# Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems
## 2 The Evolution of Biodegradable Polymeric Drug Delivery Systems
### Metal-Organic Framework Carriers  
Metal-organic frameworks (MOFs) are hybrid inorganic-organic materials that have emerged in the past decade, whereby the structure (Figure 5) is formed by self-assembled metals and organic linkers under mild conditions [164]. Generally, the metal containing nodes are made of a single-metal, transition metal, or a group of metals while the organic linkers are made of polycarboxylates, phosphonates, sulphonates, imidazonates, and phenolates, etc. [165,166]. Multi-dentate linkers such as di-carboxylates or tri-carboxylates allow the aggregation of metal ions into their cluster. After metal ions are locked into their position in the network vertex by carboxylates, rigid frameworks are established [167]. Their distinct physiochemical properties such as high pore volumes, tuneable pore size, and large surface areas enable them to encapsulate a wide range of drug agents, especially for large molecule drugs [168], leading to potential applications in drug delivery [169, 170, 171, 172]. Generally, there are two main methods for encapsulating drugs into MOFs, namely, non-covalent and covalent [174]. The non-covalent method is the traditional method that is used widely and involves impregnating the porous MOFs into a solution of drug molecules and trapping the drug [175]. The advantage is that the method can be applied to a variety of drugs, regardless of their hydrophilic or hydrophobic physicochemical properties. However, as drug encapsulation is an inherently reversible process, premature release of the drug(s) of interest may be observed [176]. To overcome this problem, covalent methods have been developed [177], whereby the drug molecule is entrapped by tethering it to the MOF surface via a covalent bond [178]. For example, loading of cisplatin into an  
Figure 5: Schematic illustration of MOFs structure and functional applications (adapted from [PERSON] et al., 2019 [173]). amino-functionalized MIL-101 (Fe) using a covalent method and covered with a silica layer, achieved relatively high loading (12.8%) and a prolonged release time (up to 14 h) [179]. For use of this method, the MOF surface should have specific functional groups [180] that interact with the functional group(s) of the drug(s) of interest to facilitate covalent attachment [181, 182]. Additionally, the chemical bond should be cleavable from the MOFs under specific biological conditions [164, 183, 184]. Typically, the release of encapsulated drug is via diffusion through the pores on the surface as well as degradation of the matrix [185, 186, 187]. There are three factors that significantly affect the release profile: (i) the interaction between the drug and the matrix surface; (ii) the size of pores on the surface; and (iii) the kinetics of matrix degradation [188]. Thus, controlled release may be achieved, by controlling interactions between encapsulated drugs and MOFs, modulation of the pore size and surface area as well as regulation of degradation rate [189, 190, 191]. There are several advantages distinguishing the MOFs from other materials. Firstly, their physicochemical properties can be adjusted along with the modification of the metal and organic linker components [192, 193], which means that the pore size and surface morphology are highly tunable [194]. Secondly, as the surface area is large compared with other materials, the potential drug loading capacity is relatively high [195]. Furthermore, the pore size on the surface is large (up to 6 nm), enabling them to accommodate large molecule drugs [196]. However, for practical drug delivery applications, non-toxic or low toxicity MOFs with good biocompatibility properties need be developed. Moreover, systematic assessment of stability and a comprehensive understanding of the release mechanisms of drug-MOF hybrids in vitro and in vivo are essential for development of clinical applications [183]. Typically, for drug delivery applications, MOFs are categorized as individual MOF carriers or stimuli-responsive MOF carriers [183].