Lipid-Based Pharmaceutical Nanocarriers for Imaging Applications - Nanotechnology for Biomedical Imaging and Diagnostics - page 59

An important analysis of pharmacokinetics of long-circulating (pEg-coated)
nanocarriers was performed by Allen [66]. it clearly follows from this analysis that
association of drugs with carriers such as nanocarriers has pronounced effects of
pharmacokinetic profiles of both the drug and the carrier. The most important conse-
quences of such association for the drug are delayed drug absorption, restricted drug
biodistribution, decreased volume of drug biodistribution, delayed drug clearance,
and retarded drug metabolism [66-68]. All these effects are determined by hindered
interstitial penetration of a drug and lesser drug accessibility for the biological milieu
because of entrapment into nanolipidic vesicle (or other drug carriers). The presence
of protective polymer on the carrier surface changes all these parameters still further
[69]. Thus, while “plain” nanocarriers have nonlinear, saturable kinetics, long-
circulating nanocarriers demonstrate dose-independent, nonsaturable, and log-linear
kinetics [66-68]. The appearance of log-linear kinetics for long-circulating nanocar-
riers (and, evidently, other sterically protected carriers) is explained by a significant
decrease in the first phase of particulate carrier clearance into a high-affinity and
relatively low-capacity system, such as rEs [70]. All pharmacokinetic effects
depend on the route of nanocarrier administration and their size and composition and
always are less expressed for sterically protected pEg carriers [71]. Naturally, many
of these features are common for all long-circulating drugs and carriers including
imaging agents.
3.3 speciaL coNsideratioNs for target visuaLizatioN
via coNtrast-Loaded Lipid NaNocarriers
3.3.1 effect of Nanocarrier properties on the In Vivo Behavior
of the radiolabeled formulation
it was demonstrated earlier that the mean vesicle size is a major factor affecting the
circulation time of “plain” nanocarriers [72]. A nonlinear pharmacokinetics of mLV
was observed, and the variability in the mLV sizes was assumed to be the underlying
reason. The effect of particle size was later studied [73], and the circulation times of
the carriers of identical lipid composition but varying in mean size (200 vs. 400 nm)
were compared in mice. The larger carriers cleared much faster ( t 1/2 = 0.2 h) than the
smaller vesicles ( t 1/2 = 1.5 h). The vesicle in vitro and in vivo properties depend also
on their composition. The lipid composition and the preparation technique determine
the characteristics of the nanocarriers. overall, the use of phospholipids with longer
saturated acyl chains and the inclusion of cholesterol (Chol) yield more stable vesi-
cles. Therefore, for application as a radiopharmaceutical (when the radionuclide is
incorporated in the aqueous phase), the nanocarriers should preferably contain such
components to prevent leakage of the radionuclide from the nanovesicle [59]. The
incorporation of Chol into the liposomal bilayers and the use of sphingomyelin (sm)
and/or phospholipids with long and saturated acyl chains prolong also the vascular
residence of nanocarriers [74-76]. moreover, nanocarriers are cleared from the
circulation by rEs in a dose-dependent manner [77, 78]. it was shown in mice that