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S M Moghimi

Publications and source records attributed to S M Moghimi.

At least 37 records · Page 2Linked to original sources
PubMed1997

Prolonging the circulation time and modifying the body distribution of intravenously injected polystyrene nanospheres by prior intravenous administration of poloxamine-908. A 'hepatic-blockade' event or manipulation of nanosphere surface in vivo?

Intravenously injected uncoated small (60 nm) and large (250 nm) size model polystyrene particles (which are cleared rapidly from the blood by macrophages of the reticuloendothelial system) can be converted to long-circulatory and splenotropic particles in vivo, respectively, if such particles are injected shortly (up to 3 h) after an appropriate dose of the block polymer non-ionic surfactant, poloxamine-908. Evidence indicates that small and large size polystyrene beads can acquire a coating of poloxamine-908 and/or poloxamine-protein complexes in vivo. The adsorption of such complexes on to the bead surface could explain their altered body distribution since small and large size polystyrene beads that were precoated with poloxamine-908 exhibit similar biodistribution following i.v. injection.

Drug Carriers↗
PubMed1997

Activation of the mononuclear phagocyte system by poloxamine 908: its implications for targeted drug delivery.

PURPOSE: To investigate the effect of poloxamine 908 on the MPS activity and the importance of its mode of presentation to the immune system. METHODS: Solutions of endotoxin free poloxamine 908 were injected daily intravenously to rats, and the effect on the degree of sequestration by the liver of I125 labelled, poloxamine 908-coated 60 nm polystyrene particles was investigated by studying effect of dosing regimen(s) and assessment of opsonic activity. RESULTS: After 3 or 4 days repeated dosing with poloxamine 908 (0.7 mg) in solution, the poloxamine 908-coated polystyrene particles (60 nm) were rapidly cleared from the circulation. The increase sequestration of the particles by the liver lasted for more than 7 days after last dosing with the poloxamine 908 solution. In subsequent studies, it was found that a single dose of poloxamine 908 (0.7 mg) in solution was sufficient to activate the MPS 4 days after the injection. The increased uptake was found not be mediated by a serum component, nor was it due to proliferation of the Kupffer cells in the liver. CONCLUSIONS: The results provide evidence that a solution of endotoxin-free poloxamine 908 activates the MPS so that 4 days after injection otherwise long-term circulating poloxamine 908-coated particles are sequestered by the liver. This finding has implications for use of such coated systems in therapeutic situations.

Animals↗
PubMed1997

A single dose of intravenously injected poloxamine-coated long-circulating particles triggers macrophage clearance of subsequent doses in rats.

1. Adsorption of the block copolymer non-ionic surfactant poloxamine-908 on to the surface of polystyrene nanospheres (60 nm in diameter) produced 'phagocyte-resistant' particles (otherwise known as long-circulating particles). This was reflected by a profound reduction in uptake of such engineered nanospheres by macrophages of the reticuloendothelial system and extended blood circulation time, after intravenous administration to rats. 2. A single intravenous administration of poloxamine-908-coated particles dramatically affected the circulation half-life and body distribution of a second subsequent dose. The degree of alteration depended on the interval between the two doses. At 3 days after a single intravenous injection of poloxamine-coated particles, Kupffer cells and spleen macrophages could clear a second dose of long-circulating beads from the blood. When tested at day 14, the second dose of intravenously injected poloxamine-coated particles avoided rapid uptake by liver and spleen macrophages and remained in the blood. 3. The coating polymer (poloxamine-908) apparently triggered bead clearance by resident Kupffer cells and certain sub-populations of spleen macrophages, since a single intravenous dose of an endotoxin-free solution of poloxamine 3 days before the administration of long-circulating particles induced similar effects. When the interval between the two injections was 2 weeks, poloxamine-coated particles again exhibited long circulation half-life. This cycle could be repeated after intravenous administration of a second poloxamine dose 2 weeks after the first poloxamine injection. 4. The mechanism of particle recognition by resident tissue macrophages was found to be independent of opsonization processes. 5. These studies could have important implications in biomedical application, design and engineering of poloxamine-based long-circulating drug carriers for repeated intravenous administration.

