Particulate nanomedicines.
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Diagnostic Techniques and Procedures↗
Biomedical subjects
S M Moghimi
Publications and source records attributed to S M Moghimi.
The effect of methoxy-PEG chain length and molecular architecture on lymph node targeting of immuno-PEG liposomes.
The rate of drainage and lymphatic distribution of subcutaneously injected liposomes is controlled by inclusion of methoxypoly(ethyleneglycol), mPEG-phospholipid into the liposomal bilayer. The effect is most dramatic with liposomes containing 15 mol% mPEG-lipid, with an average PEG molecular mass of 350 Da. These vesicles are drained rapidly from the injection site into the initial lymphatics when compared to unmodified liposomes, and are retained more favourably by the scavengers of the regional lymph node. Liposomes decorated with longer surface mPEG chains (6.7 mol% of mPEG2000-lipid) exhibit faster drainage rates than vesicles having 15 mol% mPEG350-lipid in their lipid bilayer, but their lymph node retention is very poor. The lymph node retention of rapidly drained PEG-bearing vesicles was increased dramatically following conjugation of a non-specific IgG to the distal end of PEG, using a functionalized PEG2000 lipid. Adjusting the molecular architecture of surface mPEG and IgG-PEG chains to a "nearly overlapped mushroom" regime further enhanced target recognition of immuno-PEG2000 liposomes without compromising their drainage rate from the interstitium. The lymph node retention of these vesicles was further optimized by enriching their lipid bilayer with 20 mol% phosphatidylserine. These approaches have established important compositional and structural variables that control lymphatic targeting of immuno-PEG liposomes and their application in experimental medicine and biology is discussed.
Animals↗
Cellular distribution of nonionic micelles.
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Animals↗
Real-time evidence of surface modification at polystyrene lattices by poloxamine 908 in the presence of serum: in vivo conversion of macrophage-prone nanoparticles to stealth entities by poloxamine 908.
Intravenously injected polystyrene nanoparticles, which are prone to rapid sequestration by professional phagocytes, are converted to stealth entities by prior bolus intravenous injection of poloxamine 908. This behaviour is not due to alteration in macrophage phagocytic activity. Laser Doppler anemometry and surface plasmon resonance were used to unravel the mechanisms fundamental to generation of such stealth entities in vivo by poloxamine 908. Electrophoretic mobility of poloxamine pre-coated monodisperse polystyrene nanoparticles in serum, which behave as stealth entities in vivo, was similar to that of uncoated nanoparticles incubated in poloxamine pre-treated serum. This observation supported the notion that poloxamine in serum can modify the surface of nanoparticles with similar topography to that of stealth poloxamine pre-coated particles, i.e. with polyoxyethylene chains projected from the surface. Surface plasmon resonance optical phenomenon was used for real-time monitoring of protein-poloxamine interactions and adsorption at the polystyrene interface. It was found that poloxamine can not only adsorb to a serum-modified surface but in addition poloxamine in serum can form macromolecular complexes with high affinity for adsorption to a polystyrene lattice. A role for serum albumin in surface modification of nanoparticles by poloxamine 908 is also identified. Hence, our biophysical observations correlate precisely with the in vivo longevity of uncoated polystyrene nanoparticles in poloxamine pre-treated rats. This rational and sensitive biophysical approach has unravelled the probable mechanism fundamental to generation of stealth entities in vivo and therefore has application in the design and nano-engineering of stealth colloidal carriers for optimal biological performance.
Animals↗
Modulation of lymphatic distribution of subcutaneously injected poloxamer 407-coated nanospheres: the effect of the ethylene oxide chain configuration.
Lymphatic distribution of interstitially injected poloxamer 407-coated nanospheres (45 nm in diameter) is controlled by surface configuration of the ethylene oxide (EO) segments of the adsorbed copolymer. At low poloxamer surface coverage, EO tails spread laterally on a nanosphere surface and assume a 'flat or mushroom-like' configuration. Such entities drain rapidly from the subcutaneous site of injection into the initial lymphatic, when compared to uncoated nanospheres, and subsequently are captured by scavengers of the regional lymph nodes. In vitro experiments have also confirmed that such entities are prone to phagocytosis. When the equilibrium poloxamer concentration is at 75 microg/ml or greater the EO chains become more closely packed and project outward from the nanosphere surface. These surface-engineered nanospheres drain faster than those with EO chains in mushroom configurations into the initial lymphatic, escape clearance by lymph node macrophages, reach the systemic circulation, and remain in the blood for prolonged periods. These experiments provide a rational approach for the design and engineering of nano-vehicles for optimal lymphatic targeting and are discussed.
