# Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems
## 2 The Evolution of Biodegradable Polymeric Drug Delivery Systems
### Metal-Organic Framework Carriers
The first example of a drug loaded MOF hybrid was reported in 2006 [197]. Ibuprofen was successfully loaded into MIL-100(Cr) and MIL-101(Cr) and their drug loading and release profiles were investigated. MIL-101(Cr) demonstrated extremely high drug loading (up to 60%) and sustained release for up to 6 days [197]. Since the MIL-101(Cr) is toxic due to the chromium ions, biomedical applications are not feasible. Subsequently, a less-toxic MOF material, MIL-53(Fe) was developed. Following loading with ibuprofen, the release profiles in vitro displayed slow sustained release for up to 3 weeks [198]. Based on these findings, a wide range of anticancer and antiviral drugs were investigated with relatively high loading achieved [199], namely, 24% for azidothimidine triphosphate [200] and 16.1% for cidofovir [197, 201]. As zinc ions have low-toxicity, Zn-based MOFs have also been investigated. For instance, 5-fluorouracilacil loaded Zn-MOFs demonstrated high loading (up to 34%) as well as prolonged release for up to a week [202]. Apart from neutral drugs, loading of cationic drugs such as procainamide HCl, which has a short half-life in vivo, into Zn-MOFs, resulted in prolonged release ranging from 20 h to 72 h [203]. Furthermore, based on zirconium-based MOFs, co-delivery of cisplatin and multidrug resistance (MDR) gene-silencing siRNAs demonstrated enhanced chemotherapeutic activity compared with bare cisplatin in vitro [204]. Stimuli-responsive MOFs are also promising for achieving controllable release in response to specific stimuli, such as pH, ions, temperature, magnetic field, light, and pressure [183]. Among them, pH-responsive MOFs are well investigated, especially for cancer therapy [205, 206]. Based upon the low pH of the tumour microenvironment, the release of drug-MOF hybrids could be triggered within this acidic microenvironment, showing enhanced anticancer efficacy as well as being non-toxic to healthy cells [207, 208]. For instance, doxorubicin (DOX) loaded gadolinium-based MOFs demonstrate pH-sensitive release at 44% within 5 days at pH 5.4, whereas only 22% was released after 5 days at pH 7 [209]. In the past decade, multifunctionalized MOFs with a core-shell structure have been widely investigated. Coated with a thin silica layer, drug MOF hybrids showed controlled release. This along with adjustment of the silica shell thickness and increased cellular uptake, led to enhanced anticancer efficacy [210]. Moreover, for stabilizing and slowingdown the release rate, novel lipid layers based on cholesterol or 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-Poly(ethylene glycol) (DSPE-PEG) have been developed. With lipid or lipid-PEG layers, the initial burst release is reduced [211]. In summary, due to their tunable structure and high loading capacity, MOFs are a promising platform for drug delivery systems [181]. However, for practical applications and potential marketable products, they are in their relative infancy. Drug Encapsulation Methods and Mechanisms Underpinning Degradation of Biodegradable Polymeric Based Formulations  
To achieve highly efficient and tunable biodegradable polymeric formulations, multiple techniques have been developed and investigated in drug delivery systems. However, to effectively deploy these systems to produce therapeutic products, there are a number of challenges remaining to be addressed including relatively low drug loading, undesirable release profile in vivo, and control of particle size [212]. These topics are addressed below.