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G Storm

Publications and source records attributed to G Storm.

At least 19 recordsLinked to original sources
PubMed2006

Bone targeting potential of bisphosphonate-targeted liposomes. Preparation, characterization and hydroxyapatite binding in vitro.

The main constituent of bone is hydroxyapatite (HAP). Since HAP is only present in 'hard' tissues like bone and teeth, it represents a promising target for the selective drug delivery to bone. Due to the exceptional affinity of bisphosphonates (BP) for HAP, cholesteryl-trisoxyethylene-bisphosphonic acid (CHOL-TOE-BP), a new tailor-made BP derivative, was used as bone targeting moiety for liposomes. CHOL-TOE-BP-targeted liposomes were designed for the treatment of bone-related diseases to achieve prolonged local exposure to high concentrations of the bioactive compounds, thereby enhancing therapeutic efficacy and minimizing systemic side effects. The CHOL-TOE-BP-targeted liposomes were characterized regarding particle size and zeta potential. To study the bone targeting potential of these conjugates, an in vitro HAP binding assay was established. The obtained binding data indicate that CHOL-TOE-BP is useful as targeting device for liposomal drug delivery to bone.

Binding Sites↗
PubMed2004

Steric stabilization of poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes mediates prolonged circulation and tumor targeting in mice.

BACKGROUND: Efficient tumor targeting of polymeric gene transfer systems (polyplexes) represents a major challenge. To establish tumor targeting after intravenous (IV) administration, the circulation lifetime of these systems should be sufficiently long. Since naked polyplexes are rapidly eliminated from the circulation after IV adminstration, strategies have to be developed to improve their pharmacokinetics. METHODS: Complexes of plasmid DNA and poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-graft-PEG or AB di-block copolymers of pDMAEMA and PEG, as well as PEGylated complexes prepared via PEGylation of preformed complexes (postPEGylation), were evaluated for their physicochemical properties (size and charge) their interactions with blood constituents and transfection activity in vitro. The pharmacokinetics and biodistribution of PEG-polyplexes were studied in mice after IV administration. The degree of accumulation in two subcutaneous (SC) mouse tumors after IV administration was evaluated for the system with the longest circulation time. RESULTS: It is shown that the surface charge of the pDMAEMA-polyplexes was effectively shielded by two PEGylation methods (i.e. the use of pDMAEMA-graft-PEG polymers and postPEGylation). The shielding effect was the highest for the postPEGylation method with PEG(20000), yielding polyplexes that hardly show interactions with blood components (i.e. albumin and erythrocytes) and show substantially prolonged circulation time in mice after IV administration. The superior colloidal stability and circulation kinetics of the postPEGylated polyplexes translated into tumor accumulation which amounted to about 3.5% of the injected dose per gram tumor tissue in a SC Neuro2A tumor model and to about 4.2% of the injected dose per gram tumor tissue in a SC C26 tumor model. CONCLUSIONS: This study shows that postPEGylation of pDMAEMA-based polyplexes is the most attractive method to prepare polyplexes with long circulating properties. Tumor targeting capacity after intravenous administration was demonstrated in two subcutaneous tumor models.

Adenocarcinoma↗
PubMed2004

Liposomal targeting of glucocorticoids to synovial lining cells strongly increases therapeutic benefit in collagen type II arthritis.

OBJECTIVE: To investigate the effect of a single intravenous treatment with glucocorticoids (GC) encapsulated in long-circulating PEG-liposomes on both joint inflammation and cartilage destruction and to investigate the phenomenon of selective homing of these liposomes in the inflamed synovium. METHODS: Mice with collagen type II-induced arthritis (CIA) were intravenously treated with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of the disease. Joint inflammation was scored during 1 week after treatment, after which sections of the knee joints were prepared for assessment of cartilage damage. In addition, arthritic mice were treated with liposomes containing colloidal gold. 24 hours after injection, knee joint sections were prepared in which the location of liposomes was visualised. RESULTS: Treatment of CIA with 10 mg/kg liposomal PLP resulted in a strong and lasting resolution of joint inflammation. 10 mg/kg free PLP only became slightly effective after repeated daily injections. Although joint inflammation recurred 1 week after treatment with liposomal PLP, knee joint sections prepared at this time indicated that the cartilage damage was still reduced. Localisation of gold labelled liposomes in the inflamed joints was seen in the proximity of blood vessels, in the cellular infiltrate, but mainly in the synovial lining. Unaffected joints did not take up liposomes. CONCLUSIONS: By using the property of long-circulating liposomes to target the synovial lining selectively in inflamed joints, the anti-inflammatory activity of GC can be greatly increased, showing also the beneficial effect of reduced cartilage destruction.

