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Biomedical subjects

M C Woodle

Publications and source records attributed to M C Woodle.

At least 19 recordsLinked to original sources
PubMed1998

Cationic liposomes coated with polyethylene glycol as carriers for oligonucleotides.

Modification of liposome surface with polyethylene glycol was used to improve oligodeoxyribonucleotide (ODN) loading, stability of the resulting complexes, and specificity of cellular delivery of ODN by cationic liposomes. Liposomes composed of a cationic lipid (DOTAP, DOGS, DDAB), a neutral lipid (DOPE), and a phospholipid derivative of polyethylene glycol (PEG-PE) formed a complex with 18-mer phosphorothioate up to ODN/lipid molar ratio of 0.25. The complexes showed intact vesicular structures similar to original liposomes and their size (100-130 nm) was unchanged after several weeks of storage, whereas complexes lacking PEG-PE showed progressive aggregation and/or precipitation. After exposure to human plasma, PEG-modified cationic liposomes retained over 60% of the originally bound ODN. PEG-coated complexes resulted in 4-13-fold enhancement of the ODN uptake by human breast cancer cells in serum-supplemented growth medium, relative to free ODN. Complexes containing conjugated anti-HER2 F(ab') fragments at the distal termini of PEG chains efficiently delivered ODN primarily into the cytoplasm and nuclei of HER2 overexpressing cancer cells and greatly enhanced the biological activity of antisense ODN. The development of PEG-modified cationic liposomes may lead to improved ODN potency in vivo.

Animals↗
PubMed1996

Targeting of stealth liposomes to erbB-2 (Her/2) receptor: in vitro and in vivo studies.

Long-circulating (stealth) liposomes coated with polyethylene glycol (PEG), which show reduced uptake by the reticuloendothelial system (RES) and enhanced accumulation in tumours, were used for conjugation to monoclonal antibodies (MAbs) as a drug-targeting device. A MAb (N-12A5) directed against erbB-2 oncoprotein, a functional surface antigen, was used. Amplification and overexpression of the erbB-2 gene product, being unique to malignancy, confer onto this antibody-mediated therapy high tumour specificity. In vitro binding of [3H]cholesteryl ether ([3H]Chol ether) labelled anti-erbB-2 conjugated liposomes to N-87 cells (erbB-2-positive human gastric carcinoma) was compared with the binding of non-targeted liposomes and indicated a 16-fold increase in binding for the targeted liposomes. No difference in binding to OV1063 cells (erbB-2-negative human ovary carcinoma) was observed. These results indicate highly selective binding of antibody-targeted liposomes to erbB-2-overexpressing cells. Despite increased cell binding, doxorubicin (DOX) loaded in anti-erbB-2-conjugated liposomes did not cause increased in vitro cytotoxicity against N-87 cells, suggesting lack of liposome internalisation. In vivo, the critical factor needed to decrease the non-specific RES uptake and prolong the circulation time of antibody-conjugated liposomes is a low protein to phospholipid ratio ( < 60 micrograms mumol-1). Using these optimised liposome preparations loaded with DOX and by monitoring the drug levels and the [3H]Chol ether label, biodistribution studies in nude mice bearing subcutaneous implants of N-87 tumours were carried out. No significant differences in liver and spleen uptake between antibody-conjugated and plain liposomes were observed. Nevertheless, there was no enhancement of tumour liposome levels over plain liposomes. Both liposome preparations considerably enhanced DOX concentration in the tumour compared with free drug administration. Therapeutic experiments with N-87 tumour-bearing nude mice indicated that anti-tumour activity of targeted and non-targeted liposomes was similar, although both preparations had an increased therapeutic efficacy compared with the free drug. These studies suggest that efficacy is dependent on drug delivery to the tumour and that the rate-limiting factor of liposome accumulation in tumours is the liposome extravasation process, irrespective of liposome affinity or targeting to tumour cells.

Animals↗
PubMed1995

Pharmacokinetics and anti-tumor activity of vincristine encapsulated in sterically stabilized liposomes.

