Biomedical subjects

G Storm

Publications and source records attributed to G Storm.

At least 73 records · Page 4Linked to original sources

PubMed1998

Lymphatic uptake and biodistribution of liposomes after subcutaneous injection . IV. Fate of liposomes in regional lymph nodes.

The ability of clodronate-containing liposomes to deplete lymph nodes of macrophages was used as a tool to investigate the fate of liposomes in regional lymph nodes after subcutaneous (s.c.) administration. Reduced lymph node localization of liposomes in macrophage-depleted lymph nodes confirmed that phagocytosis by macrophages plays an important role in lymph node retention of liposomes. Depletion of macrophages had less effect on lymph node localization of small liposomes than on the lymph node localization of large liposomes. Inclusion of distearoylphosphatidylethanolamine (DSPE)-poly(ethyleneglycol) (PEG-PE) into the liposomes, which is known to oppose macrophage uptake, did not affect lymph node localization in macrophage-depleted or control lymph nodes. We conclude that PEG-liposomes retained by lymph nodes are also taken up by lymph node macrophages. Morphological observations visualizing the uptake of PEG-liposomes by lymph node macrophages support this conclusion.

Animals↗

PubMed1998

The influence of the route of administration and liposome composition on the potential of liposomes to protect tissue against local toxicity of two antitumor drugs.

The present paper reports on the influence of the route of administration and liposome stability on the protective effect of liposome encapsulation of two model antitumor agents, mitoxantrone and doxorubicin. The results demonstrate that liposome encapsulation can protect surrounding tissue from the cytotoxic effects of the drugs after subcutaneous (s.c.) and intramuscular (i.m.) administration. The route of administration is an important factor influencing tissue damage. Liposomal mitoxantrone caused much less tissue irritation after im injection than after s.c. injection. Liposome stability is also an important factor. Liposomes composed of 'fluid-state' phospholipids only delayed the damaging effects of doxorubicin when injected sc. Liposomes with a more rigid nature were much more effective in preventing local tissue damage over a longer period of time when administered sc. Results suggest that slow release of liposome-associated drugs may eventually cause severe local tissue damage. The incorporation of the hydrophilic lipid derivative distearoylphosphatidylethanolamine-poly(ethyleneglycol) (PEG-PE) had no apparent effect on the protective effect of liposomes after sc administration.

Animals↗

PubMed1998

Interaction of recombinant interleukin-2 with liposomal bilayers.

Liposomes have been employed as a delivery system for recombinant interleukin-2 (rIL-2) in cancer immunotherapy. In this study the effects of the rIL-2-bilayer interaction on protein structure were investigated. It was shown that rIL-2 adsorbs to liposomal membranes when added to preformed liposomes. Polarized fluorescence decay studies showed that the single tryptophan in "native" rIL-2 has a relatively large motional freedom, although iodide quenching of this residue's fluorescence was relatively ineffective. However, adsorption of rIL-2 to liposomes alters this situation dramatically- fluorescence intensity increased 2-fold and the residue became more susceptible to iodide quenching. At the same time, the average fluorescence lifetime of the fluorophore is extended. Interestingly, circular dichroism studies showed that no major conformational changes occurred in rIL-2's secondary structure upon adsorption. These observations support the hypothesis that intramolecular quenching takes place in the native rIL-2 molecule, which is abrogated upon adsorption to the liposomal membrane, resulting in a higher fluorescence intensity. Fluorescence anisotropy decay experiments indicate that the protein forms self-aggregates under the low-ionic strength conditions used, confirming the earlier observations on the tendency of the protein to precipitate in salt-containing media.

Calorimetry, Differential Scanning↗

PubMed1998

Doxorubicin entrapped in sterically stabilized liposomes: effects on bacterial blood clearance capacity of the mononuclear phagocyte system.

