Every year thousands of potential active pharmaceutical ingredients (APIs) are rejected during production. This occurs at various stages with research and development being the most prominent. Many highly active compounds made during development suffer from poor bioavailability due to poor water solubility and/or cell membrane permeability. Even though these compounds may have high affinity for their target, desirable pharmacokinetics and good efficacy, they are not able to be progressed further due to safety concerns arising from the high dose required for optimal therapeutic effect. At high doses these APIs can exhibit significant off-target effects, therefore will not pass through thorough safety testing or will not show an improvement over current on the market medications. About forty percent of newly developed APIs are affected by poor bioavailability and therefore rejected by pharmaceutical companies with an additional seventeen percent of existing APIs suffering from suboptimal performance. A growing need for new drug delivery systems which can enhance bioavailability is of high importance.
As polymer science has evolved over the past two centuries the emergence of nanoscience has led to many macromolecular structures being synthetically accessible. Control over size, topology, chemistry and properties of these structures has led to various applications such as drug delivery. Nanostructures are an attractive target for drug delivery as drug carriers should generally be in the nanometer range and uniform in size. This enhances their ability to cross cell membranes, reduces cellular clearance in the both the liver and spleen and as they exceed the renal threshold and are therefore generally not filtered out by the kidneys.
Dendrimers provide an attractive platform for the delivery of APIs. Dendrimers are well defined macromolecules that are synthesized in layers, known as generations, around a central core unit. Their layered structure allowed for control over size, branching points, surface groups and properties which makes them desirable carriers for small molecules.
There are five main properties that make dendrimers a useful tool for drug delivery. (i) Container properties (i.e. encapsulation), (ii) scaffolding properties (i.e. surface attachment), (iii) biocompatibility, (iv) their layered nature allows tuning to meet specific requirements of the API and (v) size. This review will explore PAMAM dendrimers, their toxicity and applications in drug delivery.