Vincristine is used clinically for the treatment of various types of cancer. Recent significant therapeutic improvements obtained by entrapping anthracyclines in sterically stabilized liposomes raised the question whether the therapeutic index of vincristine can be similarly increased by formulation into such long-circulating liposomes. Encapsulation of vincristine in sterically stabilized liposomes (SL-VCR) prolonged the drug's distribution phase plasma half-life in rats from 0.22 to 10.5 hr. There was no significant difference in LD50 (> < or = 2.5 mg/kg, i.v.), but mice given sublethal doses of SL-VCR experienced significantly less weight loss than those given the same dose of free drug. Compared to free drug, SL-VCR was most effective against i.p. or s.c. implanted tumors. However, i.v. tumor inoculation nullified the therapeutic advantage of encapsulation. A single i.v. 2 mg/kg dose of SL-VCR increased the life span of mice bearing i.v. implanted P388 cells by only 44%, while the life span of i.p. P388 implanted mice was increased by 199%. In an s.c. implanted murine colon carcinoma, multiple doses of free drug did little to slow the growth of the tumors, but SL-VCR was able to produce long-term survivors in several dose regimens. These results indicate that prolonged circulation time increases the therapeutic index of VCR entrapped in liposomes against s.c. or i.p. implanted tumors, but does not improve the drug's activity against rapidly growing i.v. disseminated leukemias.

Animals↗
PubMed1995

Efficacy of gentamicin or ceftazidime entrapped in liposomes with prolonged blood circulation and enhanced localization in Klebsiella pneumoniae-infected lung tissue.

Polymer (PEG-PE)-coated liposomes exhibit prolonged circulation time in blood and substantial localization in Klebsiella pneumoniae-infected lung tissue in rats. Therefore, to determine the therapeutic effect, gentamicin and ceftazidime were entrapped in these liposomes and administered to rats experimentally infected with pneumonia: Relatively high and sustained concentrations of liposome-associated antibiotic in blood were observed. Compared with antibiotics alone, one dose of liposome-entrapped gentamicin or ceftazidime increased the therapeutic effect of the drugs, survival of rats, and bacterial killing in lungs. One dose of liposome-entrapped ceftazidime was as effective as a continuous 2-day infusion of nonentrapped ceftazidime. Since antibiotic-containing liposomes are stable during circulation and liposome-entrapped ceftazidime and gentamicin have low bactericidal activity in vitro, the superior therapeutic effect of the liposome-encapsulated antibiotics results from localization and subsequent degradation of liposomes and the resulting release of entrapped antibiotic at the infection site.

Animals↗
PubMed1994

Long circulating, cationic liposomes containing amino-PEG-phosphatidylethanolamine.

Ligand attachment to polyethylene glycol (PEG) grafted, long circulating liposomes at the polymer terminus is of interest for targeting but the effect of positively charged groups is unknown. Amino-polyethylene glycol-phosphatidylethanolamine (AminoPEG-PE), prepared in four steps from alpha-amino-omega-hydroxy-PEG, was tested for influence on liposome interactions in vivo: blood circulation and biodistribution. Despite surface amines on each liposome conferring cationic behavior, in vivo properties are comparable to those obtained with methoxy-PEG-PE. The consequences are profound for targeting and possibly systemic delivery of cationic lipidic-polynucleotide complexes.

Amines↗
PubMed1994

Liposomes in the treatment of infections.

