Predictive Model for Delivery Efficiency: Erythrocyte Membrane-Camouflaged Magnetofluorescent Nanocarriers Study

Delivery
efficiencies of theranostic nanoparticles (NPs) based
on passive tumor targeting strongly depend either on their blood circulation
time or on appropriate modulations of the tumor microenvironment.
Therefore, predicting the NP delivery efficiency before and after
a tumor microenvironment modulation is highly desirable. Here, we
present a new erythrocyte membrane-camouflaged magnetofluorescent
nanocarrier (MMFn) with long blood circulation time (92 h) and high
delivery efficiency (10% ID for Ehrlich murine tumor model). MMFns
owe their magnetic and fluorescent properties to the incorporation
of manganese ferrite nanoparticles (MnFe2O4 NPs)
and IR-780 (a lipophilic indocyanine fluorescent dye), respectively,
to their erythrocyte membrane-derived camouflage. MMFn composition,
morphology, and size, as well as optical absorption, zeta potential,
and fluorescent, magnetic, and magnetothermal properties, are thoroughly
examined in vitro. We then present an analytical
pharmacokinetic (PK) model capable of predicting the delivery efficiency
(DE) and the time of peak tumor uptake (tmax), as well as changes in DE and tmax due
to modulations of the tumor microenvironment, for potentially any
nanocarrier. Experimental PK data sets (blood and tumor amounts of
MMFns) are simultaneously fit to the model equations using the PK
modeling software Monolix. We then validate our model analytical solutions
with the numerical solutions provided by Monolix. We also demonstrate
how our a priori nonmechanistic model for passive
targeting relates to a previously reported mechanistic model for active
targeting. All in vivo PK studies, as well as in vivo and ex vivo biodistribution studies,
were conducted using two noninvasive techniques, namely, fluorescence
molecular tomography (FMT) and alternating current biosusceptometry
(ACB). Finally, histopathology corroborates our PK and biodistribution
results.