Elsevier

Biomaterials

Volume 27, Issue 24, August 2006, Pages 4356-4373
Biomaterials

Review
Parameters influencing the stealthiness of colloidal drug delivery systems

https://doi.org/10.1016/j.biomaterials.2006.03.039Get rights and content

Abstract

Over the last few decades, colloidal drug delivery systems (CDDS) such as nano-structures have been developed in order to improve the efficiency and the specificity of drug action. Their small size permits them to be injected intravenously in order to reach target tissues. However, it is known that they can be rapidly removed from blood circulation by the immune system. CDDS are removed via the complement system and via the cells of the mononuclear phagocyte system (MPS), after their recognition by opsonins and/or receptors present at the cell surface. This recognition is dependent on the physicochemical characteristics of the CDDS. In this study, we will focus on parameters influencing the interactions of opsonins and the macrophage plasma membrane with the surface of CDDS, whereby parameters of the polymer coating become necessary to provide good protection.

Introduction

Colloidal drug delivery systems (CDDS) consist of lipid, natural or synthetic polymer particles, such as liposomes, solid lipid nanoparticles (SLN), poly d,l-lactide (PLA) or poly d,l-lactide-co-glycolide (PLGA) nanoparticles (NP), micelles, etc., encapsulating drugs, nucleic acids or plasmids. Following injection into the bloodstream, many studies have highlighted their rapid removal resulting from their interactions with the mononuclear phagocyte system (MPS) [1], [2] or with the complement system. This premature elimination prevents from reaching the target by using mechanisms such as the accentuated microvascular permeability of the tumor [3]. CDDS are recognized by opsonins such as the complement protein C3b, immunoglobulins G and M, fibronectin and apolipoproteins, or by specific or non-specific receptors present at the surface of the macrophage plasma membrane. Thus, the blood half-life could be accentuated by increasing the amount of injected CDDS, resulting from the fact that the endocytic capacity of macrophages and the amount of opsonins in the blood are limited [3]. Nevertheless, research has dealt with understanding the parameters influencing these interactions in order to escape immune system effects. Long-circulating CDDS, as well as CDDS of which the interest is to be captured by the MPS, have been formulated. Indeed, the latter constitute a line of attack in AIDS strategies [4], or following infection of the macrophages by micro-organisms [5]. Otherwise, CDDS can also be used as adjuvants [6], [7].

In this review, we will focus on the parameters influencing the stealthiness of CDDS such as their size, composition, and apparent electrical charge, as far as their physicochemical surface properties and their own inter-relations in the presence of a polymer coating are concerned. The role of polyethylene glycol (PEG) molecular weight, density, flexibility and spatial conformation in the fate of pegylated CDDS by governing interactions with macrophage receptors or complement proteins will also be described.

Section snippets

The mononuclear phagocyte system

CDDS are generally eliminated by the mononuclear phagocyte system (MPS). This is composed of cells (macrophages and monocytes) able to remove senescent cells from the blood circulation and to provide phagocytic cells to inflammatory sites following their recruitment by cytokines or complement proteins. Macrophage physiology and activation are well described by Adams et al. [8]. The principal phagocytic cells are found in the liver (Kuppfer cells), in the spleen and in bone marrow [9]. CDDS can

The complement system

The complement system is one of the major mechanisms by which foreign bodies are recognized, leading to an immune reaction in response to the intrusion. It constitutes one of the protagonists, with MPS, of the innate immune system. It is composed of about 30 proteins, the plasmatic ones having an enzymatic or binding function, the others being receptors present at the surface of many cells of the immune system [36]. The activation of these proteins (Fig. 2) occurs by enzymatic cleavage in a

The nature of components

Most of time, CDDS are composed of synthetic polymers such as PLA, PLGA, polystyrene (Pst), polymethyl methacrylate (PMMA) or polyalkylcyanoacrylate (PACA) [16], [46], [47], [48], [49], some of these not being biocompatible. Indeed, Cruz et al. [50] showed that in cultured mouse peritoneal macrophages, nanoparticles (NP) of polycyanoacrylate (PCA) induced the production of reactive oxygen species, which caused changes in the cell metabolism of both resident and elicited macrophages.

