Pharmaceutical Nanotechnology

Nanocochleate delivery vehicles (also known as Bioral™ Technology) are a broad-based enabling technology for the delivery of a wide range of therapeutic products. Cochleate delivery vehicles are stable phospholipid-cation precipitates composed of simple, naturally occurring materials, for example, phosphatidylserine and calcium. They consist of alternating layers of phospholipid and multivalent cations existing as stacked sheets, or continuous, solid, lipid bilayer sheets rolled up in a spiral configuration, with little or no internal aqueous space.
Nanocochleates Allow Oral Delivery of Cargo Molecules
This unique structure provides protection from degradation for associated, or “encochleated,” molecules. Since the entire cochleate structure is a series of solid layers, components within the interior of the cochleate structure remain intact, even though the outer layers of the cochleate may be exposed to harsh environmental conditions or enzymes. This includes protection from digestion in the stomach. Animal studies performed at BDSI demonstrate nanocochleates cross across the digestive epithelium and deliver their cargo molecules into target cells:
Taking advantage of these unique properties of Nanocochleates, BDSI has used nanocochleates to mediate and enhance the oral bioavailability of a broad spectrum of important but difficult to formulate biopharmaceuticals, including compounds with poor water solubility, protein and peptide drugs, and large hydrophilic molecules. BioDelivery Sciences and collaborators have performed proof of principle studies in appropriate animal models in each of these areas:
· Nanocochleate-mediated oral delivery of Amphotericin B (Bioral Amphotericin B)
· Nanocochleate-mediated oral delivery of large DNA constructs/plasmids (Bioral DNA Vaccines and Bioral Gene Therapy)
· Nanocochleate-mediated oral delivery of peptide formulations
· Nanocochelate-mediated oral delivery of anti-inflammatory formulations (Bioral Aspirin)
· Autologous HIV Vaccine Development
· Nanocochleate-mediated oral delivery of peptide-based vaccines
These initial animal studies demonstrate that nanocochleate formulations are widely suitable to a broad range of therapeutic applications.
Nanocochleate Cell-Targeted Delivery
The interaction of cations with negatively charged lipids has been extensively studied. Many naturally occurring membrane fusion events involve the interaction of cations with negatively charged phospholipids (generally phosphatidylserine and phosphatidylglycerol interacting with calcium). Cation induced perturbations of membranes containing negatively charged lipids, and the subsequent membrane fusion events, are important mechanisms in many natural membrane fusion processes.
Cochleates can be envisioned as membrane fusion intermediates. During the past several years substantial research by BDSI scientists and their collaborators has demonstrated that nanocochleate formulations are simple, safe and highly efficacious mediators of the in vivo delivery of proteins, peptides and DNA for the induction of antigen specific immune responses following oral, intranasal, and intramuscular administration. Significantly, the ability of nanocochleates to mediate the induction of antigen specific, CD8+ cytotoxic lymphocytes, as well as the efficient induction of immune responses to plasmid encoded antigens, supports the hypothesis that nanocochleates facilitate the cytoplasmic delivery of nanocochleate associated bioactive molecules.
Our observations indicate that, as the cation rich, highly ordered membrane of a nanocochleate first comes into close approximation to a natural membrane, a perturbation and reordering of the cell membrane is induced, resulting in a fusion event between the outer layer of the nanocochleate and the cell membrane. This fusion results in the delivery of a small amount of the encochleated material into the cytoplasm of the target cell. The nanocochleate may slowly fuse or break free of the cell and be available for another fusion event, either with this or another cell. Nanocochleates may also be taken up by endocytosis, and fuse from within endocytic vesicles.