Animals↗
PubMed1996

Altered tissue-specific opsonic activities and opsono-recognition of liposomes in tumour-bearing rats.

Reticuloendothelial phagocytic and serum opsonic activity was evaluated at terminal stages of tumour growth in rats transplanted subcutaneously with chondrosarcoma in an attempt to evaluate the role of opsonic protein(s) in governing liposome recognition and clearance by the macrophage system. The liver of the tumour-bearing animals manifested a decline in the uptake of multilamellar vesicles composed of egg phosphatidylcholine: cholesterol: dicetyl phosphate (mole ratio 7:2:1) from the blood when compared to healthy animals. In contrast, an increase in splenic clearance of liposomes was encountered in tumour-bearing rats. Studies with isolated liver non-parenchymal cells suggested that liposome recognition in both health and at terminal stages of cancer growth is influenced by a serum opsonin, which can be precipitated by 35-50% ammonium sulphate, as well as the concentration of calcium levels in serum. Serum of healthy animals equally enhanced liposome recognition by the hepatic macrophages of both normal and tumour-bearing rats. In contrast, both cell populations manifested poor liposome recognition in the presence of serum pooled from tumour-bearing animals and the results were comparable to the corresponding liposome-cell interaction in the absence of serum. The opsonic activity of serum derived from tumour-bearing rats could be demonstrated either by prior dialysis of serum against de-ionized water or by addition of EGTA. Liver phagocytes of healthy animals recognized more liposome in the presence of dialysed or EGTA-chelated tumour-serum than that of liver cells derived from tumour transplanted rats. A significant increase in serum calcium concentration was found in all tumour-bearing rats. When the concentration of calcium in the serum of normal animals was increased to the level that is encountered in tumour-bearing rats, a sharp drop in liposome recognition by liver phagocytes was observed. This drop in opsonic activity was not related to changes in the ionic strength of serum. The ammonium sulphate precipitated opsonin was also calcium-sensitive and its opsonic activity was abolished in the presence of calcium. Studies with isolated splenic phagocytes suggested that an increase in the opsonic activity of serum, but not the elevated calcium level, was responsible for hyperphagocytosis of liposomes by the splenic phagocytes of tumour-transplanted animals. The opsonic molecule which enhanced liposome recognition by liver non-parenchymal cells failed to enhance liposome clearance by the splenic phagocytes. These findings suggest that the alteration in macrophage clearance of liposomes during the terminal growth of cancer may be mediated in part by changes in the opsonic capacity of serum.

Animals↗
PubMed1994

Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes.

The concept of steric stabilization as used in colloid science is applied to carefully manipulate the drainage and lymphatic distribution of subcutaneously administered model polystyrene nanospheres. A wide range of synthetic polyoxyethylene (POE)/polyoxypropylene (POP) block co-polymers of poloxamine and poloxamer series have been used to produce sterically stabilized nanospheres. We have found a correlation between the length of the stabilizing POE chains of the block co-polymers and nanosphere drainage and passageway across tissue lymph interface in dermal lymphatic capillaries in the rat footpads; the longer the POE chains, the faster the particle drainage. Nanospheres conditioned with block co-polymers of POE chains of 5-15 ethylene oxide units are effectively opsonized in lymphatics; a process which dramatically enhances sequestration (up to 40% of the administered dose) by macrophages of the regional lymph nodes. If the dimensions of the stabilizing POE chains of the poloxamines and poloxamers exceed the range of the Van der Waals force of attraction, opsonization fails to occur and rapidly drained engineered vehicles escape clearance by macrophages of the regional nodes, reach the systemic circulation and remain in the blood for prolonged periods. These observations suggest that a lymphatic delivery composition based on polymer-coated particles will be advantageous for many applications in clinical and experimental medicine.

Animals↗
PubMed1994

Innovations in avoiding particle clearance from blood by Kupffer cells: cause for reflection.