Animals↗
Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties.
This article critically examines and evaluates the likely mechanisms that contribute to prolonged circulation times of sterically protected nanoparticles and liposomes. It is generally assumed that the macrophage-resistant property of sterically protected particles is due to suppression in surface opsonization and protein adsorption. However, recent evidence shows that sterically stabilized particles are prone to opsonization particularly by the opsonic components of the complement system. We have evaluated these phenomena and discussed theories that reconcile complement activation and opsonization with prolonged circulation times. With respect to particle longevity, the physiological state of macrophages also plays a critical role. For example, stimulated or newly recruited macrophages can recognize and rapidly internalize sterically protected nanoparticles by opsonic-independent mechanisms. These concepts are also examined.
Adsorption↗
Endothelial cells as therapeutic targets in cancer: new biology and novel delivery systems.
The significance of the endothelial cell as a target for antitumor therapy has been recognized for some time, but so far the results of clinical trials exploiting this approach have not been encouraging. The subject is likely to gain new momentum, however, following a number of important recent findings that shed new light on the origins and nature of tumor vasculature. Coupled with rapid developments in the use ofphage-displayed peptide libraries to characterize the human vascular map, as well as highly selective delivery systems, this new understanding of tumor vascular biology should provide many fresh and exciting avenues to explore.
Drug Delivery Systems↗
PEGylation of microspheres generates a heterogeneous population of particles with differential surface characteristics and biological performance.
Surface PEGylation of polystyrene microspheres with methoxy-poly(ethylene glycol)-5000 (mPEG-5000) generated a heterogeneous population of entities that differed in surface characteristics and in vitro biological performance (phagocytosis and complement activation). Surface heterogeneity was determined by hydrophobic interaction chromatography, measurements of particle electrophoretic mobility in a defined field and adlayer thickness of the projected mPEG chains. The particle population separation by hydrophobic interaction chromatography demonstrated a remarkable linear relationship between the particle zeta potential and phagocytosis by J774 A1 macrophage-like cells. Microsphere populations bearing a predominant surface of mPEG molecules as high-density mushroom-brush intermediate and/or brush configuration were most resistant to phagocytosis and activated the human complement system poorly. Conversely, those populations with predominant surface mPEGs in a mushroom regime were potent activators of the complement system and were prone to phagocytosis. Therefore, surface heterogeneity explains why a fraction of intravenously injected 'long-circulating' nanoparticles is cleared rapidly by macrophages of the reticuloendothelial system. Hydrophobic interaction chromatography can readily assess the extent of surface heterogeneity of PEGylated particulate drug delivery systems and pre-select particles with optimal retention times in the blood. These observations may also be relevant with respect to successful surface camouflaging of cells, drug depots and implantable devices.
Animals↗
Chemical camouflage of nanospheres with a poorly reactive surface: towards development of stealth and target-specific nanocarriers.