The introduction of long-circulating liposomes sterically stabilized by surface coating with polyethylene glycol has expanded the potential for drug targeting to tumors. In recent clinical studies, evidence of significant antitumor activity has been obtained with the industrially prepared formulation of long-circulating polyethylene glycol-coated liposomes containing doxorubicin, referred to as DOXIL. Previous studies performed in rats showed that doxorubicin-containing liposomes can exert major toxic effects on the liver macrophage population for a considerable period of time; a strong impairment of phagocytic function and even a substantial depletion of the liver macrophage populations were observed. In the present study, the phagocytic function of the mononuclear phagocyte system (MPS) after administration of DOXIL at a clinically relevant dosage schedule was evaluated in rats. Phagocytic function of the MPS was assessed by determining bacterial blood clearance capacity. The observations reported herein show that DOXIL is fairly well tolerated regarding bacterial blood clearance capacity of the MPS when administered in a regimen that resembles the clinical setting closely. This outcome has important implications with regard to the clinical utility of the liposomal drug, especially in the restricted context of immunocompromised cancer patients who easily develop systemic infections and should not be confronted with a therapy-induced reduction of the bacterial blood clearance capacity of the MPS.

Animals↗

PubMed1998

Sustained cytokine delivery for anticancer vaccination: liposomes as alternative for gene-transfected tumor cells.

Vaccination with tumor cells genetically engineered to produce interleukin (IL)-2 is an attractive strategy to enhance antitumor immune responses. The improved antitumor immunity upon vaccination with IL-2 gene-modified tumor cells may be due to the prolonged presence of the cytokine at the vaccination site. Because liposomes have been used for sustained delivery of a variety of agents, we compared the protective effect of vaccines consisting of IL-2 gene-modified B16 melanoma cells to that of vaccines composed of IL-2 liposomes and irradiated melanoma cells. The results indicate that both approaches equally protect against a lethal challenge with B16 melanoma cells. More than 20% of the protected animals developed vitiligo at the vaccination and/or tumor challenge site.

Animals↗

PubMed1998

Technetium-99m-labeled liposomes to image experimental colitis in rabbits: comparison with technetium-99m-HMPAO-granulocytes and technetium-99m-HYNIC-IgG.

UNLABELLED: Scintigraphic techniques are routinely used for the evaluation of the extent and severity of inflammatory bowel disease. Currently, the radiopharmaceutical of choice is 99mTc-hexamethyl propyleneamine oxime (HMPAO)-leukocytes. We studied the imaging potential of two recently developed 99mTc-labeled agents, polyethylene glycol (PEG)-coated liposomes and hydrazinonicotinate (HYNIC) IgG, in a rabbit model of acute colitis, and compared them with that of 99mTc-labeled, granulocyte-enriched (>90%), white blood cells. METHODS: Acute colitis was induced in rabbits by retrograde instillation of trinitrobenzene sulfonic acid. After 48 hr, 37 MBq of each radiopharmaceutical was administered intravenously. Gamma camera images were taken at 0, 1, 2, 4, 10 and 24 hr. At 4 and 24 hr postinjection, groups of rabbits were killed, and the uptake of the radiolabel in the dissected tissues was determined. For each affected 5-cm segment, the colitis index (CI, affected-to-normal-colon-uptake ratio) was calculated and correlated to the macroscopically scored severity of inflammation. RESULTS: All three agents visualized the colitis lesions within 1 hr postinjection. The CI correlated with the severity of the abnormalities. With increasing severity, the CI at 4 hr postinjection for liposomes was 3.89+/-0.73, 4.41+/-0.47 and 5.76+/-0.65; for IgG 1.67+/-0.08, 3.92+/-0.44 and 6.14+/-0.65; and for granulocytes 2.90+/-0.09, 6.15+/-0.96 and 9.36+/-3.35. For liposomes, the CI further increased during 24-hr postinjection to 6.56+/-0.84, 8.50+/-0.53 and 10.61+/-1.34, respectively. The CI for the other two agents did not change significantly with time. CONCLUSION: In this rabbit model, 99mTc-labeled granulocytes, IgG and liposomes all rapidly visualized colonic inflammation. Granulocytes and liposomes showed the highest CI. Technetium-99m-labeled PEG-liposomes may be an attractive alternative for labeled leukocytes to image inflammatory bowel disease, because they can be prepared off the shelf and no handling of blood is required.