Coating characteristics

Common coatings are based on polysaccharides and PEG residues. Polysaccharide-coated CDDS were well described in the review of Lemarchand [143]. The most used polysaccharides are dextran, chitosan, and heparin. It has been shown that dextran and its derivatives are strong activators of the complement, especially for high MW (>60 kDa), due to a high availability of their hydroxyl groups. Nevertheless, as already suggested, complement activation can be decreased by grafting sulfonate groups in the

Conclusion

Following intravenous administration, CDDS are rapidly removed via the cells of the MPS or the complement system. This review tempted to enumerate the different mechanisms operating, whether specific or not, and opsonin-dependent or not, but there probably remains unknown mechanisms, interrelated or not, or influencing environmental parameters [27].

Many studies have been performed to establish the relationship between CDDS and the immune system in order to understand the mechanisms involved in

Acknowledgements

This work was supported by the “Inserm/Région des Pays de la Loire” grant. We would like to thank the departmental committee of Maine-et-Loire of “Ligue Contre le Cancer” and the European contract “Biodegradable controlled drug delivery systems” (“BCDDS”) no. QLK3-CT-2001-02226 for the financial support.

References (181)

  • J.K. Gbadamosi et al.

    PEGylation of microspheres generates a heterogeneous population of particles with differential surface characteristics and biological performance

    FEBS Lett

    (2002)
  • A. Rolland et al.

    Flow cytometric quantitative evaluation of phagocytosis by human mononuclear and polymorphonuclear cells using fluorescent nanoparticles

    J Immunol Methods

    (1987)
  • M.F. Zambaux et al.

    Involvement of neutrophilic granulocytes in the uptake of biodegradable non-stealth and stealth nanoparticles in guinea pig

    Biomaterials

    (2000)
  • M.I. Papisov

    Theoretical considerations of RES-avoiding liposomes: molecular mechanics and chemistry of liposome interactions

    Adv Drug Deliv Rev

    (1998)
  • C.P. Sparrow et al.

    A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein

    J Biol Chem

    (1989)
  • F. Liu et al.

    Serum independent liposome uptake by mouse liver

    Biochim Biophys Acta

    (1996)
  • D. Liu et al.

    Liposome clearance from blood: different animal species have different mechanisms

    Biochim Biophys Acta

    (1995)
  • R. van Furth et al.

    Morphological, cytochemical, functional, and proliferative characteristics of four murine macrophage-like cell lines

    Cell Immunol

    (1985)
  • T. Kinoshita

    Biology of complement: the overture

    Immunol Today

    (1991)
  • C.L. Bristow et al.

    Evidence for the binding of human serum amyloid P component to Clq and Fab gamma

    Mol Immunol

    (1986)
  • C. Passirani et al.

    Interactions of nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate) with the complement system

    Life Sci

    (1998)
  • R. Gref et al.

    The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres

    Adv Drug Deliv Rev

    (1995)
  • M.T. Peracchia et al.

    Complement consumption by poly(ethylene glycol) in different conformations chemically coupled to poly(isobutyl 2-cyanoacrylate) nanoparticles

    Life Sci

    (1997)
  • M. Vittaz et al.

    Effect of PEO surface density on long-circulating PLA-PEO nanoparticles which are very low complement activators

    Biomaterials

    (1996)
  • R.H. Muller et al.

    Solid lipid nanoparticles (SLN) for controlled drug delivery–a review of the state of the art

    Eur J Pharm Biopharm

    (2000)
  • F. Chellat et al.

    Metalloproteinase and cytokine production by THP-1 macrophages following exposure to chitosan-DNA nanoparticles

    Biomaterials

    (2005)
  • A. Lamprecht et al.