The use of liposomes in the treatment of severe infections is under investigation. Classical liposomes which localize in cells of the mononuclear phagocyte system (MPS) can be exploited in two ways. First for targeting of macrophage modulators such as muramyl peptides or IFN-gamma, to stimulate the cells of the MPS to maximal blood clearance capacity. This enhanced nonspecific anti-infectious resistance is important as in immunocompromised patients micro-organisms frequently appear in the blood from a local infection. Secondly, classical liposomes are successfully used as carriers of antibiotics in experimental intracellular parasitic-, viral-, fungal- or bacterial infections in MPS tissues. Based on these data extensive studies in patients with severe fungal infections have demonstrated successful treatment with liposomal or lipid-complexed amphotericin B. More recently, liposomal amphotericin B appeared to be effective in patients with drug-resistant visceral leishmaniasis. For the treatment of Mycobacterium avium complex infection in AIDS patients the efficacy of liposomal gentamicin is under investigation. With respect to infections in non-MPS tissues the applicability of Stealth liposomes characterized by long circulation half-lives is under investigation. Substantial localization of these liposomes in infected lung tissue of rats was demonstrated. Preliminary data in experimental bacterial lung infection showed superior efficacy of antibiotic encapsulated in Stealth liposomes.

Animals↗
PubMed1994

Sterically stabilized liposomes: physical and biological properties.

Advanced liposomal therapeutics has been attained by liposome surface modification, initially with specific glycolipids and subsequently with surface-grafted PEG, reducing in vivo rapid recognition and uptake, giving prolonged blood circulation, and providing selective localization in tumors and other pathological sites, as described in recent reviews. The result is improved efficacy of encapsulated agents. The surface PEG may produce a steric barrier, as described for colloids. Reduced in vivo uptake may result from inhibition of plasma-protein adsorption, or opsonization, by the steric coating. Several physical studies support this mechanism, including electrophoretic mobility (zeta potential). Our previous results for 2000-dalton PEG indicated a coating thickness about 5 nm, in agreement with independent measurements. We report here results for 750 to 5000-dalton PEGs. The calculated coating thickness increases with molecular weight in a nonlinear fashion. The dependence of blood circulation and tissue distribution on PEG molecular weight correlates with zeta-potential estimates of PEG-coating thickness. Effects on tissue distribution are reported for liver and spleen, the major phagocytic organs. The biological properties of these liposomes depend on the surface polymer rather than the lipid bilayer, yielding important advantages for lipid-mediated control of drug interaction and release without affecting the biodistribution.

Animals↗
PubMed1993

Surface-modified liposomes: assessment and characterization for increased stability and prolonged blood circulation.

Advances in therapeutic applications of liposomes have been achieved through surface modifications increasing their biological stability: reduced constituent exchange and leakage as well as reduced unwanted uptake by cells of the mononuclear phagocytic system. The recent conclusions obtained from in vivo and in vitro studies are reviewed with an emphasis on evaluating the methods used and thus the kinds of conclusions which can be drawn. A number of issues are raised as to the limitations of the methods employed. Steric stabilization, meaning reduction in particle interactions by a surface steric barrier, has been proposed as a theoretical basis for the results and some of the initial results testing this hypothesis are reviewed here with respect to identification of the extent to which physical properties of the surface coatings correlate with the biological properties. At this time it seems that no one method is ideal so that multiple measures give the best characterization.

Animals↗
PubMed1993

67Gallium-labeled liposomes with prolonged circulation: preparation and potential as nuclear imaging agents.

A method is described for 67Ga-labeling liposomes containing a polyethylene glycol coating which exhibit prolonged blood circulation, reduced liver and spleen uptake and accumulation in tumors. Applications as agents for diagnostic imaging and delivery of therapeutic agents are considered. Previous methods were adapted to compensate for the presence of low temperature phase transition phospholipids resulting in consistent loading with low levels of residual unentrapped label.

Animals↗
PubMed1993

Liposomes with prolonged blood circulation and selective localization in Klebsiella pneumoniae-infected lung tissue.

Studies of two types of small liposomes, differing with respect to their lipid composition in terms of bilayer fluidity, charge, and hydrophilicity of the liposomal surface, were done to evaluate their usefulness for delivery of encapsulated therapeutic agents to sites of infection. The liposomes showed substantial localization in infected lung tissue after intravenous administration. This was demonstrated in a model of unilateral Klebsiella pneumoniae pneumonia in rats, in which the left lung was infected but the right lung of the same animal developed no infection. The degree of localization in the infected left lung was different for the two types of liposomes. For the liposome type with the longer blood residence time, containing a surface coating of polyethylene glycol, localization in the infected left lung was dependent on the liposomal dose, correlated with the intensity of infection, and reached 9% of the injected liposomal dose in severely infected rats.

