Fast processes of nanoparticle blood clearance: Comprehensive study
Graphical abstract
With the real-time magnetic particle quantification technique, we performed investigation of factors that influence blood circulation of non-stealth nanoparticles: from nanoagent properties to aspects of tumor growth.
Introduction
Currently, various nanoparticles (NP) are actively employed as carriers due to their abilities to transport large drug payload, possibility for active targeting, and many others [[1], [2], [3]]. Along with the NP reported in numerous research studies, many therapeutic and diagnostic nanoagents are presently at the stage of pre-clinical and clinical trials [4], and some nanoagents have been already approved for use in humans [5,6].
Polyethylenglycol (PEG) coated stealth nanoparticles have long been sought after as carriers for drug delivery [7]. PEG decreases opsonin adsorption on the particle surface and prevents NP recognition and uptake by macrophages. Despite the highly valuable advantage of prolonged blood circulation for stealth nanoparticles [[8], [9], [10]], coating them with polyethylenglycol brings some negative aspects. For example, it can lead to the development of immune response to the NP injection [11], complicate the penetration of particles into cells [12] and its endosomal escape [13], etc.
Therefore, recent studies demonstrate growing interest in the design of non-stealth nanoagents without hiding coating on the surface. It was shown that such nanoparticles can be highly efficient for delivery to tumors, sufficient for therapeutic treatment [14,15], even if they are completely cleared from the bloodstream within the first few minutes [16,17]. Also, a major part of the NP, approved for human treatment or tested in clinical trials, are non-PEGylated particles [5,6].
To develop novel nanoagents of advanced diagnostic and therapeutic capacity and to promote already efficiently operating in vitro nanosystems for medical use, it is necessary to assess NP pharmacokinetics in the organism. The information on the dynamics of circulation in the bloodstream and behavior during the first hour after administration [18,19] is of prime importance for a nanoagent. It is known that longer particle circulation is usually associated with their better tumor accumulation for both passive and active delivery strategies [20,21]. Besides, deviations in blood clearance of nanoparticles can be used for diagnostics of certain diseases, e.g., for assessing liver condition [22] or severity of thrombocytopenia [23].
The nanoparticle circulation in the bloodstream is currently studied primarily through various blood-sampling methods [24,25]. These invasive techniques, though, cannot provide the time resolution required for analysis of the behavior of many non-stealth nanoagents.
Invasive manipulations with laboratory animals may affect the kinetics of the particles clearance, e.g., due to reduction of blood volume in the organism, resulting in a high pulse rate and blood pressure variation [26], as well as in reduction of the total number of leukocytes and significant decrease in the activity of the natural killer cells [27].
Recently, non-invasive methods have appeared for real-time analysis of pharmacokinetics, e.g., intravital microscopy (fluorescence microscopy [28,29] or optoacoustic microscopy [30]). Nevertheless, because of high background signals and required delivery of light to the nanoparticles, both methods are primarily intended for analysis of small tissue fragments - one or several surface vessels [31]. Besides, the methods involve animal immobilization, associated with an increased level of stress.
With the superparamagnetic iron oxide nanoparticles (SPIONs) there are several non-invasive magnetic methods of the pharmacokinetic analysis [[32], [33], [34]]. The majority of the widely used approaches, such as MRI [32] and AC susceptometry [33], are calibrated only within a narrow range of concentrations.
The non-invasive methods for real-time quantitative measurements of NP pharmacokinetics in a wide range of concentrations are still to be developed. This acute shortage of high-quality methods has led to dramatically poor understanding of the fundamental aspects of behavior in vivo of short-lived non-stealth nanoagents.
Here, we consider in detail the use of magnetic particle quantification (MPQ) technology for comprehensive study of magnetic particles blood circulation. Non-invasiveness and high time resolution of this method has permitted to compare the influence of a broad range of parameters on the blood circulation kinetics of the non-stealth nanoagents. We demonstrate that the NP pharmacokinetics is affected not only by the surface properties of the particles, but also by the particularities of their administration, and the used animal model.
Section snippets
Chemicals
Nitric acid, Ammonium hydroxide, Iron(III) chloride hexahydrate, Iron(II) chloride tetrahydrate, Cobalt(II) chloride hexahydrate, Sodium chloride, Agarose, Formaldehyde, Potassium hexacyanoferrate (II) trihydrate, Hydrochloric acid, Eosin, Carboxymethyl-dextran sodium salt, Ferritin from horse spleen (Sigma-Aldrich, Germany); Zoletil (Virbac, France); Rometar (Bioveta, Czech Republic); Fetal bovine serum (HyClone, USA); DMEM-F12, Trypsin-EDTA in Hank's balanced salt solution (PanEco, Russia).
Nano-and microparticles
Non-invasive registration of nanoparticle concentration in the bloodstream
In this research, the circulation of non-stealth NP was recorded in the bloodstream of living animals non-invasively with high temporal resolution due to the employed registration technique of MPQ. Fig. 1 illustrates the measuring setup and the general principle of detection. The nanoparticles were administered to an animal and then quantified in its tail inserted in the measuring coil of the MPQ reader. The method employs non-linear response of superparamagnetic nanoparticles in an alternating
Conclusion
The unique combination of high sensitivity, noninvasiveness, quantitative accuracy and the possibility of real-time detection makes the MPQ technique one of the most convenient methods for investigation of nanoagent pharmacokinetics. The method may be used in large-scale studies to reveal new fundamental aspects of the nanoparticle clearance from blood. We believe that deeper understanding of the underlying mechanisms may considerably facilitate the rational design of non-stealth nanomaterials
Declaration of Competing Interest
P.I.N. is a named inventor on patents on MPQ.
Acknowledgements
The work was partially supported by the grant of the Russian Science Foundation 16-19-00131 (study of the influence of nanoparticle properties on pharmacokinetics) and by the grants of the Russian Foundation for Basic Research 19-29-04012 (nanoparticle synthesis and characterization, tumor study), 17-00-00121 (17-00-00122) (animal model study), 18-29-04065 ( injection conditions study; biodistribution study) and 19-33-51011 (ICP-MS study). The authors acknowledge the support from the MEPhI
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These authors contributed equally to this work.