# Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems
## 2 The Evolution of Biodegradable Polymeric Drug Delivery Systems
### Layered Double Hydroxy Carriers
the MTX released from MgAl-MTX-LDH hybrids showed relatively low release best described by first order kinetics with total release completed within 8 days via diffusion and crystal dissolution mechanisms [138]. 5-Fluorouracil (5-Fu) is a neutral weak acid and an anti-metabolite chemotherapeutic drug. The first 5-Fu associated LDH hybrid was reported in 2005 by [PERSON] et al. [139], which was followed in 2008 by [PERSON] et al. [140]. In their work, the drug-LDH hybrids inhibited cancer cell proliferation more effectively than the parent drug [140]. Moreover, the release profile of 5-Fu-LDH hybrids was pH sensitive such that at the same temperature, there was a higher amount of 5-Fu released at pH 7.2 compared with pH 4.8 [141]. Camptothecin (CPT) and podophyllotoxin (PPT) are cancer therapeutics that inhibit the enzyme, topoisomerase [142]. However, their utility is limited by poor water solubility and low bioavailability, fast metabolic inactivation, and drug resistance [114]. To address these issues, LDH-hybrids were formed. For example, the poor dispersion of CPT was improved by its incorporation into MgAl-LDH with the net result being a marked reduction in survival time of glioma cells in vitro [143]. Moreover, CPT-LDH hybrids prepared by a reconstruction method (intercalation of CPT into a layered gallery by reconstruction) showed enhanced solubility and increased release time in vitro [144]. For PPT-LDH hybrids, they strongly inhibited tumour cell growth compared with bare PPT due to increased circulation time as well as superior tumour cell killing [145; 146]. Non-steroidal anti-inflammatory drugs (NSAIDs) are aromatic organic compounds. Generally, they have readily ionisable carboxylic acid groups, which allow them to intercalate into the layer gallery of an LDH host via ion-exchange [147; 148]. NSAID-LDH hybrids significantly improve drug solubility in an aqueous environment as well as their absorption rate in living organisms [111; 114]. A wide range of NSAIDs, including ibuprofen, fenbufen, naproxen, diclofenac, and indomethacin have been successfully intercalated into LDH hosts through precipitation, ion exchange, and reconstruction methods [150; 151; 152; 153]. Apart from hosting anti-cancer and anti-inflammatory drugs, cardiovascular drugs employed as guests with LDHs have been well investigated [154]. For instance, captopril intercalated with LDH hybrids showed sustained release over 140 min under various pH conditions in vitro (pH 4.60 and pH 7.45, respectively). Notably, release at pH 7.45 was devoid of an initial burst, which is vitally important in controlled delivery [155]. Moreover, the LDHs can be used as carriers for DNA vaccines to enhance in vivo antibody responses [156]. In tumour-bearing mice, DNA/LDH hybrids markedly inhibited tumour growth and prolonged mean survival time [157]. Furthermore, for dental treatment, zero initial burst and remarkably long steady release (up to one year) was achieved by fluoride-LDH hybrids [158,159]. In summary, the unique structure of LDHs means that multiple drug classes can be accommodated in their interlayer gallery or attached to their surface [160]. Drug-LDH hybrids not only successfully deliver the drug(s) of interest to specific cells with an enhanced penetration rate in vitro, but they may also demonstrate steady release without side-effects in vivo [160], both of which are essential for practical applications in drug delivery. However, there are hurdles still to be overcome and improved with regard to drug-LDH hybrid products. For instance, due to the restricted interlayer space [161], only small molecule drugs can be loaded whereas large molecules can only be attached to the surface, which limits the drug-loading rate. Designing and synthesizing LDH-hybrids is challenging as the structures are complex, and there are potential problems with rapid aggregation [162] and decomposition [163].