(227q) Systemic and Local Biodistribution of Poly(amidoamine) Dendrimer and Highly Pegylated Poly(amidoamine) Dendrimer Via Pulmonary Delivery

Zhong, Q., Wayne State University
Mohammad, A. K., Pharmaceutical International, Inc
Reineke, J., Wayne State University
Merkel, O., Wayne State University
da Rocha, S. R. P., Wayne State University

Many pulmonary diseases including lung infections, cystic fibrosis, chronic obstructive pulmonary disease and various lung cancers are stubborn and even life-threatened, leaving patients in severe physical and spiritual pain.  Many drug-loaded nanocarriers (NCs) against the diseases via intravenous or oral administration result in high systemic concentration but a relatively low amount of drug locally.  In contrast, lung is a potentially ideal target for delivering the drugs and NCs directly due to the capability to avoid first-pass metabolism, enable rapid therapeutic action, high local drug concentration and minimization of systemic adsorption allowing for decreased side effects.  Thus, elucidating the systemic and local distribution of NCs via pulmonary delivery is fundamental and required research before real application.

In this work, the systemic and local pulmonary distribution of poly(amidoamine) dendrimer nanocarriers (DNCs) was investigated in detail.  3rd generation DNCs and highly PEGylated DNCs were prepared and labeled by fluorescent probe Cy3.  The DNCs were delivered into the lungs via both pharyngeal aspiration (PA) and tail intravenous injection (IV).  Pharmacokinetics result showed that the plasma concentration of the DNCs via IV in systemic circulation was much higher than that via PA route within 6.5 hours, and PEGylation conferred DNCs with significantly higher plasma concentration and longer blood circulation residence in both administration routes.  Ex-vivo tissue imaging and DNCs extraction from tissues showed liver, kidneys, and spleen were major accumulating site of the DNCs in IV route, while the DNCs given via PA were mainly found in lungs and lymph nodes.  In addition, cell tagging in conjunction with flow cytometry technique indicated the DNCs were taken up by all four tagged pulmonary cell populations: myeloid, epithelial, endothelial and ciliated cells.  Furthermore, PEGyaltion help the DNCs escape from myeloid cell trapping to some extent.  Therefore, the findings that DNCs can accumulate in lungs and lymph nodes may imply pulmonary delivery is a potentially ideal polymeric nanocarrier administration route for treating lung and lymphatic diseases.     

Key words: Biodistribution; Pulmonary delivery; PAMAM dendrimer; Cell tagging; Lymph nodes