Design and Development of Theranostic Nanomedicines - Nanotechnology for Biomedical Imaging and Diagnostics - page 432

(e.g., cannabinoid receptor, sigma receptor, mannose) should be considered alone
or in combination with folate to maximize targeting of theranostic liposomes and
improve their drug delivery and imaging capacity.
There are several preparation methods for liposomes. in 1978, szoka and
papahadjopoulos reported a systematic study for preparation of liposomes where
they correlated the formulation composition to size [98]. This study also lays out
characterization procedures, which involved size measurements, structural integrity
testing, incorporation, and release of a fluorescent dye, as a surrogate for drug
incorporation/release studies and microscopy for structural assessment. They used
phosphatidylcholine (ptdCho), phosphatidylglycerol (ptdgro), and phosphatidyl-
serine (ptdser), purified from egg yolk and bovine brain, and synthetic phosphatidic
acid and dipalmitoyl phosphatidylcholine (pal2ptdCho). The lipids were dissolved
with cholesterol in organic solvent first, and then solvent was removed under reduced
pressure. Then the aqueous phase was added to the dried lipids, and the mixture was
subjected to sonication, extrusion, and freeze-thaw cycles to obtain small-size vesi-
cles. The challenges in these approaches were small scale and use of potentially toxic
organic solvents. since the late 1970s, liposomes were extremely well researched,
and extensive literature exists on liposomal preparation [99]. recent study evaluated
the effects of liposomal composition to its physicochemical properties [100]. it was
found that the greatest mean size and polydispersity values were obtained for lipo-
somes composed of di-oleoyl-phosphatidylcholine (DopC), which contains unsatu-
rated phospholipids. liposome size also increased with incorporation of unsaturated
fatty acids in phospholipid chains due to augmentation of liposome membrane fluidity.
Furthermore, regardless of the preparation methodology, the most important factors
are the hydrophilic/hydrophobic interactions between lipid-lipid and lipid-water
molecules. The input of energy (extrusion, sonication, etc.) will further lead to lipid
molecule rearrangements and thermodynamic equilibrium necessary for overall lipo-
somal stability and performance [101]. it is easy to appreciate that as we increase
formulation complexity of liposomes by introducing one or more imaging agents and
drugs, their effects on the liposome bilayer structure and fluidity cannot be ignored.
however, for theranostic development, liposomes are highly advantageous due to well-
established manufacturing on a large scale and long history as drug delivery systems in
the clinic. here, we focus on those liposomes prepared to carry both drugs and imaging
agents. Depending on the drug chemistry, different drug incorporation approaches are
applied. For example, for small molecules, there are two ways the drug is incorporated
into the liposome: passive entrapment and active loading [94]. in a recent study,
docetaxel was incorporated into Tgps-coated theranostic liposome [102]. D-alpha-
tocopheryl polyethylene glycol 1000 succinate monoester (Tpgs) is a pegylated
vitamin e commonly used in pharmaceutical and food industry as solubilizer and
emulsifier. To incorporate the drug, ethanol injection/evaporation was followed by
ultrasonication and filtration to obtain the final product. Briefly, the drug was passively
incorporated by being codissolved with lipids in ethanol. The imaging agent, quantum
dots, was added to ethanol solution in tetrahydrofuran. Both drug and imaging agent
were introduced at the same time during liposomal formation. This method works well
for lipophilic drugs, while the imaging agent is soluble in organic solvents [102].