Dendrimer based delivery of therapeutic agents for thrombolysis and asthma

Dendrimers are highly branched, nearly monodisperse polymers with well defined architecture. As a result of their high branching density they can incorporate a large number of functional groups (i.e. to achieve high drug payloads) compared with their linear counter-parts. Therefore, dendrimers have generated a great deal of interest for medicinal purposes such as drug delivery, gene delivery and MRI imaging. In addition to being able to achieve high drug payloads, dendrimers have been shown to improve the cell entry of several drugs; however, the mechanism for dendrimer uptake is not well understood. To address this issue, we have studied the uptake of PAMAM dendrimers into A549 lung epithelial cells by using various endocytotic inhibitors to block specific transport mechanisms. We have also studied the influence of dendritic surface functionality on the uptake mechanism. These studies suggest that the carboxyl dendrimer is taken up by a caveolae receptor mediated mechanism while the hydroxyl and amine dendrimers are taken up by non-specific cellular interactions. We have also successfully synthesized and characterized conjugates of PAMAM dendrimers with streptokinase (thrombolytic agent) and methylprednisolone (asthma drug). The thrombolytic protein has retained 80% of its therapeutic activity after conjugation. To the best of our knowledge this is the first study that shows that a high molecular weight therapeutic protein (streptokinase) can be attached to a dendrimer with significant amount of protein activity retained. In the case of the dendrimer-asthmatic drug conjugate the anti-inflammatory effect is higher than that of the free drug, due to the longer lung residence time of dendrimer. This may result in a reduction in the quantity of asthmatic drug required to treat an asthmatic attack.