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Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids.

ABSTRACT: Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease, but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar lavage fluid (BALF), making this class of peptides attractive candidates for delivering nucleic acids to lung tissues. To further assess the suitability of pH responsive peptides for pulmonary delivery by inhalation, dry powder formulations of pH responsive peptides and plasmid DNA, with mannitol as carrier, were produced by either spray drying (SD) or spray freeze drying (SFD). The properties of the two types of powders were characterised and compared using scanning electron microscopy (SEM), next generation impactor (NGI), gel retardation and in vitro transfection via a twin stage impinger (TSI) following aerosolisation by a dry powder inhaler (Osmohaler™). Although the aerodynamic performance and transfection efficacy of both powders were good, the overall performance revealed SD powders to have a number of advantages over SFD powders and are the more effective formulation with potential for efficient nucleic acid delivery through inhalation.

SUBMITTER: Liang W

PROVIDER: S-EPMC3948054 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids.

Liang Wanling W Kwok Philip C L PC Chow Michael Y T MY Tang Patricia P Mason A James AJ Chan Hak-Kim HK Lam Jenny K W JK

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 20130520 1

Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease, but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar lavage fluid (BALF), making this class of pept ...[more]

PMID: 23702276

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Project description:Recent heightened interest in inhaled bacteriophage (phage) therapy for combating antibacterial resistance in pulmonary infections has led to the development of phage powder formulations. Although phages have been successfully bioengineered into inhalable powders with preserved bioactivity, the stabilization mechanism is yet unknown. This paper reports the first study investigating the stabilization mechanism for phages in these powders. Proteins and other biologics are known to be preserved in dry state within a glassy sugar matrix at storage temperatures (T s) at least ~50°C below the glass transition temperature (T g). This is because at (T g - T s) >50°C, molecules are sufficiently immobilized with reduced reactivity. We hypothesized that this glass stabilization mechanism may also be applicable to phages comprising mostly of proteins. In this study, spray dried powders of Pseudomonas phage PEV20 containing lactose and leucine as excipients were stored at 5, 25 or 50°C and 15 or 33% relative humidity (RH), followed by assessment of bioactivity (PEV20 stability) and physical properties. PEV20 was stable with negligible titer loss after storage at 5°C/15% RH for 250?days, while storage at 33% RH caused increased titer losses of 1 log10 and 3 log10 at 5 and 25°C, respectively. The plasticizing effect of water at 33% RH lowered the T g by 30°C, thus narrowing the gap between T s and T g to 19-28°C, which was insufficient for glass stabilization. In contrast, the (T g - T s) values were higher (range, 46-65°C) under the drier condition of 15% RH, resulting in the improved stability which corroborated with the vitrification hypothesis. Furthermore, phage remained stable (?1 log10) when the (T g - T s) value lay between 26-48°C, but became inactivated as the value fell below 20°C. In conclusion, this study demonstrated that phage can be sufficiently stabilized in spray dried powders by keeping the (T g - T s) value above 46°C, thus supporting the vitrification hypothesis that phages are stabilized by immobilization inside a rigid glassy sugar matrix. These findings provide a guide to better manufacture and storage practices of inhaled phage powder products using for translational medicines.

Dataset Information

Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids.

Publications

Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids.

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