF) of 45%. Importantly, the integrity of siRNA was successfully retained as evaluated by gel retardation assay and high performance liquid chromatography (HPLC).

Racial and ethnic disparities in survival of US children with acute lymphoblastic leukemia: evidence from the SEER database 1988-2008.

PURPOSE: Prior studies have shown poorer survival from childhood acute lymphoblastic leukemia (ALL) among some minorities compared to non-Hispanic whites (NHW). Here, we examine whether these survival disparities have persisted and to see whether they also exist for Asian and Hispanic subgroups. METHODS: Using data from the US National Cancer Institute's Surveillance, Epidemiology and End Results program from 1988 to 2008, we compared all natural-cause survival for children aged 19 years or under diagnosed with ALL using Cox proportional hazards models adjusted for age, diagnosis year, gender and disease immunophenotype. RESULTS: Black, Hispanic and Native American children continue to have significantly poorer survival than NHW. Unlike previous studies, we found that Asian Americans also had significantly worse survival. Among Asian subgroups, Vietnamese (relative risk [RR] = 2.44, 95 % CI = 1.50-3.97) and Filipinos (RR = 1.64, 95 % CI = (1.13-2.38) had significantly poorer survival, while other East Asian groups, except Chinese, had non-significantly worse survival. Most Hispanic subgroups had RRs around 2. CONCLUSION: Previously observed poorer prognosis for childhood ALL for some minority groups appears to be shared by most Asians as well. Further research is needed to find explanations for the poorer survival of minority children with ALL and possible treatment implications.