The dendrimer paradox – high medical expectations but poor clinical translation

Abstract

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.

Everything You Always Wanted to Know about Poly‐l‐lysine Dendrigrafts (But Were Afraid to Ask)

“…[6] However, these abiotic macromolecules exhibit some unwanted features considering their cytotoxicity and non-degradability (PAMAM and PEI), low synthetic availability (PAMAM and DPL), non-sustainable synthesis (PAMAM, DPL and PEI), high dispersities (PEI, HPL and LPL), and batch-to-batch variation (PEI and HPL), [7][8][9][10] highlightingt herefore the need of an ew generation of dendritic polymers that overcomet hose major drawbacks for real-worldb io-applications. [11] This reviewa ims at concisely presenting the innovative works reported to date in the literature on av ery recent class of polycationic dendritic polymers, the poly-l-lysine dendrigrafts (DGLs), regarding their chemical and biological features.…”

Thermo-responsive Ruthenium Dendrimer-based Catalysts for Hydrogenation of the Aromatic Compounds and Phenols

“…The physical properties of such hybrid block-copolymers, like solubility, behavior, influenced by light, acidity and salt balance, have been already widely studied by the various science teams [67,68]. However their interests are aimed mainly at the application of PEG or poly(acryl amide) (PAAm) modified dendrimers as possible drug carriers [67][68][69][70].…”

Mix and Match: Coassembly of Amphiphilic Dendrimers and Phospholipids Creates Robust, Modular, and Controllable Interfaces

“…5–7 Polyamidoamine (PAMAM) dendrimers, originally developed by Tomalia as protein mimics with a large number of amide functionalities in the interior and primary amine terminals on the surface, 8,9 have been the most extensively studied for biomedical applications. 7 Recently, amphiphilic dendrimers, constructed from long hydrophobic alkyl chains and PAMAM dendrons, have emerged as newcomers in the drug delivery field.…”