Animals↗
PubMed1992

Sterically stabilized liposomes.

Many recent reports have demonstrated that rapid uptake of liposomes in vivo by cells of the mononuclear phagocytic system (MPS), which has restricted their therapeutic utility, can be overcome by incorporation of lipids derivatized with the hydrophilic polymer polyethylene glycol (PEG). The structure-function relationship of PEG-derivatized phosphatidylethanolamine (PEG-PE) has been examined by measurement of blood lifetime and tissue distribution in both mice and rats. The results are reviewed and contrasted with those from liposomes without PEG-PE or other surface modifications. With a PEG molecular weight in the range of 1000 to 5000, prolonged circulation and reduced MPS uptake is achieved. After 24 h, up to 35% of the injected dose remains in the blood and less than 10% is taken up by the two major organs of the MPS, liver and spleen, compared with 1% and up to 50%, respectively, for liposomes without PEG-PE. Other important advantages of PEG-PE have been identified: prolonged circulation is independent of liposome cholesterol content, degree of hydrocarbon chain saturation in either the PC or the PE lipid anchor, lipid dose, or addition of most other negatively charged lipids. This versatility in lipid composition and dose is important for controlling drug release in a liposome-based therapeutic agent. Steric stabilization has been proposed as a theoretical basis for the results and some initial results testing this hypothesis have been reported. A description of a theoretical model is presented here and evaluated with the data available. The results are compared with other particulate drug carriers and the range of potential applications are considered.

Animals↗
PubMed1992

Versatility in lipid compositions showing prolonged circulation with sterically stabilized liposomes.

Efforts to overcome rapid uptake of liposomes by cells of the mononuclear phagocytic system (MPS) have identified that lipids derivatized with the hydrophilic polymer poly(ethylene glycol) (PEG) have many advantages. The structure-function relationship of PEG-derivatized phosphatidylethanolamine (PEG-PE) has been examined by studies of blood lifetime and tissue distribution in both mice and rats. Liposomes composed of phosphatidylcholine (PC), cholesterol, and 7.5 mol% of PEG-PE show prolonged circulation and reduced MPS uptake when the PEG has a molecular weight in the range of 1000 to 5000. Up to 35% of the injected dose remains in the blood and less than 10% is taken up by the MPS (liver plus spleen) after 24 h in the best cases as compared to 1% and 40%, respectively, for liposomes without PEG-PE. Prolonged circulation with PEG-PE is independent of cholesterol, degree of saturation in either the PC or the PE lipid anchor, lipid dose, or addition of other negatively charged lipids, phosphatidylglycerol or cholesterol sulfate. This versatility in lipid composition and dose without alteration of blood lifetime or tissue distribution is essential for controlling drug dosage and release properties in a liposome-based therapeutic agent.

Animals↗
PubMed1992

Sterically stabilized liposomes. Reduction in electrophoretic mobility but not electrostatic surface potential.

The electrophoretic mobility of liposomes containing a negatively charged derivative of phosphatidylethanolamine with a large headgroup composed of the hydrophilic polymer polyethylene glycol (PEG-PE) was determined by Doppler electrophoretic light scattering. The results show that this method is improved by the use of measurements at multiple angles to eliminate artifacts and that very small mobilities can be measured. The electrophoretic mobility of liposomes with 5 to 10 mol% PEG-PE is approximately -0.5 mu ms-1/Vcm-1 regardless of PEG-PE content compared with approximately -2 mu ms-1/Vcm-1 for similar liposomes but containing 7.5% phosphatidylglycerol (PG) instead of PEG-PE. Measurements of surface potential by distribution of an anionic fluorescent probe show that the PEG-PE imparts a negative charge identical to that by PG, consistent with the expectation of similar locations of the ionized phosphate responsible for the charge. The reduced mobility imparted by the surface bound PEG is attributed to a mechanism similar to that described for colloidal steric stabilization: hydrodynamic drag moves the hydrodynamic plane of shear, or the hydrodynamic radius, away from the charge-bearing plane, that of the phosphate moities. An extended length of approximately 50 A for the 2,000 molecular weight PEG is estimated from the reduction in electrophoretic mobility.