Therapeutic applications of drug carrier systems following intravenous administration have been limited because of the pronounced tendency of these carriers to localize primarily in Kupffer cells. Recently, attempts have been made to design colloids and drug carrier systems that can be disguised as "self" and remain unrecognizable, at least to a certain extent, by the hepatic macrophages. This review is designed to provide a critical view on fundamentals, current progress, limitations, and future prospects of such engineered colloids and drug carrier systems for intravenous route of administration.

Binding Sites↗
PubMed1993

Coating particles with a block co-polymer (poloxamine-908) suppresses opsonization but permits the activity of dysopsonins in the serum.

The surfaces of polystyrene microspheres (60 nm in diameter) and colloidal gold particles (17 nm in diameter) were coated with a polyoxyethylene (POE)/polyoxypropylene (POP) block co-polymer; poloxamine-908. The polymer adsorb strongly to the microspheres via its relatively hydrophobic POP segments. This leaves the POE chains in a mobile state as they extend outward from the surface and thereby provide stability to the particle suspension by suppressing aggregation. The blood clearance and biodistribution of uncoated vs. poloxamine-908-coated 125I-labelled polystyrene microspheres were compared 1 h after intravenous administration into rats. Poloxamine coating dramatically reduced liver accumulation of microspheres and kept them within the systemic circulation. These observations were further confirmed by electron microscopy, demonstrating that Kupffer cells were loaded with uncoated latex but had ingested few if any of the poloxamine-908-coated particles. The interaction of uncoated and poloxamine-coated gold particles with freshly isolated rat liver sinusoidal cells was examined by electron microscopy. The accumulation in Kupffer cells of gold particles after opsonization with autologous plasma was in accordance with previous observations where the dominant opsonizing activity had been identified as fibronectin. In contrast, coating of gold particles with poloxamine-908 prior to plasma opsonization prevented the adsorption of fibronectin onto their surface. Simultaneously, Kupffer cells failed to recognize poloxamine-908-coated gold particles before and after opsonization. Unlike Kupffer cells, liver endothelial cells endocytosed poloxamine-908-coated gold particles prior to opsonization but failed to recognize them after the opsonization process. This was taken as an indication of the presence of dysopsonic activity in plasma. This dysopsonic activity was studied using polystyrene latex microspheres, where the uptake of such particles by phagocytes is known to be independent of opsonization. The coating of 125I-labelled polystyrene microspheres with poloxamine-908 dramatically reduced their interaction with liver sinusoidal cells. This interaction was further reduced in the presence of either autologous plasma or serum. A heat-stable (60 degrees C for 15 min) serum component of molecular mass > 100 kDa was found to mediate this suppressive effect. Thus, we demonstrate that organ-specific receptors, opsonin activities and plasma dysopsonins regulate the in vivo clearance of particulate materials from the circulation. Poloxamine-908 coating modulates particle clearance by effectively blocking opsonization but still allowing for dysopsonization.

Animals↗
PubMed1993

An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rat spleen.

Earlier we demonstrated that coating the surface of large model polystyrene microspheres (220-300 nm in diameter) with the block co-polymer polyoxyethylene/polyoxypropylene poloxamine-908 triggered their accumulation in the rat spleen by a filtration mechanism following intravenous administration [Moghimi, S.M., Porter, C.J.H., Muir, I.S., Illum, L. and Davis, S.S. (1991) Biochem. Biophys. Res. Commun. 177, 861-866]. We have now demonstrated that the macrophages of the red-pulp can effectively phagocytose the filtered poloxamine-coated microspheres 24 h post-administration. This could be the result of either the loss of the surface absorbed poloxamine, and hence the steric barrier, or 'neutralization' of the effect of the anti-phagocytic material poloxamine-908 within the spleen. In order to assess the capacity of the splenic uptake mechanism(s), rats received daily intravenous administration of unlabelled large poloxamine-908 coated microspheres (220 nm in diameter) for 4 days (daily-dosed animals). Control rats received daily saline injection. On the fifth day all animals were injected with either radiolabelled large (220 nm) or small (60 nm in diameter) poloxamine-coated polystyrene microspheres. Predosing dramatically decreased the splenic uptake of the large test microspheres but had no effect on the uptake of small test-microspheres. The failure of the spleen to take up particles was not associated with an increased circulatory level of microspheres. Surprisingly, both small and large coated microspheres were sequestered by the liver and accumulated in Kupffer cells as demonstrated by electron microscopy in daily-dosed animals. In contrast, the liver of control animals did not effectively sequester poloxamine-coated microspheres. Here, microspheres predominantly remained in blood. Sequestration of poloxamine-908 coated microspheres by Kupffer cells of the liver of daily-dosed animals was the result of opsonization by an unknown serum component.