Animals↗

PubMed1998

Liposomes for scintigraphic imaging: optimization of in vivo behavior.

Liposomes, microscopic lipid vesicles consisting of concentric phospholipid bilayers enclosing discrete aqueous spaces, have been investigated extensively as carries for drugs in attempts to achieve selective deposition and/or reduced toxicity. Liposomes radiolabeled with gamma emitters (67Ga, 111In and 99mTc) have been used for imaging purposes. Liposomes as formulated in the past, are rapidly taken up by cells of the mononuclear phagocyte system, primarily those located in liver and spleen. However, it has been shown during the last two decades that the in vivo behavior of liposomes can be modulated by modifying their formulation. The size and the lipid composition have a major influence on the blood clearance rate, hepatic uptake and splenic uptake of liposomes. The development of long circulating liposomes, in particular coating of the bilayer with polyethyleneglycol (PEG) resulted in liposomes that oppose recognition by the MPS, thus displaying even longer circulatory half-lives. By carefully adjusting the liposomal formulation, the in vivo characteristics of liposomes can be tailored such that they become suitable vehicles for imaging various pathological processes in vivo. Liposomes have been proposed for tumor imaging, for infection imaging and as blood pool markers. Here, the factors that determine the in vivo behavior of liposomes and the current status of liposome-based radiopharmaceuticals are reviewed.

Animals↗

PubMed1997

Lymphatic uptake and biodistribution of liposomes after subcutaneous injection. II. Influence of liposomal size, lipid compostion and lipid dose.

The present paper reports on the results of a systematic study on liposome variables potentially affecting lymphatic disposition and biodistribution of liposomes after sc injection. Liposomal size was found to be the most important factor influencing lymphatic uptake and lymph node localization of sc administered liposomes. Lymphatic uptake from the s.c. injection site of small liposomes (about 0.04 microm) was relatively high (76% of the injected dose (%ID)) as compared to large, non-sized liposomes, which remained almost completely at the site of injection. Small liposomes were less efficiently retained by regional lymph nodes than larger liposomes. Liposomal lipid composition did not influence lymphatic uptake with one exception: Lymphatic uptake was decreased in case of neutral liposomes composed of (DPPC). Lymph node localization was substantially enhanced by inclusion of phosphatidylserine (PS) into the liposomal bilayers. Saturation of lymphatic uptake and lymph node localization did not occur over a large liposomal lipid dose range, illustrating the efficient performance of lymph nodes in capturing s.c. administered particles.

Animals↗

PubMed1997

Liposome-mediated peptide loading of MHC-DR molecules in vivo.

Amino acid residues 3-15 of mycobacterial HSP60 define a dominant T-cell epitope for HLA-DR3+ve humans and Mamu-DR3+ve rhesus monkeys. Our results show that Mamu-DR3 molecules on PBMC can be efficiently loaded in vivo with the above-mentioned peptides when they are intravenously injected encapsulated in liposomes, but not in the free form. Mamu-DR3 loading is abolished by encapsulation of a nonstimulatory peptide. These results have implications for the delivery of therapeutic peptides in vivo.

Animals↗

PubMed1997

Biopharmaceutical aspects of lipid formulations of amphotericin B.

To improve the clinical utility of amphotericin B (AmpB), several lipid-based formulations have been developed. The biopharmaceutical aspects related to the parenteral use of colloidal lipid particles as carriers of AmpB are reviewed here. The first part of the review provides an introduction to the parenteral use of colloidal particles for chemotherapy by addressing the concept of a particulate drug carrier system, the pharmaceutical technological issues, and the biological factors governing the potential and limitations of lipid particles for effective drug delivery. The second part is devoted to AmpB lipid formulations. The pharmaceutical characteristics of the various industrially produced formulations, their pharmacokinetics and possible mechanisms of action, and potential future developments are described.

