Dendrimers are routinely synthesized as tuneable nanostructures that may be designed and regulated as a function of their size, shape, surface chemistry and interior void space. They are obtained with structural control approaching that of traditional biomacromolecules such as DNA/RNA or proteins and are distinguished by their precise nanoscale scaffolding and nanocontainer properties. As such, these important properties are expected to play an important role in the emerging field of nanomedicine. This review will describe progress on the use of these features for both targeted diagnostic imaging and drug-delivery applications. Recent efforts have focused on the synthesis and pre-clinical evaluation of a multipurpose STARBURST PAMAM (polyamidoamine) dendrimer prototype that exhibits properties suitable for use as: (i) targeted, diagnostic MRI (magnetic resonance imaging)/NIR (near-IR) contrast agents, (ii) and/or for controlled delivery of cancer therapies. Special emphasis will be placed on the lead candidate, namely [core: 1,4-diaminobutane; G (generation)=4.5], [dendri-PAMAM(CO(2)Na)(64)]. This dendritic nanostructure (i.e. approximately 5.0 nm diameter) was selected on the basis of a very favourable biocompatibility profile [The Nanotechnology Characterization Laboratory (NCL), an affiliate of the National Cancer Institute (NCI), has completed extensive in vitro studies on the lead compound and have found it to be very benign, non-immunogenic and highly biocompatible], the expectation that it will exhibit desirable mammalian kidney excretion properties and demonstrated targeting features.
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.
The U.S. National Institutes of Health through the National Cancer Institute (NCI) have been charged with the goal of eliminating death and suffering from cancer by the year 2015. In order to achieve this very ambitious goal, the development of novel nanotechnology-based devices and therapeutics that are capable of one or more clinically important functions is envisioned. There is great hope and expectation in the development of theranostic nanocarriers, which combine diagnostic and therapeutic agents in one entity. Main delivery approaches include prodrugs, liposomes, polymersomes, and polymeric micelles and nanoparticles. Diagnostic and therapeutic agents are physically entrapped or conjugated to the nanocarriers, or they are conjugated to carefully designed polymers which subsequently form nanocarriers. This focus discusses pros and cons of the different theranostic approaches and tries to answer the question which approach has the highest probability to translate into the clinic and benefit patients. Carefully designed polymers, conjugated with diagnostic and therapeutic agents, that either self-assemble or can be processed to form nanocarriers offer clear advantages over random physical entrapment or conjugation of these agents to existing nanocarriers. These polymers can optionally be fitted with terminal stabilizing or anchoring functionalities and a targeting ligand. However, the need for nanocarriers that are subjected to the enhanced permeability and retention (EPR) effect to carry ligands for active targeting still needs to be demonstrated. Thirty-seven of the 41 nanocarrier-based formulations that are on the market or are under investigation at different levels of clinical development rely on passive targeting. The answer to the title question, not surprisingly, can only be no, but very promising approaches are being developed that have the potential to translate into the clinic and meet regulatory requirements.
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