Animals↗
PubMed1993

Enhanced hepatic clearance of intravenously administered sterically stabilized microspheres in zymosan-stimulated rats.

The blood clearance and organ deposition of sterically stabilized (poloxamine-908 coated) polystyrene microspheres of two different sizes (60 and 220 nm in diameter) were compared in control and zymosan-stimulated rats 3 h after intravenous administration. Poloxamine coating dramatically decreased the uptake of 60-nm microspheres by organs of the reticuloendothelial system and, concomitantly, kept microspheres in the blood. Large poloxamine-coated microspheres (220 nm) initially remained in the blood, but eventually a large fraction of these microspheres was filtered by the spleen. Daily administration of zymosan produced a marked increase in the intravascular clearance of the large, but not the small, poloxamine-coated microspheres. The enhanced intravascular clearance of large poloxamine-coated microspheres in zymosan-treated rats was the result of hepatic sequestration. On the other hand, the splenic filtration of these microspheres was depressed by 225% below the control values, despite the dramatic increase in spleen size of zymosan-treated rats. Preincubation of large poloxamine-coated microspheres in serum derived from both the control and zymosan-treated animals suggested that the enhanced hepatic uptake of large sterically stabilized microspheres following zymosan stimulation was not the result of "specific opsonization" processes. Instead, the changes in the proliferative as well as the phagocytic response of Kupffer cells appeared to be responsible for these observations. The preferred hepatic uptake of large poloxamine-coated microspheres, as opposed to smaller particles, is suggested to be due to differences in surface characteristics and the properties of microspheres. These may include differences in polymer density and the surface conformation of the polyoxyethylene segments of the polymer in the biological environment and the way they interact with both plasma components and the macrophage surface. These observations could be of importance in the use of sterically stabilized drug carriers for delivery of therapeutic agents to sites other than the reticuloendothelial system in clinical conditions associated with globally or regionally enhanced reticuloendothelial activity.

Animals↗
PubMed1993

Effect of splenic congestion associated with haemolytic anaemia on filtration of 'spleen-homing' microspheres.

1. The surface of large model 125I-labelled polystyrene microspheres (220 nm in diameter) was coated with the polyoxyethylene/polyoxypropylene block co-polymer poloxamine-908. The coated microspheres were injected intravenously into rats. Up to 40% of the administered dose had accumulated in the spleen by a filtration mechanism, as compared with 5% for uncoated microspheres, at 3 h after administration. The enhanced splenic sequestration of microspheres was accompanied by a decrease in the liver uptake. In contrast, smaller poloxamine-908-coated microspheres (60 nm in diameter) effectively avoided uptake by both the liver and the spleen and remained in systemic circulation. 2. The effect of splenic congestion, associated with phenylhydrazine-induced haemolytic anaemia, on filtration of poloxamine-908-coated microspheres was studied. The enlarged spleen of the anaemic rats was incapable of efficiently filtering large poloxamine-908-coated microspheres when compared with the spleen of normal animals. This was suggested to be the result of extensive 'clogging' of the red pulp by damaged erythrocytes. However, the splenic filtration of large coated microspheres was still five-fold higher than that of uncoated microspheres of similar size in anaemic animals. 3. The potential use of large sterically stabilized colloids and drug carriers for selective spleen scanning and splenic drug delivery in pathological conditions, where anaemia prevails, is discussed. 4. Sterically stabilized microspheres may have potential for re-examining the microcirculatory pathways in healthy spleen and various splenomegalies.