Animals↗
PubMed2003

Peptide-targeted PEG-liposomes in anti-angiogenic therapy.

Peptides with the RGD amino acid sequence show affinity for the alpha(v)beta(3) integrin, an integrin which is over-expressed on angiogenic endothelium and involved in cell adhesion. A peptide with the sequence ATWLPPR has been demonstrated to show affinity for the vascular endothelial growth factor (VEGF) receptor, a receptor involved in the proliferation of endothelial cells. By coupling these peptides to liposomes, these liposomes can serve as a site-specific drug delivery system to tumor endothelial cells in order to inhibit angiogenesis. In the present study we demonstrate that the coupling of cyclic RGD-peptides or ATWLPPR-peptides to the surface of PEG-liposomes results in binding of these liposomes to endothelial cells in vitro. Subsequent studies with RGD-peptide targeted liposomes in vivo also demonstrate specific binding to the tumor endothelium.

Angiogenesis Inhibitors↗
PubMed2003

Preparation and characterization of folate-targeted pEG-coated pDMAEMA-based polyplexes.

A folate-poly(ethylene glycol) conjugate capable of covalent coupling to primary amines present at the surface of polyplexes was developed. Coating of poly(dimethylaminomethyl methacrylate (pDMAEMA)-based polyplexes with this folate-pEG conjugate led to a sharp decrease of the zeta-potential, and a small increase in particle size. The size of the particles in isotonic medium did not change markedly in time demonstrating that rather stable particles were formed. The in vitro cellular toxicity of the pEGylated polyplexes with and without folate ligands was lowered considerably compared to uncoated polyplexes. The toxicity observed for the targeted pEGylated polyplexes was slightly higher than that of corresponding untargeted polyplexes, which might indicate an increased cellular association of targeted polyplexes. Transfection of OVCAR-3 cells in vitro was markedly increased compared to untargeted pEGylated polyplexes, suggesting targeted gene delivery.

Drug Delivery Systems↗
PubMed2002

Liposomes for intravenous drug targeting: design and applications.

Drug targeting with liposomes has been studied for over 25 years and has demonstrated its value in clinical practice. This mini review offers an overview of the design and application of liposomes for i.v. drug targeting. Two approaches are outlined: passive and active targeting. The former approach is based on liposomes with prolonged circulation and selective target localization properties, while in the latter approach specific targeting ligands are coupled to the liposome surface in order to achieve enhanced interaction with target cell membranes.

Animals↗
PubMed2001

Targeting influenza virosomes to ovarian carcinoma cells.

Reconstituted influenza virus envelopes (virosomes) containing the viral hemagglutinin (HA) have attracted attention as delivery vesicles for cytosolic drug delivery as they possess membrane fusion activity. Here, we show that influenza virosomes can be targeted towards ovarian carcinoma cells (OVCAR-3) with preservation of fusion activity. This was achieved by incorporating poly(ethylene glycol) (PEG)-derivatized lipids into the virosome membrane. This PEG layer serves as shield to prevent interaction of HA with ubiquitous sialic acid residues and as spatial anchor for antibody attachment. Coupling of Fab' fragments of mAb 323/A3 (anti-epithelial glycoprotein-2) to the distal ends of PEG lipids resulted in specific binding of virosomes to OVCAR-3 cells. These antibody-redirected virosomes fused with membranes of OVCAR-3 cells in a pH-dependent fashion.

Cell Membrane↗
PubMed2001

Liposomes to target the lymphatics by subcutaneous administration.

Liposomes have been proposed as carriers for the delivery of therapeutic and diagnostic agents to the lymphatic system. Subcutaneous (s.c.) injection is the route of administration most extensively studied for this purpose. Decisive factors influencing lymphatic absorption and lymph node uptake of s.c. administered liposomes are liposome size and the anatomical site of injection. Generally, other factors such as lipid composition, charge and the presence of a hydrophilic PEG-coating on the liposome surface do not substantially affect lymphatic absorption and lymph node uptake of s.c. administered liposomes. Studies on the intranodal fate of liposomes demonstrate that phagocytosis by macrophages is the most important mechanism for lymph node uptake of liposomes. The observation of relatively high uptake of liposomes in regional lymph nodes after s.c. administration has stimulated research on lymphatic targeting of liposomes for diagnostic and therapeutic applications.

Animals↗
PubMed2001

Microscopic localization of PEG-liposomes in a rat model of focal infection.

