The dendrimer paradox--high medical expectations but poor clinical translation.

This review was written with the intention to critically evaluate the status of dendrimers as drug carriers and find answers as to why this class of compounds has not translated into the clinic despite 40 years of research. Topics addressed and challenged are the current state of dendrimer synthesis, for example the importance for surface multifunctionality and internal functional groups. Large numbers of surface groups are deemed one of the advantages of dendrimers; however, only small amounts of drugs can be conjugated to the surface without altering the dendrimer's performance, for example its solubility. On the other hand, the rarely utilized feature of internal functionalities for drug conjugation would allow drug loading without altering the surface composition and therefore lead to improved carrier-to-active weight ratios, a major concern for industrial drug product development. Synthetic approaches resulting in truly multifunctional nanocarriers based on chemical conjugation are being discussed, involving orthogonal and 'click' chemistries. Random conjugation of drug, imaging agent, and targeting ligand to the surface of pre-existing dendrimers results in poorly-defined compound mixtures that are unlikely to pass regulatory revision and translate into the clinic. Similarly, using dendrimers for physical drug entrapment is an approach with little clinical future because alternative, low-cost carriers are available and have translated to the market. Finally, a case is being made to evaluate other dendritic polymers such as dendrons, dendrigrafts, hyperbranched polymers, and dendronized polymers for delivery applications. Non-spherical shapes and structural flexibility are features generally discussed in vector-based drug delivery applications and therefore criteria worthwhile to evaluate.