Amphotericin B↗

PubMed1997

Lymphatic uptake and biodistribution of liposomes after subcutaneous injection: III. Influence of surface modification with poly(ethyleneglycol).

PURPOSE: The aim of the present paper was to assess the effect of inclusion of distearoylphosphatidylethanolamine-poly(ethyleneglycol) (DSPE-PEG) into liposomal bilayers on the lymphatic uptake and lymph node localization of liposomes after subcutaneous administration. METHODS: [3H]-Cholesteryloleylether labeled liposomes of various composition and sizes were injected s.c. into the dorsal side of the foot of rats. At several time-points after injection, blood levels of liposomes were determined. Lymphatic uptake from the s.c. site of injection and lymph node localization in regional lymph nodes were determined at the end of the 52 h observation period. RESULTS: The results demonstrate that inclusion of DSPE-PEG into several types of liposomes has only a modest effect on lymphatic uptake. Also lymph node localization is only slightly affected by PEG-mediated steric stabilization. CONCLUSIONS: Factors other than the presence of a steric barrier are more important in determining lymphatic uptake from the s.c. injection site. The observation that lymph node localization was only slightly affected by PEG-coating strongly suggests that macrophage uptake is not the only important mechanism of lymph node localization of s.c. administered liposomes.

Animals↗

PubMed1997

Colloidal systems for tumor targeting.

The potential and limitations of targeted delivery of anticancer agents with colloidal particulate carriers is the subject of this contribution. Because over the years liposomes have gained the most attention as carrier system in the category of colloidal carrier systems, this paper focuses on the utility of the liposomal system for tumor targeting. It is imperative that an intended therapeutic application of liposomes should be well matched with the liposome behavior in vivo. Therefore, the in vivo fate of the first-generation liposomes and the more recently developed second-generation liposomes (surface-modified liposomes such as the immunoliposomes and long-circulating liposomes) is analyzed in terms of accessibility of target sites, time-, and site-controlled drug release and potential target sites for rational targeted delivery are discussed. A few examples of areas in cancer chemotherapy, with a strong rationale for the use of liposomes, are given. It is concluded that, although several options are available on the drawing board, issues such as tumor cell heterogeneity, access to the target site, shedding of antigens, and target site-specific release of the liposome-associated drug need to be addressed early in the development process.

Animals↗

PubMed1997

Technetium-99m labelled liposomes to image experimental arthritis.

OBJECTIVES: Liposomes sterically stabilised with polyethylene glycol (PEG) labelled with technetium-99m were tested for their ability to image adjuvant arthritis in a rat model. METHODS: Adjuvant arthritis was induced in the ankle joint of the left hind foot by injection of Mycobacterium butyricum in Freund's incomplete adjuvant in the foot pad. Seven days later animals received the following radiopharmaceuticals labelled with 99mTc (a) non-PEG-liposomes, (b) PEG-liposomes or (c) non-specific human polyclonal IgG. For each of the radiopharmaceuticals the in vivo distribution of the radiolabel was monitored both scintigraphically as well as by counting the dissected tissues at two, eight, and 24 hours after injection. RESULTS: The pharmacokinetics of the radiopharmaceuticals differed considerably (halflife in the blood: PEG-liposomes (18 hours) > 99mTc-IgG (3 hours) > non-PEG liposomes (1 hour)). The inflamed focus was visualised with each of the agents. The uptake of each of the radiopharmaceuticals in the inflamed ankle region correlated with their residence time in the blood (inflamed joint uptake: PEG liposomes (1.15% injected dose (ID)/ g) > 99mTc-IgG (0.35% ID/g) > non-PEG-liposomes (0.05% ID/g)). Quantitative analysis of the images showed that the inflamed ankle to background ratio was highest with the PEG-liposomes (7.5 at 24 hours after injection), while with the other two agents this ratio did not exceed 4. CONCLUSION: This study shows that 99mTc-labelled PEG-liposomes may be an excellent agent to visualise arthritis. Increased label uptake in the inflamed joint and increased target to background ratios can be obtained with PEG-liposomes because of their long circulating properties. In addition to their use as vehicles for scintigraphic imaging of arthritis PEG-liposomes might also be used for the site specific delivery of antirheumatic drugs.