Anemia, Hemolytic↗
PubMed1992

Opsonophagocytosis of liposomes by peritoneal macrophages and bone marrow reticuloendothelial cells.

We investigated the opsonic effect of serum on the phagocytosis of cholesterol-poor and cholesterol-rich liposomes with freshly prepared rat bone marrow and peritoneal phagocytes in suspension. The presence of serum in incubation increased the uptake of cholesterol-rich but not cholesterol-poor liposomes in bone marrow cells, whereas serum enhances phagocytosis of both liposome preparations in peritoneal phagocytes. The opsonic activity of serum on the uptake of liposomes by both cell types is destroyed by heat, ammonium hydroxide, and zymosan treatments of serum, which suggests the involvement of complement in phagocytosis of liposomes. However, bone marrow cells and peritoneal macrophages responded differently when incubated with dialysed or EGTA-chelated serum. These treatments result in complete loss of the opsonic effect of serum on the uptake of liposome in bone marrow cells. Addition of serum dialysate or divalent cations to dialysed serum do not reinstall its lost opsonic activity. Thus these results shade doubt on possibility of involvement of complements in phagocytosis of liposomes by bone marrow cells. Dialysed or EGTA-treated serum also failed to promote liposome uptake by peritoneal macrophages but unlike in the case of bone marrow cells replacement of divalent cations to such sera reinstalls its opsonic activity and enhances phagocytosis of liposomes by peritoneal macrophages. These observations suggest the involvement of different serum components on liposome uptake by bone marrow cells and peritoneal macrophages, and emphasize the complexities associated with RES-mediated blood clearance of the intravenously injected liposomes. The properties of these opsonins are compared with those of 'liver-' and 'spleen-specific' opsonins responsible for phagocytosis of liposomes by Kupffer cells and spleen macrophages, respectively [4]. It is suggested that these tissue specific opsonins are responsible for distribution of intravenously injected liposomes in various organs of the reticuloendothelial system.

Ammonium Hydroxide↗
PubMed1992

The polyoxyethylene/polyoxypropylene block co-polymer poloxamer-407 selectively redirects intravenously injected microspheres to sinusoidal endothelial cells of rabbit bone marrow.

Small colloidal particulates (150 nm and below, in diameter) can be redirected specifically to the rabbit bone marrow following intravenous administration by coating their surface with the block co-polymer poloxamer-407, a non-ionic surfactant. The coated colloids are sequestered by the sinusoidal endothelial cells of the bone marrow and are accumulated in dense bodies within these cells. The uptake of poloxamer-407-coated colloids by marrow endothelial cells suggests that the steric repulsive barrier, imposed by the polyoxyethylene segment of the polymer, to particle-cell interaction can apparently be overcome by a specific interaction mechanism(s) with the cell surface. Such a dramatic uptake cannot be achieved with other block co-polymers of similar structure to poloxamer-407. The application of the current model for the site-specific targeting of drug carriers to bone marrow and the prevention of the adherence of metastases of tumours which selectively colonize the bone marrow endothelium is discussed.

Animals↗
PubMed1991

Non-phagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating.

A recent development in prolonging the circulation time of drug carriers, such as liposomes and microspheres, has been to minimize their removal by macrophages of the reticuloendothelial system by covering their surface with hydrophilic polymers such as poloxamers, poloxamines and poly(ethyleneglycols). Here we demonstrate that this strategy may not necessarily prolong the circulatory half-life of drug carriers in all animal models. In rats, as opposed to rabbits, a non-phagocytic mechanism in the spleen may be triggered to remove efficiently from the blood drug carriers coated with hydrophilic coatings. Both the size of particle and its hydrophilic coating may act synergistically to trigger this non-phagocytic mechanism. In rats, a remarkable log to log relationship between particle size and spleen uptake was observed for both uncoated and polymeric coated microspheres. The potential implication of these observations in site-specific delivery of drug carriers is discussed.

Animals↗