Self-assembled tannic acid complexes for pH-responsive delivery of antibiotics: Role of drug-carrier interactions.

Self-assembled particles, based on non-covalent interactions, are attractive drug carriers with a relatively simple structure and easy preparation. Tannic acid (TA) is an anionic polyphenolic compound with a wide range of molecular interactions and diverse applications in drug delivery research. Here, we propose the use of TA complexes with cationic antibiotics as a new pH-responsive drug carrier of high drug loading and optimal stability. TA complexes were prepared with three water-soluble antibiotics; colistin sulfate (COL), gentamicin sulfate (GEN) and gatifloxacin (GAT). Complexes' size ranged from several-hundred nanometers to few microns. For selected particles, drug loading ranged from 30 to 36%. Importantly, we demonstrate the impact of drug-carrier interactions, studied via infrared spectroscopy and molecular modeling, on final complex stability and performance; the complexes resisted dissociation in presence of serum at physiological pH to variable degrees and showed different drug release profiles. However, all complexes dissociated upon medium acidification, releasing their drug payload and demonstrating expected antibacterial effect. These results demonstrate that TA/antibiotic self-assembled complexes represent an excellent carrier for pH-sensitive delivery of water-soluble drugs. In addition to system's simplicity and low cost, complexes were easily prepared with high drug loading and desirable pH-dependent association/dissociation profile.

Adenovirus vector-based multi-epitope vaccine provides partial protection against H5, H7, and H9 avian influenza viruses.

The emergence of H5, H7, and H9 avian influenza virus subtypes in humans reveals their pandemic potential. Although human-to-human transmission has been limited, the genetic reassortment of the avian and human/porcine influenza viruses or mutations in some of the genes resulting in virus replication in the upper respiratory tract of humans could generate novel pandemic influenza viruses. Current vaccines do not provide cross protection against antigenically distinct strains of the H5, H7, and H9 influenza viruses. Therefore, newer vaccine approaches are needed to overcome these potential threats. We developed an egg-independent, adenovirus vector-based, multi-epitope (ME) vaccine approach using the relatively conserved immunogenic domains of the H5N1 influenza virus [M2 ectodomain (M2e), hemagglutinin (HA) fusion domain (HFD), T-cell epitope of nucleoprotein (TNP). and HA α-helix domain (HαD)]. Our ME vaccine induced humoral and cell-mediated immune responses and caused a significant reduction in the viral loads in the lungs of vaccinated mice that were challenged with antigenically distinct H5, H7, or H9 avian influenza viruses. These results suggest that our ME vaccine approach provided broad protection against the avian influenza viruses. Further improvement of this vaccine will lead to a pre-pandemic vaccine that may lower morbidity, hinder transmission, and prevent mortality in a pandemic situation before a strain-matched vaccine becomes available.

Beta-defensin 2 enhances immunogenicity and protection of an adenovirus-based H5N1 influenza vaccine at an early time.

Reports of human infections with highly pathogenic H5N1 avian influenza viruses in many countries in Asia and Africa with varying case fatality rates highlight the pandemic potential of these viruses. In order to contain a rapidly spreading influenza virus in a pandemic scenario, a vaccine which can induce rapid and robust immune responses, preferably in a single dose, is necessary. Murine beta-defensin 2 (Mbd2), a small molecular weight protein expressed by epithelial cells, has been shown to enhance antigen-specific immune responses by recruiting and activating professional antigen presenting cells to the site of vaccination. This study assessed the potential of Mbd2 to enhance the immunogenicity and protective efficacy of a human adenovirus (HAd)-based vaccine expressing the hemagglutinin (HA) and nucleoprotein (NP) [HAd-HA-NP] of an H5N1 influenza virus. A single inoculation of mice with both HAd-HA-NP and a HAd vector expressing Murine ß-defensin 2 (HAd-Mbd2) resulted in significantly higher levels of both humoral and cell-mediated immune responses compared to the groups vaccinated only with HAd-HA-NP. These responses were evident even at day 7 post-immunization. Furthermore, the HAd-HA-NP+HAd-Mbd2-immunized group receiving the lowest vector dose (2 × 10(7)+1 × 10(7)) was completely protected against an rgH5N1 virus challenge on day 7 post-vaccination. These results highlight the potential of Mbd2 as a genetic adjuvant in inducing rapid and robust immune responses to a HAd-based vaccine.