(409a) Aerosol Nanocomposite Systems Comprised of Cell Membrane-Coated Nanoparticles for the Treatment of Pulmonary Diseases

The lungs are an attractive route for drug delivery applications that offer many advantages, such as a large surface area, high blood flow, and limited enzymatic activity of the lungs, in addition to the ability to directly target lung tissue through aerosol delivery of therapeutics. There has been increasing interest in the aerosol administration of nanoparticles (NP) to achieve controlled delivery of drugs via the lungs to allow for extended release of therapeutics (in particular those that are poorly water soluble), direct targeting to the site of disease, and the potential for NP to penetrate physiological barriers in the lungs such as mucus, tumors, and the air-blood barrier. Our group has developed nanocomposite microparticles (nCmP) that involve drug-loaded biodegradable NP that are encapsulated into microparticles via spray drying. Micron-sized nCmP have the ability to be effectively delivered to the alveolar region of the lungs, while the NP that disassociate from the nCmP have the ability to avoid phagocytosis by alveolar macrophages, thereby acting as a ‘Trojan horse’ system.

Cell membrane coated nanoparticles (CMCNP) have attracted recent attention in the field of NP drug delivery owing to the ability to target diseased tissue and be used in a wide variety of medical applications such as imaging and detoxification. CMCNP are comprised of a base NP core (biodegradable or otherwise) that is coated with a cell membrane comprised from cell such as platelets, red blood cells, immune cells, and endothelial cells. In this work we have developed CMCNP comprised of a drug-loaded biodegradable acetalated dextran core coated with two different lung epithelial cell lines (A549 and H441). The CMCNP were compared with two lipid-coated NP systems (anionic DPPC and cationic DOTAP) and two polymer-coated NP systems (polyethylene glycol (PEG) and polyvinyl alcohol (PVA)). The NP were encapsulated with fluorescent curcumin (CUR) as a model poorly water soluble therapeutic. The CMCNP were then spray dried to form aerosol nCmP. Overall, we sought to determine how varying surface properties affected the ability of NP to internalize into and/or transport across an in vitro pulmonary epithelial barrier in addition their impact on size, surface charge, physicochemical properties, and aerosol dispersion properties.

The NP systems were all ~200nm in diameter and exhibited appropriate surface charges according to their respective coatings - negative for A549 NP, H441 NP, and DPPC NP; positive for DOTAP NP, and neutral for PEG NP and PVA NP. No significant NP toxicity was observed when H441 cells were exposed to the NP, and controlled CUR release from the NP was achieved. CMCNP more readily internalized and transported across a pulmonary H441 cell monolayer and nCmP were produced the exhibit favorable aerosol dispersion properties. Furthermore, A549 CMCNP and PVA NP were administered intratracheally to mice to demonstrate the ability of the NP to be delivered to the alveolar region of the animals’ lungs. In summary, this research demonstrates the first time epithelial lung-based CMCNP and nCmP were fabricated. These systems have the potential to be used in pulmonary drug delivery applications for the treatment of a variety of pulmonary diseases. Future studies will include the elucidation of the ability of CMCNP to cross the air-blood barrier for systemic NP delivery or NP homing to disease tissue.