Biotransport kinetics and intratumoral biodistribution of malonodiserinolamide-derivatized [60]fullerene in a murine model of breast adenocarcinoma

Abstract

[60]Fullerene is a highly versatile nanoparticle (NP) platform for drug delivery to sites of pathology owing to its small size and both ease and versatility of chemical functionalization, facilitating multisite drug conjugation, drug targeting, and modulation of its physicochemical properties. The prominent and well-characterized role of the enhanced permeation and retention (EPR) effect in facilitating NP delivery to tumors motivated us to explore vascular transport kinetics of a water-soluble [60]fullerene derivatives using intravital microscopy in an immune competent murine model of breast adenocarcinoma. Herein, we present a novel local and global image analysis of vascular transport kinetics at the level of individual tumor blood vessels on the micron scale and across whole images, respectively. Similar to larger nanomaterials, [60]fullerenes displayed rapid extravasation from tumor vasculature, distinct from that in normal microvasculature. Temporal heterogeneity in fullerene delivery to tumors was observed, demonstrating the issue of nonuniform delivery beyond spatial dimensions. Trends in local region analysis of fullerene biokinetics by fluorescence quantification were in agreement with global image analysis. Further analysis of intratumoral vascular clearance rates suggested a possible enhanced penetration and retention effect of the fullerene compared to a 70 kDa vascular tracer. Overall, this study demonstrates the feasibility of tracking and quantifying the delivery kinetics and intratumoral biodistribution of fullerene-based drug delivery platforms, consistent with the EPR effect on short timescales and passive transport to tumors.

Evaluation of the Biodistribution of Serinolamide-Derivatized C60 Fullerene

“…The DLS measurements showed that C 60 -NOTA conjugate forms uniform aggregates in water with an average diameter of 182 nm and an average polydispersity index of 0.27. These results agreed with the aggregate size that C 60 -serinol itself has shown to form in aqueous solution (median aggregate size 100-200 nm) [47]. These DLS results were also in good agreement with the aggregate size found in the solid state as determined by atomic force microscopy (AFM) images ( Figure S11) which showed the average aggregate size to be 195 nm.…”

“…The ζ-potential of C 60 -NOTA and C 60 -Cu(NOTA) were also investigated to determine the surface charge on the conjugate, which can affect the biodistribution of the material [49]. The ζ-potential of C 60 -NOTA and C 60 -Cu(NOTA) were −22.5 mV and −11.4 mV, respectively, which agrees well with ζ-potential measurements of C 60 -serinol and other water soluble C 60 materials [39,47,50]. The C60-NOTA conjugate was then chelated with nonradioactive Cu 2+ to demonstrate the chelating ability of NOTA while appended to the C60 cage.…”

“…The biodistribution data for C 60 -serinol-PF also showed significant uptake in the heart at greater than 100 h p.i., indicating that the material was still circulating in the blood as a blood-pool agent. In fact, a recent study of C 60 -serinol-PF biotransport kinetics reported that the material does not leak from normal vasculature as it does in tumor vasculature [47], leading to the conclusion that the PF fluorophore converts the C 60 -serinol platform into a blood pool agent.…”

A [60]fullerene nanoconjugate with gemcitabine: synthesis, biophysical properties and biological evaluation for treating pancreatic cancer

“…1 Chemical structure of nanoC 60 -GEM file 1: Fig. S4), and which may be disintegrated into smaller individual fullerenes inside the cell (Lapin et al 2017b). The zeta potential measurements of our gemcitabine nanoconjugate (Additional file 1: Fig.…”

Biological activity of fullerenes - reality and prospects

“…В частности, прижизненная микроскопия применя-лась для изучения внутриутробной кинетики био-трансляции производного C 60 -ser, вводимого вну-тривенно, в подкожных опухолях рака груди 4T1-luc в сравнении с нормальной тканью у живых мышей. Конъюгация C 60 -ser с флуоресцентным красителем PromoFluoro-633 (C 60 -serPF) позволила отслеживать флуоресценцию и относительную количественную оценку C 60 -ser in vivo [99]. Авторы считают, что, по-скольку этот флуорофор (~ 650 Да) сопоставим по размеру и структуре с низкомолекулярными препа-ратами для лечения рака, такими как паклитаксел (854 Да), его можно рассматривать как стерически модельный препарат для исследования C 60 -serPF в качестве носителя лекарственного средства.…”