(416a) Design of Dendrimer-Doxorubicin Conjugates for Transport Modulation Across in Vitro Pulmonary Epithelium and Their Solution Formulation in Pressurized-Metered Dose Inhalers

Lung cancer is the leading cause of cancer death among both men and women in the United States.  Adenocarcinoma accounts for more than 40% of all lung cancer cases.  Doxorubicin (DOX) is an FDA-approved chemotherapeutic that has been widely used as primary anticancer drug in the treatment of a variety of cancers including lung cancers.  However, rapid elimination, uncontrolled release, and life-threatening cardiotoxicity, has hindered the applicability of DOX and other potent anti-cancer agents.  The potential use of DOX in the treatment of lung adenocarcinoma with DOX is also limited by its low accumulation in the lungs, which is generally administered through systemic route.  The development of polymeric carriers for the modulation of transport, targeting and controlled release of potent anti-cancer agents and their aerosol formulation for local lung delivery is, therefore, of great relevance in the treatment of lung adenocarcinoma.

In this work, a series of PEGylated poly(amidoamine) dendrimer nanocarriers with acid-labile and acid-nonlabile DOX conjugates were synthesized and characterized.  We investigated the effect of PEGylation density (low, medium and high) and number of DOX conjugates (low and medium) on the release of DOX from the dendrimer nanocarrier, in vitro cytotoxicity, and transport of dendrimer nanocarriers across a model of the lung epithelium (Calu-3 cells).  PEGylation retards the release of DOX in acidic medium.  PEGylation density also affects cytotoxicity as seen by a slight increase in IC₅₀ for DOX-conjugated dendrimer compared to free DOX, due to the controlled release of the therapeutic.  PEGylation degree significantly helped dendrimer nancarriers escape mucus trapping compared to bare dendrimer, aiding their transport to the basolateral side.  Reduced transepithelial electrical resistance (TEER) and limited cellular internalization demonstrated that paracellular transport plays a vital role in transporting dendrimer-DOX conjugates across airway epithelium.  The PEGylated dendrimer-DOX conjugates were directly formulated in the propellant-based metered-dose inhalers (pMDIs) without the aid of any surfactants and co-solvents, forming a solution aerosol formulation.  The solution formulation tends to deliver dendrimer-DOX conjugates with high efficiency to the alveolar region (up to 80%).  The results suggest the targeting, transport, release and formulation of the dendrimers can be controlled by careful design of the nanocarriers.