Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 338

• The drugs/agents are “encapsulated” as is, namely, in their
native form without the need of covalent binding or other
chemical modification;
• For hydrophilic and amphipathic drugs/agents, encapsulation
is “passive” in nature, which means it is done during the
process of liposome fabrication. For amphipathic drugs/
agents, encapsulation is determined mainly by the interaction
of the drug/agent with the liposomal membrane (Barenholz,
2003; Kedar et al., 1994a, 1994b; Joseph et al., 2006; Even-
Or et al., 2010). For water-soluble drugs, the encapsulation
is determined by two main parameters: drug/agent degree
of solubility in the lipid hydration medium and the liposome
trapped aqueous volume (Barenholz, 2001, 2003, Grant et
al., 2001). This means that for most applications of water-
soluble drugs that require nano-liposomes, the passive
loading approaches are a poor option (especially for drugs/
agents having poor aqueous solubility) as the product
will have a drug-to-lipid ratio that is too low for achieving
therapeutic drug concentration for human use. For example
the therapeutic dose of doxorubicin is ~ 50 mg/m 2 (~100 mg
per each administration);
• The pharmacokinetics (PK) and biodistribution (BD) of the
drug/agent encapsulated are modified to a large extent by
being encapsulated in liposomes, especially to achieve high
accumulation in the RES and to avoid many other tissues
(e.g., heart). This can be controlled to some extent by the
physicochemical properties of the liposomes [size distribution,
electrical charge, and level of rigidity (fluidity)];
• The physicochemical properties can be controlled by liposome
lipid composition and method of liposome preparation;
• Phospholipids, glycolipids, and sterols, which are the main
building blocks of liposomes, are of natural sources, or are semi-
synthetic or fully synthetic, having natural stereochemistry,
and therefore believed to be biocompatible.
In the 1980s, the overall expectation of liposomes as a broad
spectrum drug delivery system was low. This was summarized in
an almost “lethal” (to the medical application of liposomes) Cancer
Research paper by Poste et al. (1982). This 1982 important paper
claimed the following: