Elsevier

Journal of Controlled Release

Volume 326, 10 October 2020, Pages 181-191
Journal of Controlled Release

Fast processes of nanoparticle blood clearance: Comprehensive study

https://doi.org/10.1016/j.jconrel.2020.07.014Get rights and content

Abstract

Blood circulation is the key parameter that determines the in vivo efficiency of nanoagents. Despite clinical success of the stealth liposomal agents with their inert and shielded surfaces, a great number of non-stealth nanomaterials is being developed due to their potential of enhanced functionality. By harnessing surface phenomena, such agents can offer advanced control over drug release through intricately designed nanopores, catalysis-propelled motion, computer-like analysis of several disease markers for precise target identification, etc. However, investigation of pharmacokinetic behavior of these agents becomes a great challenge due to ultra-short circulation (usually around several minutes) and impossibility to use the invasive blood-sampling techniques. Accordingly, the data on circulation of such agents has been scarce and irregular. Here, we demonstrate high-throughput capabilities of the developed magnetic particle quantification technique for nanoparticle circulation measurements and present a comprehensive investigation of factors that affect blood circulation of the non-stealth nanoparticles. Namely, we studied the following 9 factors: particle size, zeta-potential, coating, injection dose, repetitive administration, induction of anesthesia, mice strain, absence/presence of tumors, tumor size. Our fundamental findings demonstrate potential ways to extend the half-life of the agents in blood thereby giving them a better chance of achieving their goal in the organism. The study will be valuable for design of the next generation nanomaterials with advanced biomedical functionality.

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.

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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

References (67)

  • M.P. Nikitin et al.

    Multiplex biosensing with highly sensitive magnetic nanoparticle quantification method

    J. Magn. Magn. Mater.

    (2018)
  • J. Wells et al.

    Probing particle-matrix interactions during magnetic particle spectroscopy

    J. Magn. Magn. Mater.

    (2019)
  • S.L. Znoyko et al.

    Ultrasensitive quantitative detection of small molecules with rapid lateral-flow assay based on high-affinity bifunctional ligand and magnetic nanolabels

    Anal. Chim. Acta

    (2018)
  • S.H. Crayton et al.

    ICP-MS analysis of lanthanide-doped nanoparticles as a non-radiative, multiplex approach to quantify biodistribution and blood clearance

    Biomaterials

    (2012)
  • T. Liu et al.

    RES blockade: a strategy for boosting efficiency of nanoparticle drug

    Nano Today

    (2015)
  • C. Fang et al.

    In vivo tumor targeting of tumor necrosis factor-alpha-loaded stealth nanoparticles: effect of MePEG molecular weight and particle size

    Eur. J. Pharm. Sci.

    (2006)
  • A.P. Herrera et al.

    Monitoring colloidal stability of polymer-coated magnetic nanoparticles using AC susceptibility measurements

    J. Colloid Interface Sci.

    (2010)
  • V.R. Cherkasov et al.

    Nanoparticle beacons: supersensitive smart materials with on/off-switchable affinity to biomedical targets

    ACS Nano

    (2020)
  • J.M. Caster et al.

    Investigational nanomedicines in 2016: a review of nanotherapeutics currently undergoing clinical trials

    Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol.

    (2017)
  • A.C. Anselmo et al.

    Nanoparticles in the clinic

    Bioeng. Transl. Med.

    (2016)
  • A.C. Anselmo et al.

    Nanoparticles in the clinic: an update

    Bioeng. Transl. Med.

    (2019)
  • L. Cheng et al.

    Organic stealth nanoparticles for highly effective in vivo near-infrared photothermal therapy of cancer

    ACS Nano

    (2012)
  • N.J. Butcher et al.

    Drug delivery: unravelling the stealth effect

    Nat. Nanotechnol.

    (2016)
  • V.M. Petriev et al.

    Nuclear nanomedicine using Si nanoparticles as safe and effective carriers of 188Re radionuclide for cancer therapy

    Sci. Rep.

    (2019)
  • E.C. Cho et al.

    The effect of sedimentation and diffusion on cellular uptake of gold nanoparticles

    Nat. Nanotechnol.

    (2011)
  • H. Hatakeyama et al.

    The polyethyleneglycol dilemma: advantage and disadvantage of PEGylation of liposomes for systemic genes and nucleic acids delivery to tumors

    Biol. Pharm. Bull.

    (2013)
  • M.-X. Wu et al.

    Metal-organic framework (MOF)-based drug/cargo delivery and cancer therapy

    Adv. Mater. Weinheim.

    (2017)
  • S. Saha et al.

    Gold nanoparticle reprograms pancreatic tumor microenvironment and inhibits tumor growth

    ACS Nano

    (2016)
  • I.V. Zelepukin et al.

    Nanoparticle-based drug delivery via RBC-hitchhiking for the inhibition of lung metastases growth

    Nanoscale

    (2019)
  • Z. Zhao et al.

    Erythrocyte leveraged chemotherapy (ELeCt): nanoparticle assembly on erythrocyte surface to combat lung metastasis

    Sci. Adv.

    (2019)
  • A.J. Tavares et al.

    Effect of removing Kupffer cells on nanoparticle tumor delivery

    Proc. Natl. Acad. Sci. U. S. A.

    (2017)
  • Stefan Wilhelm et al.

    Analysis of nanoparticle delivery to tumours

    Nat. Rev. Mater.

    (2016)
  • H. Wang et al.

    Diagnostic imaging and therapeutic application of nanoparticles targeting the liver

    J. Mater. Chem. B

    (2015)
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    These authors contributed equally to this work.

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