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

Abstract

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 membranecamouflaged 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 (MnFe 2 O 4 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 (t max ), as well as changes in DE and t max 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.

In vivo magnetic nanoparticle hyperthermia: a review on preclinical studies, low-field nano-heaters, noninvasive thermometry and computer simulations for treatment planning

“…Indeed, now is well established that particles smaller than around 5 nm are eliminated from the body through renal clearance, while larger ones use the hepatic clearance route [123]. In most applications using MIONPs the particle sizes are larger than 10 nm, but during biodegradation diameter might be reduced and some smaller nanoparticles could be eliminated through renal clearance [124,125]. In the case of applications with distinct ferrites, the ions eliminated from biodegradation might also be an important toxicity parameter that should be controlled by tuning the amount of magnetic material administrated in the body.…”

“…Second, the 3D geometry of the tumor is reconstructed from two-dimensional ultrasound images by a technique known as freehand 3D ultrasound reconstruction [184]. Finally, to extract information about the location of the nano-heaters, we developed a multifunctional nanocarrier that contains fluorescent tracers in the near infrared, which surface-coat Mn-doped iron oxide-based nanoparticles, so that their location within the tumor can be extracted using the fluorescence molecular tomography (FMT) technique [125,185].…”

Folate-Targeted PEGylated Magnetoliposomes for Hyperthermia-Mediated Controlled Release of Doxorubicin

“…Manganese ferrite (MnFe 2 O 4 ) nanoparticles were synthesized via co-precipitation, as previously described ( Sousa-Junior et al, 2020 ). Briefly, 90 ml of methylamine (CH 3 NH 2 , Sigma-Aldrich) were first diluted in 400 ml of ultrapure water (MilliQ) under magnetic stirring and heating until boiling.…”

Magnetic particle imaging: tracer development and the biomedical applications of a radiation-free, sensitive, and quantitative imaging modality

“…318 The first proposed use of magnetic hyperthermia with iron oxide particles was as early as 1957, 319 yet it remains a prevalent research field today with significant work on the development of novel hyperthermia-tailored nanocarriers. 143,320 Interest as a therapeutic treatment can be attributed to multiple key advantages, including: no fundamental depth limitation, synergy with many other therapies (e.g., chemotherapies), and internalisation of the 'fluidic' heat source. 321 The most frequently used MFH application paradigms are whole-body MFH (Fig.…”