Lipid-Based Pharmaceutical Nanocarriers for Imaging Applications - Nanotechnology for Biomedical Imaging and Diagnostics - page 53

attached to distearoyl phosphatidylethanolamine (dspE), which is added to the
liposomal nanocarrier formulation during the manufacture. reduced 99m Tc is then
incubated with the HYNiC nanocarriers where it becomes chelated by the HYNiC
on the nanocarrier surface.
Another approach aimed at the amplification of the diagnostic signal using poly-
chelating polymers, for higher loading capacity of reporter molecules, was suggested
[40-42]. since it is rather difficult to enhance the signal intensity from a given reporter
metal in nanovesicles, one may attempt to increase the quantity of carrier-associated
reporter metal (such as gd for mri or 111 in for scintigraphy) [43]. in this design, a
series of single terminus-activated polychelating polymers were synthesized using
poly-l-lysine (pLL) as a main chain and chelating moieties (such as dTpA) as side
groups. These polychelating polymers were additionally modified with a hydro-
phobic residue to assure their firm incorporation into the nanocarrier membrane. As a
result, polychelating amphiphilic polymers (pAp) have been obtained, a family of
copolymers containing a hydrophilic fragment with multiple chelating groups and
relatively short but highly hydrophobic phospholipid fragment on one end of a poly-
meric chain suitable for incorporation into hydrophobic nanocarrier membrane or
micelle core [44]. The chemistry was based on the use of carbobenzoxy (CBZ)-
protected pLL with free terminal amino group, which was used to modify the pLL
chain with the phospholipid anchor, with subsequent CBZ deprotection and incorpo-
ration of dTpA residues at lysine amino groups in pLL. This polychelator was found
to easily incorporate into the liposomal membrane in the process of nanocarrier prep-
aration and sharply increases the number of chelated heavy metal atoms attached to a
single lipid anchor (fig. 3.2, panel A).
As noted by the authors of [45], one of the major challenges in mri is the quanti-
fication of the local concentration of contrast agents. To solve the problem, they have
proposed a multimodal radiolabeled paramagnetic liposomal agent, which allows
for the simultaneous imaging with spECT and mri. spECT-based quantification
permits to determine the concentration of gd and thus deconvolute the mri signal.
The amphiphilic polychelator N,N -(dTpA-polylysyl)glutaryl phosphatidyletha-
nolamine (dTpA-pLL-NgpE) easily incorporates into the liposome membrane or
micelle core in the process of liposome of micelle preparation and sharply increases
the number of chelated gd atoms attached to a single lipid anchor. After the saturation
of polychelator with gd 3+ ions, the elemental analysis has revealed that gd-dTpA-
pLL-NgpE contains about 40% (w/w) gd, which corresponds to 8-10 metal atoms
per single lipid-modified polymer molecule assuming its molecular weight to be
3500-4000da. Higher gd content leads to better relaxivity and, consequently, to
greater mr signal intensity (assuming the gd tissue concentration does not exceed
millimolar range). Additionally, upon the incorporation into the liposome membrane
or micelle core, the NgpE anchor grafted with pAp keeps chelating groups above the
liposomal membrane or within the micelle's corona. in both cases, metal atoms che-
lated into pAp are directly exposed to the exterior water environment and have better
access to the adjacent tissue water protons. This might lead to the corresponding
enhancement of the vesicle contrast properties. As a result, amphiphilic polychelator-
containing nanovesicles have higher relaxation influence on water protons compared