ReviewParameters influencing the stealthiness of colloidal drug delivery systems
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)
- et al.
Long-circulating microparticulate drug carriers
Adv Drug Deliv Rev
(1995) - et al.
Pharmacokinetics of long-circulating liposomes
Adv Drug Del Rev
(1995) Immunomodulating activities of soluble synthetic polymer-bound drugs
Adv Drug Deliv Rev
(2002)- et al.
In vitro evaluation of nanoparticles spleen capture
Life Sci
(1999) - et al.
Cationic albumin conjugated pegylated nanoparticle with its transcytosis ability and little toxicity against blood-brain barrier
Int J Pharm
(2005) - et al.
Subcutaneous and intravenous delivery of diagnostic agents to the lymphatic system: applications in lymphoscintigraphy and indirect lymphography
Adv Drug Deliv Rev
(1999) - et al.
A film tension theory of phagocytosis
J Colloid Interface Sci
(1997) - et al.
Relationship between complement activation, cellular uptake and surface physicochemical aspects of novel PEG-modified nanocapsules
Biomaterials
(2001) - et al.
Phagocytic uptake of fluorescent stealth and no-stealth solid lipid nanoparticles
Int J Pharm
(1998) - et al.
Evaluation of particle uptake in human blood monocyte-derived cells in vitro. Does phagocytosis activity of dendritic cells measure up with macrophages?
J Control Release
(2001)
PEGylation of microspheres generates a heterogeneous population of particles with differential surface characteristics and biological performance
FEBS Lett
Flow cytometric quantitative evaluation of phagocytosis by human mononuclear and polymorphonuclear cells using fluorescent nanoparticles
J Immunol Methods
Involvement of neutrophilic granulocytes in the uptake of biodegradable non-stealth and stealth nanoparticles in guinea pig
Biomaterials
Theoretical considerations of RES-avoiding liposomes: molecular mechanics and chemistry of liposome interactions
Adv Drug Deliv Rev
A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein
J Biol Chem
Serum independent liposome uptake by mouse liver
Biochim Biophys Acta
Liposome clearance from blood: different animal species have different mechanisms
Biochim Biophys Acta
Morphological, cytochemical, functional, and proliferative characteristics of four murine macrophage-like cell lines
Cell Immunol
Biology of complement: the overture
Immunol Today
Evidence for the binding of human serum amyloid P component to Clq and Fab gamma
Mol Immunol
Interactions of nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate) with the complement system
Life Sci
The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres
Adv Drug Deliv Rev
Complement consumption by poly(ethylene glycol) in different conformations chemically coupled to poly(isobutyl 2-cyanoacrylate) nanoparticles
Life Sci
Effect of PEO surface density on long-circulating PLA-PEO nanoparticles which are very low complement activators
Biomaterials
Solid lipid nanoparticles (SLN) for controlled drug delivery–a review of the state of the art
Eur J Pharm Biopharm
Metalloproteinase and cytokine production by THP-1 macrophages following exposure to chitosan-DNA nanoparticles
Biomaterials
Lipid nanocarriers as drug delivery system for ibuprofen in pain treatment
Int J Pharm
Inhibition of liposome-induced complement activation by incorporated poly(ethylene glycol)-lipids
Arch Biochem Biophys
Mannan-binding protein, a complement activating animal lectin
Immunopharmacology
Interaction of immunoglobulin-coupled liposomes with rat liver macrophages in vitro
Exp Cell Res
Uptake of liposomes by cultured mouse bone marrow macrophages: influence of liposome composition and size
Biochim Biophys Acta
Conformational epitopes of C3 reflecting its mode of binding to an artificial polymer surface
Mol Immunol
Regulation by sulphonate groups of complement activation induced by hydroxymethyl groups on polystyrene surfaces
Biomaterials
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
Poloxamers and poloxamines in nanoparticle engineering and experimental medicine
Trends Biotechnol
Specific antibodies enhance Sephadex-induced activation of the alternative complement pathway in human serum
Biomaterials
Effects of negatively charged lipids on phagocytosis of liposomes opsonized by complement
Biochim Biophys Acta
The structure and biologic activities of plasma fibronectin
Blood
Binding of fibronectin to phospholipid vesicles
J Biol Chem
Phagocytosis of particulate activators of the alternative complement pathway: effects of fibronectin
Adv Immunol
Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties
Prog Lipid Res
Phagocytosis in vitro of polyethylene glycol-modified liposome-encapsulated hemoglobin by human peripheral blood monocytes plus macrophages through scavenger receptors
Life Sci
The class B scavenger receptors SR-BI and CD36 are receptors for anionic phospholipids
J Biol Chem
Enhanced IgG- and complement-independent phagocytosis of sulfatide-enriched human erythrocytes by human monocytes
FEBS Lett
Liposome-complement interactions in rat serum: implications for liposome survival studies
Biochim Biophys Acta
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
Polymeric micro and nanoparticles as drug carriers
Macrophage targeting of azidothymidine: a promising strategy for AIDS therapy
AIDS Res Hum Retroviruses
Macrophage activation by polymeric nanoparticles of polyalkylcyanoacrylates: activity against intracellular Leishmania donovani associated with hydrogen peroxide production
Pharm Res
Capture of stealth nanoparticles by the body's defences
Crit Rev Ther Drug Carrier Syst
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