A two-step approach is described to chemically camouflage the inert surface of model polystyrene nanospheres of 60 nm in diameter against recognition by the body's defenses. The first step was based on the strong protein adsorbing potency of polystyrene, and the second step utilized the chemical reactivity of the adsorbed proteins for conjugation with cyanuric chloride-activated methoxypoly(ethyleneglycol)5000, mPEG5000. Bovine serum albumin (BSA) and rat IgG were used as models of non-immune and immune proteins, respectively. The maximum adsorbance values for both proteins were near expectation for a close-packed monolayer. Adsorption isotherms studies and analysis of the hydrodynamic thickness of the adsorbed protein layer confirmed the close-packed side-on mode of adsorption for BSA and the end-on mode of adsorption for IgG, respectively. Nucleophiles on the adsorbed proteins were then reacted with cyanuric chloride activated mPEG5000. The average poly(ethyleneglycol) (PEG) content for a 60-nm nanospheres was found to be 13.7+/-0.4 micromol PEG/micromol BSA and 3.6+/-0.3 micromol PEG/micromol IgG. The interaction of both PEG-bearing nanospheres with the hydrophobic column material octyl-agarose indicated surface heterogeneity among the nanospheres. Only nanospheres with the most hydrophilic phenotype (approximately 70% of the total population) exhibited stealth properties after intravenous injection to rats. In contrast to the described approach, incubation of uncoated nanospheres with preformed BSA-mPEG5000 conjugates failed to produce long circulating entities. For design of splenotropic particles cyanuric chloride-activated mPEG5000 was conjugated to BSA-coated polystyrene beads of 225 nm in diameter. Despite their stealth property to hepatic Kupffer cell recognition, these nanospheres were cleared by the splenic red pulp macrophages.
Adsorption↗
Modulation of murine liver macrophage clearance of liposomes by diethylstilbestrol. The effect of vesicle surface charge and a role for the complement receptor Mac-1 (CD11b/CD18) of newly recruited macrophages in liposome recognition.
We have studied the blood clearance and reticuloendothelial organ distribution of intravenously injected neutral (egg phosphatidylcholine, egg PC/cholesterol, mol ratio 7:2), anionic (egg PC/cholesterol/dicetylphosphate, mol ratio 7:2:1), and cationic (egg PC/cholesterol/stearylamine, mol ratio 7:2:1) liposomes of approximately the same size distribution in mice 3 days after treatment with the synthetic oestrogen diethylstilbestrol (DES). Male mice administered DES intraperitoneally at a dose of 1 mg per mouse (body weight 22-25 g) manifested an increase in the vascular clearance rate of liposomes irrespective of the initial vesicle surface charge. The enhancement in the vascular clearance of liposomes in DES-treated animals was associated with a concomitant increase in liver weight as well as hepatic phagocytosis. However, DES treatment significantly enhanced the hepatic sequestration (on the basis of % of injected dose of liposomes per g of liver tissue) of positively charged liposomes when compared to both neutral and negatively charged vesicles of similar size distribution. This observation was also confirmed by the 'hepatic-blockade' experiments where blockade was induced by prior intravenous injection of liposomes of the same size distribution and charge to that of test vesicles. The in vitro cell suspension studies suggested that the enhanced liposome uptake (irrespective of the initial vesicle surface charge) by Kupffer cells of DES-treated mice was independent of changes in the blood opsonization processes. Furthermore, in vitro studies also showed the operation of multiple mechanisms and involvement of different populations of liver macrophages (resident and recruited cells) in liposome recognition following DES treatment. For example, in DES-treated animals, the newly recruited liver macrophages were found to play a major role in the clearance of stearylamine incorporated liposomes via complement receptors (Mac-1). The resident Kupffer cells seem to recognize cationic vesicles via other receptors as the expression of Mac-1 is virtually absent in these cells. On the other hand, complement receptors seem to play a minor role in the uptake of anionic DCP vesicles by hepatic macrophages of DES-treated mice. DES appears to offer a new approach in dissecting the mechanisms of liposome-macrophage interaction.
Animals↗
Recognition and clearance of methoxypoly(ethyleneglycol)2000-grafted liposomes by macrophages with enhanced phagocytic capacity. Implications in experimental and clinical oncology.
Intravenous injection of an endotoxin-free solution of poloxamine-908 to rats can enhance the phagocytic clearance capacity of tissue macrophages, particularly those of the liver and the spleen. Such stimulated cells were able to clear a significant portion of intravenously injected methoxypoly(ethyleneglycol)2000 liposomes (mean size of 87 nm), labelled with technetium-99m via the N-hydroxysuccinimidyl hydrazine nicotinate hydrochloride derivative of distearoyl phosphatidylethanolamine, within 4 h post administration. These liposomes, otherwise, exhibit long circulatory behaviour in control animals, with poor localization to the liver and spleen. We suggest that such technetium-99m-labelled engineered vesicles may be of aid for detection of the liver and spleen macrophages with enhanced phagocytic clearance capacity by gamma scintigraphy. Alterations in the phagocytic activity of liver and spleen macrophages is known to occur during cancer. Therefore, such diagnostic procedures may prove useful for patient selection or for monitoring the progress of treatment with long circulating nanoparticles carrying anti-cancer agents, thus minimizing damage to this important line of body's defence cells, and are discussed.