In the present study the microscopic localization of polyethylene glycol (PEG) liposomes in infected tissues was studied with both light microscopy (LM) and transmission electron microscopy (TEM) in rats with focal intramuscular Staphylococcus aureus infection. PEG-liposomes containing colloidal gold were prepared and injected intravenously in rats with focal S. aureus infection and tissues were dissected at 24 h post injection. Sections were cut and liposomes were visualized for microscopic evaluation using silver enhancement. Uptake of PEG-liposomes was visualized by both scintigraphy and LM in the abscess, liver and spleen. In the infected area, the liposomes were mainly found in the vicinity of blood vessels. TEM showed that the liposomes were localized in the macrophages and to a lesser extent in endothelial cells in the infectious tissue. In the liver, the liposomes appeared mainly localized in Kupffer cells. In the spleen, uptake was only seen in cells of the red pulp and in cells around the central arteries. Our microscopic observations indicate that uptake and retention of PEG-liposomes in the infectious focus is a result of enhanced extravasation due to increased vascular permeability and subsequent phagocytosis of PEG-liposomes by macrophages in the infected tissue.

Abscess↗
PubMed2001

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↗
PubMed2001

Immunoadjuvant activity of interferon-gamma-liposomes co-administered with influenza vaccines.

In an attempt to potentiate the relatively low immunogenicity of the currently used influenza vaccines, especially in high-risk groups, monovalent and divalent subunit vaccine preparations were co-administered with free or liposome-associated murine interferon gamma (mIFNgamma) as an adjuvant. Recombinant murine IFNgamma was entrapped (50-70% efficiency) in two types of large multilamellar vesicles: mIFNgamma-LIP A-'conventional' liposomes, and mIFNgamma-LIP B- 'surface-depleted' liposomes, in which 60 and 8% of the associated cytokine was located at the external liposome membrane, respectively. Subunit preparations containing the viral surface proteins hemagglutinin and neuraminidase (HN) were injected once, i.p. (0.5 microg each), into BALB/c mice, alone and combined with free or liposomal mIFNgamma (mIFNgamma-LIP, 0.5 or 3.0 microg). Sera were tested 3-16 weeks post-vaccination by hemagglutination inhibition (HI), and by ELISA for IgG1 and IgG2a antibodies (Abs). In addition, protective immunity against intranasal viral infection was assayed at 11 and 17 weeks post-vaccination. The results showed that: (a) Vaccination with HN alone produces very low HI and IgG titers and does not afford any protection. (b) Although co-administration with free mIFNgamma (particularly using 3.0 microg) markedly enhances HI titer as well as the IgG1 and IgG2a levels, protection is negligible (0-33%). (c) In most cases, mIFNgamma-LIP is significantly more potent than free mIFNgamma (2-40-fold increase in Ab titer), and the low dose (0.5 microg) is generally more efficient than the high dose. Up to 83% of the mice co-vaccinated with mIFNgamma-LIP were protected against viral challenge. (d) Both the IgG2a level and the HI titer appear to be crucial for protection. (e) Although the two liposomal preparations differ in their cytokine release profile in vivo and in their bioactivity in vitro, their adjuvant activity is comparable.

Adjuvants, Immunologic↗
PubMed2001

Liposomes as sustained release system for human interferon-gamma: biopharmaceutical aspects.

Interferon-gamma (IFNgamma) has proven to be a promising adjuvant in vaccines against cancer and infectious diseases. However, due to its rapid biodegradation and clearance, its efficacy is severely reduced. Liposomal association might prolong the residence time of IFNgamma, but no efforts have been made to optimize the biopharmaceutical characteristics of liposomal IFNgamma for its application in therapy or as vaccine immunoadjuvant. In the present study, various liposomal formulations of recombinant human IFNgamma (hIFNgamma), differing in lipid composition, were prepared via the film hydration method and characterized in vitro regarding association efficiency and bioactivity, and in vivo regarding cytokine release kinetics after subcutaneous (s.c.) administration into mice. Human IFNgamma can be formulated in large, multilamellar liposomes with high association efficiency (>80%) and preservation of bioactivity. A critical parameter is the inclusion of negatively charged phospholipids to obtain a high liposome association efficiency, which is dominated by electrostatic interactions. The fraction of externally adsorbed protein compared to the total associated protein can be minimized from 74+/-9% to 8+/-3% by increasing the ionic strength of the dispersion medium. After injection of free (125)I-hIFNgamma, the radiolabel was detectable up to 48 h at the injection site. Liposomal encapsulation of (125)I-hIFNgamma increased the local area under the curve 4-fold, and the presence of the radiolabeled hIFNgamma at the injection site was prolonged to 7 days. The release kinetics and overall residence time of the cytokine at the s.c. administration site was influenced by depletion of the externally adsorbed IFNgamma, reducing the initial burst release. Increasing the rigidity of the liposome bilayer also resulted in a more pronounced reduction of the burst release and a 19-fold increase in the residence time of the protein at the s.c. administration site, compared to the free cytokine. As adjuvanticity of liposomal IFNgamma may strongly depend on the release kinetics of cytokines in vivo, the findings in this paper may contribute to a rational design of liposomal-cytokine adjuvants in vaccines against cancer and infectious diseases.