Biophysical Phenomena↗
PubMed1992

Prolonged systemic delivery of peptide drugs by long-circulating liposomes: illustration with vasopressin in the Brattleboro rat.

The value of novel systemically long-circulating liposomes to prolong the duration of an antidiuretic hormone, arg8-vasopressin (VP), was investigated as a representative of low molecular weight peptides with rapid clearance. Cholesterol content was found to have a controlling effect on VP release in serum. Three types of liposomes were selected for urine production measurements in VP deficient Brattleboro rats. One contained phosphatidylserine (PS), which was rapidly cleared from the circulation. In the other two liposomes, the PS component was replaced by either phosphatidylglycerol or a novel phospholipid derivatized with polyethylene glycol (PEG); both showing prolonged circulation. Free VP (up to 8 micrograms/kg) gave reduced urine production for less than 24 hr. The PG formulation exhibited a dose-dependent prolonged duration of bioactivity of up to 4 days. Substitution of PEG-PE resulted in a 2-day delay followed by a prolonged duration of bioactivity for over 4 days. The duration of the prolonged bioactivity was not dose dependent but the amplitude was. This is attributed to VP release from liposomes which have distributed intact to another compartment without having been taken up by the RES. By balancing liposome circulation time, release rate, and dose, long-circulating liposomes can be applied to prolong the biological activity of a therapeutic peptide.

Animals↗
PubMed1991

Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy.

The results obtained in this study establish that liposome formulations incorporating a synthetic polyethylene glycol-derivatized phospholipid have a pronounced effect on liposome tissue distribution and can produce a large increase in the pharmacological efficacy of encapsulated antitumor drugs. This effect is substantially greater than that observed previously with conventional liposomes and is associated with a more than 5-fold prolongation of liposome circulation time in blood, a marked decrease in uptake by tissues such as liver and spleen, and a corresponding increased accumulation in implanted tumors. These and other properties described here have expanded considerably the prospects of liposomes as an effective carrier system for a variety of pharmacologically active macromolecules.

Animals↗
PubMed1986

Photoinitiated ion movements in bilayer membranes containing magnesium octaethylporphyrin.

A photocurrent produced by planar lipid bilayers containing Mg-octaethylporphyrin in the presence of oxygen has been investigated to determine if the current is due to movement of the MgOEP+ ion in the bilayer. Photoexcitation of the MgOEP is known to produce MgOEP+ in the bilayer when an electron acceptor is present. However, the aqueous electron acceptors ferricyanide and methyl viologen (MV+2) have opposite effects on the photocurrent. Ferricyanide decreases the photo current, even in the presence of oxygen, whereas methyl viologen increases the photocurrent, but only when oxygen is present. We attribute most of the photocurrent to the movement of superoxide anion. The difference in effect between ferricyanide and methyl viologen is attributed to the different rates of reduction of O2 by reduced MV+ (fast) vs. ferrocyanide (slow) and the known competition between ferricyanide and oxygen as the acceptor for the photoexcited porphyrin. It is inferred that most of the MgOEP is localized in the polar region of the lipid bilayer. Addition of ferrocyanide to the aqueous phase on one side of the bilayer, to trap MgOEP+ produced on the other side by MV+2, fails to increase the lifetime of the photovoltage. With a pH gradient across the bilayer, we observed only 5% of the photovoltage expected for the selective transport of H+ or OH- by MgOEP+. Thus, these measurements set the lower limit for the cross bilayer transit time of MgOEP+ or its charge in the range of 0.1-0.5 s.

Bacteriorhodopsins↗