    Lipid nanocarriers as drug delivery system for ibuprofen in pain treatment

    Int J Pharm

    (2004)
  • A.J. Bradley et al.

    Inhibition of liposome-induced complement activation by incorporated poly(ethylene glycol)-lipids

    Arch Biochem Biophys

    (1998)
  • S. Thiel

    Mannan-binding protein, a complement activating animal lectin

    Immunopharmacology

    (1992)
  • J.T. Derksen et al.

    Interaction of immunoglobulin-coupled liposomes with rat liver macrophages in vitro

    Exp Cell Res

    (1987)
  • T.M. Allen et al.

    Uptake of liposomes by cultured mouse bone marrow macrophages: influence of liposome composition and size

    Biochim Biophys Acta

    (1991)
  • U.R. Nilsson et al.

    Conformational epitopes of C3 reflecting its mode of binding to an artificial polymer surface

    Mol Immunol

    (1993)
  • B. Montdargent et al.

    Regulation by sulphonate groups of complement activation induced by hydroxymethyl groups on polystyrene surfaces

    Biomaterials

    (1993)
  • A. Chonn et al.

    Beta 2 glycoprotein I is a major protein associated with very rapidly cleared liposomes in vivo, suggesting a significant role in the immune clearance of “non-self” particles

    J Biol Chem

    (1995)
  • S.M. Moghimi et al.

    Poloxamers and poloxamines in nanoparticle engineering and experimental medicine

    Trends Biotechnol

    (2000)
  • M.P. Carreno et al.

    Specific antibodies enhance Sephadex-induced activation of the alternative complement pathway in human serum

    Biomaterials

    (1988)
  • F. Roerdink et al.

    Effects of negatively charged lipids on phagocytosis of liposomes opsonized by complement

    Biochim Biophys Acta

    (1983)
  • M.W. Mosesson et al.

    The structure and biologic activities of plasma fibronectin

    Blood

    (1980)
  • J.D. Rossi et al.

    Binding of fibronectin to phospholipid vesicles

    J Biol Chem

    (1983)
  • J.K. Czop

    Phagocytosis of particulate activators of the alternative complement pathway: effects of fibronectin

    Adv Immunol

    (1986)
  • S.M. Moghimi et al.

    Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties

    Prog Lipid Res

    (2003)
  • N. Shibuya-Fujiwara et al.

    Phagocytosis in vitro of polyethylene glycol-modified liposome-encapsulated hemoglobin by human peripheral blood monocytes plus macrophages through scavenger receptors

    Life Sci

    (2001)
  • A. Rigotti et al.

    The class B scavenger receptors SR-BI and CD36 are receptors for anionic phospholipids

    J Biol Chem

    (1995)
  • M.V. Serra et al.

    Enhanced IgG- and complement-independent phagocytosis of sulfatide-enriched human erythrocytes by human monocytes

    FEBS Lett

    (1992)
  • D.V. Devine et al.

    Liposome-complement interactions in rat serum: implications for liposome survival studies

    Biochim Biophys Acta

    (1994)
  • S. Rudt et al.

    In vitro phagocytosis assay of nano- and microparticles by chemiluminescence. III. Uptake of differently sized surface-modified particles, and its correlation to particle properties and in vivo distribution

    Eur J Pharma Sci

    (1993)
  • F. Puisieux et al.

    Polymeric micro and nanoparticles as drug carriers

  • R. Lobenberg et al.

    Macrophage targeting of azidothymidine: a promising strategy for AIDS therapy

    AIDS Res Hum Retroviruses

    (1996)
  • R. Gaspar et al.

    Macrophage activation by polymeric nanoparticles of polyalkylcyanoacrylates: activity against intracellular Leishmania donovani associated with hydrogen peroxide production

    Pharm Res

    (1992)
  • S.M. Moghimi et al.

    Capture of stealth nanoparticles by the body's defences

    Crit Rev Ther Drug Carrier Syst

    (2001)
  • Cited by (665)

    View all citing articles on Scopus
    View full text