# Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems
## 2 The Evolution of Biodegradable Polymeric Drug Delivery Systems
### Liposomes  
The earliest nanoscale research began with liposome and polymer-drug conjugates. First generation liposomes were introduced in the early 1980s and the aim was to reduce cardiac uptake whilst preserving the anti-tumour activity of adriamycin [50]. However, due to its relatively rapid uptake into the bloodstream, this pioneering formulation type achieved only a limited therapeutic benefit, thereby impeding more widespread application [51; 52; 53]. The second generation of liposomes was developed as a means to enhance the stability and circulation time in the bloodstream. As poly(ethylene glycol) (PEG) was introduced into the structure to form sterically-stabilized liposomes, they are normally named PEGylated liposomes [54]. The PEG chain connected on the surface of the liposome establishes a steric barrier preventing opsonisation, leading to a longer half-life [52] as well as reduced drug-related side effects [55; 56; 57]. However, the general drawback of PEGylated liposomes is that they impair the approaching ability and interaction with target membranes [58]. To address this problem, a large variety of liposomal structures that shed their PEG coat have been designed such as attaching PEG to short acyl chains or co-administration with uncoated vesicles to act as a sink [59]. Promising ligand-targeted liposomes have emerged in this decade aimed at delivering drugs selectively to designated cell types or organs in vivo that express or over-express specific ligands at the site of the disease [60; 61]. Generally, liposomes are phospholipid vesicles comprised of a discrete aqueous phase core enclosed by one or more concentric lipid bilayers (Figure 2). Many types of ligands are possible including peptide, protein, antibody, small molecule, and carbohydrate. Although the application of ligand-targeted liposomes is potentially broad, limitations on the performance of immunoliposomes have been reported [62,63]. To overcome the limitations of currently available site-specific liposomal carriers, a new generation of liposomal platforms has been designed and introduced [64]. The key strategy integrates advantages of different types of liposomes and establishing a hybrid structure. For instance, adding PEG chains to immunoliposomes can sterically stabilize and improve their pharmacokinetics [65,66,67]. Compared to conventional formulations, liposome formulations should demonstrate better efficacy and/or reduced side effects compared with their conventional counterparts or existing therapies in clinical trials before successfully entering the market. Apart from products currently marketed (Table 1), there are a number of liposomal formulations currently in clinical trials, and these are also summarized in Table 1. Although there are still some challenges to be overcome, liposomal formulations have a promising future. \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Encapsulated** & **Regulatory** & **Product Name** & **Treatment** & **Annual Sales** & **Delivery System** & **References** \\
**Drug** & **Approval Year** & **Product Name** & **Treatment** & **Annual Sales** & **Delivery System** & **References** \\ \hline Small interfering & 2018 & Onpattro® & Peripheral never disease & 166.4 million (2019) & Liposomal injection & [68] \\ \hline \multirow{4}{*}{\begin{tabular}{c} Daunorubicin \\ and cytarabine \\ \end{tabular} } & \multirow{4}{*}{2017} & \multirow{4}{*}{Vyxeos®} & Therapy-Related Acute Myeloid Leukemia (t-AML) & \(\sim\)100 million (2018) & Liposomal injection & [69] \\ \hline \multirow{4}{*}{\
\begin{tabular}{c} Irinotecan \\ \end{tabular} } & \multirow{4}{*}{2015} & \multirow{4}{*}{Onivyde®} & Metastatic pancreatic adenocarcinoma (2016) & Liposomal injection & \multirow{4}{*}{[70]} \\  & & & (mPAC) & & & \\ \hline \multirow{2}{*}{
\begin{tabular}{c} Doxorubicin \\ \end{tabular} } & \multirow{2}{*}{2013} & \multirow{2}{*}{Lipo-Dox®} & Some types of cancers & \(\sim\)800 million (2015) & Liposome injection & [71] \\ \hline \hline \end{tabular}
\end{table}