Animals↗

PubMed1997

Optimization of technetium-99m-labeled PEG liposomes to image focal infection: effects of particle size and circulation time.

UNLABELLED: In previous studies we have shown that liposomes sterically stabilized with polyethylene glycol (PEG), preferentially localize in infectious and inflammatory foci. In this study, we further optimized the formulation of PEG liposomes for infection imaging in a rat model. METHODS: The biodistribution and imaging characteristics of different liposomal formulations labeled with 99mTc were determined in rats with S. aureus infection of the left calf muscle. The influence of liposomal size (mean diameter varying from 90 nm to 220 nm) as well as circulation time (modulated by inclusion of 0-10 mole% phosphatidylserine) were studied. RESULTS: The smallest liposomes displayed improved characteristics for infection imaging: 90-nm liposomes revealed the highest abscess uptake (1.6% +/- 0.4% ID/g, 24 hr postinjection) in combination with the lowest splenic accumulation (6.9% +/- 0.7% ID/g, 24 hr postinjection) as compared to the larger sized preparations. Enhanced abscess-to-blood ratios (4.0 versus 1.3 at 24 hr postinjection) were obtained by including 1.0 mole% phosphatidylserine in the lipid bilayer of the PEG liposomes. However, enhanced blood clearance of these liposomes reduced their absolute abscess uptake. CONCLUSION: These results indicate that the in vivo behavior of PEG liposomes can be modulated to optimize their characteristics for infection imaging.

Abscess↗

PubMed1997

Scintigraphic evaluation of experimental colitis in rabbits.

UNLABELLED: Scintigraphic techniques are frequently used for evaluation of inflammatory bowel disease. The radiopharmaceutical of choice is labeled leukocytes. In this study, two new agents, 111In-labeled polyethylene glycol-coated liposomes and 111In-labeled human nonspecific gamma globulin (immunoglobulin G; IgG), were compared with 111In-leukocytes in a rabbit model of colitis. METHODS: In rabbits, acute colitis was induced by colonic instillation of trinitrobenzene sulfonic acid at 25 cm from the anal sphincter. After 24 hr, 15 MBq of the radiopharmaceuticals was injected intravenously in groups of four rabbits. Twenty-four hours after injection, the animals were killed and macroscopic abnormalities were scored in seven consecutive affected colonic segments of 5 cm each (0 = normal, 1 = inflammation, 2 = ulcers). The ex vivo uptake was measured in the normal ascending colon and the affected colonic segments. The colitis index (CI, affected-to-normal colon-uptake ratio) was calculated. RESULTS: Histologically, an acute, patchy, transmural colitis was observed at the site of instillation and the distal colon. The CI of all agents in colitis lesions correlated with the severity of the abnormalities. With increasing severity, the CI for liposomes was 1.86 +/- 0.24, 4.88 +/- 0.42 and 7.42 +/- 0.54 (r2 = 0.68, p < 0.001); for leukocytes 1.77 +/- 0.32, 3.10 +/- 0.58 and 5.54 +/- 0.83 (r2 = 0.31, p < 0.01); for IgG 1.60 +/- 0.29, 2.81 +/- 0.21 and 2.65 +/- 0.21 (r2 = 0.29, p < 0.02). CONCLUSION: Indium-111-labeled-leukocytes, -IgG and -liposomes all show increased uptake in inflamed colonic tissue. Indium-111-liposomes showed the highest CI, which correlates best with the morphological abnormalities. Indium-111-leukocytes and 111In-liposomes are superior to 111In-IgG for this indication.