Animals↗
Recognition by macrophages and liver cells of opsonized phospholipid vesicles and phospholipid headgroups.
The interaction of liposomes with blood proteins is believed to play a critical role in the clearance pharmacokinetics and tissue distribution of intravenously injected liposomes. In this article we have focused our discussion on the interaction of liposomes with key blood proteins, which include immunoglobulins, complement proteins, apolipoproteins, fetuin, von Willebrand factor, and thrombospondin, and their role in liposome recognition by professional phagocytes and nonmacrophage hepatic cells. Alternatively, macrophages as well as hepatocytes and liver endothelial cells may phagocytose/endocytose liposomes via direct recognition of phospholipid headgroups. A number of plasma membrane receptors such as lectin receptors, CD14, various classes of scavenger receptors (e.g., classes A, B, and D), Fc-gammaRI and FcgammaRII-B2 may participate in phospholipid recognition. These concepts are also discussed.
Animals↗
Long-circulating and target-specific nanoparticles: theory to practice.
The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.
Animals↗
Capture of stealth nanoparticles by the body's defences.
This article highlights and discusses our experience in the design, handling, and biological evaluation of long-circulating nanoparticles based on polyoxypropylene/polyoxyethylene copolymer nonionic surfactants. A frequently observed but ignored phenomenon following intravenous injection of such polymer-modified long-circulating colloidal systems is their eventual recognition and clearance by macrophages of the reticuloendothelial system. The pharmacokinetics as well as the tissue distribution of such so-called 'stealth" nanoparticles are also altered after repeated intravenous injection in a time-dependent manner. An understanding of immunological and pathological factors that control the pharmacokinetic and biological behavior of long-circulating particles after single or repeated administration is therefore crucial for the design of a system with an optimal diagnostic and/or therapeutic performance. Therefore, we have also examined and discussed the concept of macrophage recognition of a 'stealth-like nature" and factors that initiate this cascade. A critical discussion of the future of this interesting area of nano-biotechnology/engineering is also provided.
Animals↗
Recent advances in cellular, sub-cellular and molecular targeting.
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Animals↗
Poloxamers and poloxamines in nanoparticle engineering and experimental medicine.
Poloxamers and poloxamine nonionic surfactants have diverse applications in various biomedical fields ranging from drug delivery and medical imaging to management of vascular diseases and disorders. Although this is a progressive, rapidly advancing field in biotechnology, the future will depend on the recognition and rectification of a range of toxicity issues, which have to be addressed but have frequently been ignored until now.
Adjuvants, Immunologic↗
Re-establishing the long circulatory behaviour of poloxamine-coated particles after repeated intravenous administration: applications in cancer drug delivery and imaging.
In accordance with earlier observations, a single intravenous injection of long circulatory poloxamine-908-coated polystyrene particles to rats dramatically affected the circulation half-life and body distribution of a second dose when administered 10 days later. Both liver and spleen macrophages recognised and cleared from the blood the majority of the second dose of poloxamine-908-coated particles. The second dose of poloxamine-908-coated particles, however, regained their long circulatory behaviour when administered 1-3 h after a bolus intravenous injection of 30 mg free poloxamine-908 or poloxamer-407 (in saline)/150 g body weight. When the interval between free copolymer and particle administration was increased to 24 h then macrophage-rich organs were able to extract poloxamine-coated beads from the blood. In contrast to poloxamine-908 and poloxamer-407, prior administration of poloxamer-188 and polyethyleneglycol-20000 also failed to restore the long circulatory behaviour of the second dose of poloxamine-908-coated particles. These observations are of interest in experimental drug delivery, particularly in experimental cancer therapy (diagnostic imaging and drug delivery), involving multiple injections of poloxamine-based long circulating nanosized vehicles.
Animals↗
Humoral-mediated recognition of 'phagocyte-resistant' beads by lymph node macrophages of poloxamine-treated rats.
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Animals↗