Adjuvants, Immunologic↗
PubMed2001

The fate of poly(2-dimethyl amino ethyl)methacrylate-based polyplexes after intravenous administration.

Poly(2-dimethyl amino ethyl) methacrylate (pDMAEMA) cationic polymers have been shown to be efficient vectors for gene delivery in vitro. This contribution deals with the in vivo properties of polyplexes based on this polymer. In mice, pDMAEMA/[32P]-pLuc complexes distributed primarily to the lungs. The gene expression profile matched the biodistribution profile. In vitro turbidity experiments in serum showed severe aggregation upon addition of cationic polyplexes, pointing out the involvement of aggregates in the dominant lung uptake of the positively charged polyplexes. Incubations of polyplexes with albumin yielded a decline of the zeta potential of the complexes to negative values, making an electrostatic mechanism in the dominant lung uptake less likely. Hemagglutination experiments showed that the polyplexes induce the formation of extremely large structures when incubated with washed erythrocytes. Altogether, the present data indicate that aggregate formation and trapping of the formed aggregates in the lung capillary bed is probably responsible for the dominant lung uptake and transfection. Poly(ethylene)glycol (PEG) of the polymeric structures prevented the increase in the observed turbidity in serum seen with polyplexes and was also able to reduce interactions with erythrocytes. Currently, the in vivo fate of the PEGylated polyplexes is under investigation.

Animals↗
PubMed2001

Therapeutic efficacy of liposomal gentamicin in clinically relevant rat models.

Sterically stabilized liposomes are able to localize selectively at sites of infection, potentially permitting targeted drug delivery. Up to now, the majority of studies investigating therapeutic efficacy of liposomes have been conducted in animals with an intact host defense infected with high antibiotic-susceptible bacteria. In the present study, the therapeutic efficacy of gentamicin encapsulated in sterically stabilized liposomes, alone or in combination with the free drug was studied in rats with intact host defense as well as leukopenic rats. Rats were inoculated with a high gentamicin-susceptible or low-gentamicin susceptible Klebsiella pneumoniae in the left lung, resulting in an acute unilateral pneumonia. Survival rates demonstrate the valuable therapeutic properties of the liposome-encapsulated drug in these clinically relevant animal models.

Animals↗
PubMed2001

Radiopharmaceuticals for scintigraphic imaging of infection and inflammation.

Scintigraphic imaging of infection and inflammation is a powerful diagnostic tool in the management of patients with infectious or inflammatory diseases. Most infectious and inflammatory foci can be visualized accurately with radiolabeled autologous leukocytes. However, preparation of this radiopharmaceutical is laborious and requires the handling of potentially contaminated blood. Nowadays, a few radiopharmaceuticals are available that could replace radiolabeled leukocytes, such as: 67Ga-citrate, 99mTc-IgG and 99mTc-labeled antigranulocyte antibody preparations. Furthermore, various agents labeled with 99mTc are currently developed for this application: chemotactic peptides, cytokines and liposomes. Here, the characteristics and the diagnostic potential of established and experimental radiopharmaceuticals for infection and inflammation imaging are reviewed.

Antibodies↗
PubMed2001

Host factors influencing the preferential localization of sterically stabilized liposomes in Klebsiella pneumoniae-infected rat lung tissue.

PURPOSE: To gain insight into the host factors influencing liposome localization at sites of bacterial infection. METHODS: In a unilateral Klebsiella pneumoniae pneumonia rat model, capillary permeability and number of circulating leukocytes was quantified and related to the degree of liposome target localization. RESULTS: Liposome localization was highest in the hemorrhagic zone of infection, a zone characterized by markedly increased capillary permeability and high bacterial numbers. Both liposome localization and capillary permeability correlated positively with severity of infection. Lung instillation of other inflammatory stimuli, such as lipopolysaccharide or 0.1 M HCl inducing increased capillary permeability, also promoted liposome localization. As liposomal target localization in leukopenic rats was similar to that in immunocompetent rats, contribution of circulating leukocytes seems limited. Intrapulmonary distribution of liposomes shows that leukocytes at the target site are involved in liposome uptake after extravasation. CONCLUSIONS: Increased capillary permeability plays a crucial role in liposome localization at the infected site, whereas contribution of leukocytes is limited. These results suggest inflammatory conditions that could benefit from liposomal drug delivery. The involvement of leukocytes in liposome uptake at the target site could be important information in the selection of appropriate drugs.

Animals↗