Animals↗

PubMed1996

Biosynthetically lipid-modified human scFv fragments from phage display libraries as targeting molecules for immunoliposomes.

A human anti-CD22 single chain (sc) Fv antibody fragment from a synthetic phage antibody display library was biosynthetically lipid-tagged by using Escherichia coli lipoprotein sequences. The purified anti-CD22 scFv lipoprotein was incorporated into liposomes by detergent dilution. Anti-CD22 immunoliposomes were shown to bind specifically in a dose- and time-dependent manner to CD22+ cell lines and CD22+ B-lymphocytes present in freshly isolated samples of blood mononuclear cells. The immunoliposomes were demonstrated to accumulate in intracellular compartments. Biosynthetically lipid-tagged human scFv antibody fragments isolated from phage display libraries may facilitate the construction of immunoliposomes with improved properties.

Antigens, CD↗

PubMed1996

Targeted delivery of diphtheria toxin via immunoliposomes: efficient antitumor activity in the presence of inactivating anti-diphtheria toxin antibodies.

Diphtheria toxin (DT) has attracted considerable attention for anti-cancer therapy. However, its extensive use is prohibited by (i) its non-specific action which can result in substantial toxicity, (ii) most patients have low serum levels of anti-DT antibodies (AT antibodies) which can inactivate DT and (iii) its immunogenicity will boost the circulating AT antibody level, thereby further compromising the antitumor activity. To overcome these limitations, we have developed a new approach for targeted delivery of DT utilizing immunoliposomes. In this approach, protection against the non-specific action of DT is combined with efficient antitumor activity even in the presence of inactivating AT antibodies.

Animals↗

PubMed1996

Immunoliposomes as enzyme-carriers (immuno-enzymosomes) for antibody-directed enzyme prodrug therapy (ADEPT): optimization of prodrug activating capacity.

PURPOSE: Immuno-enzymosomes are tumor-specific immunoliposomes bearing enzymes on their surface. These enzymes are capable of converting relatively nontoxic prodrugs into active cytostatic agents. The enzyme beta-glucuronidase (GUS)4 was coupled to the external surface of immunoliposomes directed against ovarian carcinoma cells. This study aimed at optimization of the prodrug-activating capacity of these immuno-enzymosomes by increasing the enzyme density on the immunoliposomal surface. METHODS: To achieve coupling of GUS to the liposomes, introduction of extra thiol groups was required. Two thiolating agents were examined: iminothiolane and SATA. RESULTS: When iminothiolane was used, aggregation of enzymosomes was observed above enzyme densities of 10 micrograms GUS/mumol lipid (TL). An increased electrostatic repulsion of the enzymosomes, created by inclusion of additional negatively charged lipids and by lowering the ionic strength of the external aqueous medium resulted in enzyme densities > or = 20 micrograms GUS/mumol TL without aggregation. Utilizing SATA, > or = 30 micrograms GUS/mumol TL could be coupled without aggregation, even at physiological ionic strength. It was shown that the enzyme density on immuno-enzymosomes, and thus on the tumor cell surface, strongly influences the antitumor effect of the prodrug daunorubicin-glucuronide against in vitro cultured ovarian cancer cells. The antitumor effect of immuno-enzymosomes with enzyme densities of about 20 micrograms GUS/mumol TL was similar to that of the parent drug daunorubicin. CONCLUSIONS: SATA-mediated thiolation of GUS-molecules enabled the preparation of immuno-enzymosomes with high enzyme densities while avoiding spontaneous aggregation. In vitro antitumor activity experiments showed that the improved immuno-enzymosome system is able to completely convert the prodrug daunorubicin-glucuronide into its parent compound.

Animals↗