# Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems
## 2 The Evolution of Biodegradable Polymeric Drug Delivery Systems
### Layered Double Hydroxy Carriers  
Layered Double Hydroxides (LDHs) belong to the group of layered materials, also known as anionic clays [110]. Compared with other members in the layered materials group, they are lamellar solids with inorganic components [111,112]. The first generation of LDHs comprised natural material, identified, and reported in Sweden in 1842 [113]. After that, a wide range of layered materials was developed and introduced. Generally, they are constructed by brucite-like hydroxide sheets expanding the two-dimensional layers and the exchangeable anions between the layers (Figure 4), which form a three-dimensional structure altogether [114]. The brucite-like layers are typically composed of divalent or trivalent cations with positive charge, whereas the interlayer galleries are made up of anions and water molecules compensating the charge via electrostatic interaction [115]. A large number of divalent or trivalent cations can be used to build the layers (Mg2+, Zn2+, Ni2+, Al3+, Ga3+, Fe3+, or Mn2+, etc. ), whereas the compositions of the interlayer gallery can be selected from simple or complex anions (CO3-, NO3-, Cl-, SO42-, or RCO2-, etc. ), anionic coordination compounds, and even polyoxo materials [117, 118, 119, 120, 121]. The LDH hybrid matrix demonstrates a tunable structure and morphology [111], and with modification of the ordering of cations and charge density of the layers, the physicochemical properties of the interlayer gallery can be consequently adjusted, leading to better biocompatibility [122], which is vitally important for incorporating drug(s) of interest and designing the drug delivery system. Employed as carriers in drug delivery systems, a wide range of molecules can be intercalated with LDHs such as amino acids, peptides, ATP (adenosine triphosphate), vitamins, and even polysaccharides [114, 123]. Because of their unique structures built by cation layers and anion interlayers, drug molecules can be loaded into the interlayer gallery by anion exchange. By adjustment of surface charge, their chemical stability can be adjusted  
Figure 4: Schematic illustration of loading the cisplatin prodrug, disucinatocisplatin (DSCP), into Layered Double Hydroxides through ion exchange (adapted from [PERSON], et al. _Journal of Materials Chemistry B_, 2014 [116]). to various environments [124], leading to controlled release in both rate and site. For instance, in 2004, [PERSON] et al. reported the use of LDHs as a reservoir for folate derivatives facilitating a significant increase in drug delivery efficiency [125]. In another example, a significant decrease in release rate was achieved with a fluvastatin-LDH hybrid [126]. The underpinning rationale was that hydrophobic LDH hybrids have slower release compared with hydrophilic hybrids driven by fast anion exchange and intraparticle drug diffusion. It is important to note that size and morphology can be precisely controlled with LDH hybrids [127; 128] and targeted delivery of drugs to tumour tissue with sustained drug release has been achieved [129; 130; 131]. Since 2000, the use of LDHs as carriers in drug delivery systems has become increasingly attractive [132]. Most therapeutic agents intercalated as guests can be categorized as targeting diseases, such as anti-cancer, anti-inflammatory, and cardiovascular therapy, and so on. Chemotherapy drug-LDH hybrids have been designed and utilized in the past decade [133]. Examples include methotrexate (MTX), 5-fluorouracil, folic acid, camptothecin (CPT), and podophyllotoxin (PPT) [133; 134]. In a series of papers by [PERSON] et al., MTX-LDH hybrids demonstrated a significantly higher penetration rate through the cell membrane [135] and lower cytotoxicity for certain cells [136]. Additionally, the in vitro study of MTX-LDH by [PERSON] et al. showed that the MTX-LDH could achieve the same drug efficacy as MTX alone in spite of the 5000-fold lower concentration in the two osteosarcoma cell lines [137]. In other work by [PERSON] et al.