# Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems
## 2 The Evolution of Biodegradable Polymeric Drug Delivery Systems
### Dendrimers  
Dendrimers are a class of well-defined highly-branched macromolecules in contrast to linear polymers. Their architecture is comprised of a common core and discrete dendritic branches radiating out in layers around a central core until a spherical structure is established [89; 90; 91]. In these unique structures (Figure 3), drugs of interest can be contained within the void space of the interior and/or connected onto the surface by chemical modification. Dendrimers have been employed in biomedical applications, including as  
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drug carriers by encapsulation and/or conjugation [92; 93; 94], as well as being utilized as a part of a formulation or as complexing agents [95; 96; 97]. Furthermore, dendrimers as contrast/imaging agents carrying magnetic resonance imaging (MRI) agents and fluorophores have attracted strong interest in research and development [98; 99; 100].  
Compared with traditional linear polymer carriers, there are many advantages for dendrimer carriers. Firstly, by controlled synthesis and their monodisperse nature, an exact number of drugs can be loaded into the carriers and subsequently delivered [102]. Secondly, as dendrimer carriers can undergo two encapsulation processes, physically absorbed and chemically attached, their drug loading abilities are enhanced [91]. Finally, their physicochemical properties are highly correlated with their structures and determine their pharmacokinetics [103; 104]. Thus, a predictable and repeatable release profile can be achieved with appropriate modification and optimization of their structure.  
However, there are some challenges in translation of dendrimer platforms from the research laboratory to the marketplace. The dendrimer platforms are complex systems with multiple components such as dendritic branches, linkers, and encapsulated drugs, and so the design and synthesis processes are complex. For example, with the same components, linking via an ester bond or via an amide bond of the same drug with two possible sites, these dendrimers display totally different activities in vivo [105; 106]. Furthermore, the cytotoxicity and permeability profile are correlated with concentration and surface charge, which means evaluation is challenging and it needs to be conducted on a case-by-case basis.  
In summary, dendrimer carriers have considerable potential in biomedical applications. Notably, most of the first generation of dendrimer-based products are used as imaging agents or as diagnostic devices [107; 108]. The first dendrimer-based product in the therapeutics field (Vivagel) [109] has antiviral and antibacterial properties and is approved for clinical use in Australia and New Zealand. The phase 3 clinical trial results for both the treatment of bacterial vagnosis (BV) (2012) and the prevention of recurrent BV (2017) strongly supported their marketing applications. The New Drug Application (NDA) for VivaGel(r) BV was submitted to the FDA in 2019 under the Fast Track designation.  
Figure 3: Schematic diagram of the general structure of dendrimers. The architecture is comprised of core and interior branching radiating out in layers. The drug of interest can be filled into the void space and/or connected onto the surface (adapted from _Pharmaceutical Technology_, 2008 [101]).