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Biomedical subjects

K J Widder

Publications and source records attributed to K J Widder.

At least 19 recordsLinked to original sources
PubMed1998

Lack of bioeffects of ultrasound energy after intravenous administration of FS069 (Optison) in the anesthetized rabbit.

The current study was designed to provide a sensitive in vivo model to maximize the potential bioeffects (measured by hemolysis) of B-mode ultrasound energy in combination with FS069 (Optison). B-mode ultrasound energy was delivered to anesthetized male New Zealand white rabbits with a phased array 5 MHz transducer on a Hewlett-Packard Sonos 1500 ultrasonograph, with transmit level set to maximum (40 dB, approx 135 W/cm2). FS069 (Optison), latex particles in human albumin, or human albumin alone (vehicle) was infused via an ear vein at 0.6 mL/kg. No statistically significant changes were noted in serum free hemoglobin or lactate dehydrogenase either over time or between groups.

Albumins↗
PubMed1987

Magnetite albumin microspheres: a new MR contrast material.

A superparamagnetic MR contrast agent was synthesized by incorporating 150-250-A particles of magnetite (Fe3O4, Fe2O3) in 1-5 microns human serum albumin microspheres. Magnetite albumin microspheres (MAM) target almost exclusively to the reticuloendothelial system after IV administration, are stable in vitro and in vivo, and possess a long shelf life. The agent has a large magnetic susceptibility effect that selectively reduces T2 with little effect on T1. Biodistribution studies that use a dose of 20 mg MAM/kg show prompt clearance from the blood pool with marked decrease in T2 for rat liver (40%) and spleen (45%) with a small decrease in liver (5%) and spleen (10%) T1 values. Pulmonary T1 and T2 decrease transiently over the first 24 hr, while no significant changes were observed in other tissues. Imaging of a rabbit VX2 tumor model resulted in a 200% increase in the contrast ratio of VX2 tumor to normal liver on T2-weighted and mixed T1-/T2-weighted pulse sequences after administration of contrast agent. The extreme potency, excellent targeting, and apparent lack of toxicity of this agent suggest that MAM probably will have a clinical application in detecting focal hepatic and splenic lesions.

Animals↗
PubMed1986

Elevated erythrocyte adenosine deaminase activity in patients with acquired immunodeficiency syndrome.

Acquired immunodeficiency syndrome (AIDS) is an often fatal disease caused by a retrovirus frequently resulting in malignancy and/or opportunistic infection. Because the immune deficiency in AIDS is similar to that in some purine enzyme deficiencies, we measured erythrocyte adenosine deaminase (ADA) and purine nucleoside phosphorylase activities in patients with AIDS, heterosexual controls, and a high-risk asymptomatic population. We found that erythrocyte ADA activity was significantly elevated in patients with AIDS (40 +/- 11 nmol/mg of hemoglobin per hr, mean +/- SD) relative to heterosexual controls (25 +/- 10, P less than 0.001). We also measured ADA activity in a group of individuals at high risk for AIDS and found that approximately half had significantly elevated ADA activities (45 +/- 4, P less than 0.002) that correlated with the presence of antibody to the lymphadenopathy retrovirus. Purine nucleoside phosphorylase activity was relatively normal in patients with AIDS as well as in individuals at risk for AIDS. Increased ADA appears to be a diagnostic marker of AIDS and may be useful in conjunction with antibody to the AIDS-related retrovirus in detecting the presence of infection in asymptomatic high-risk individuals. These data also suggest that, in addition to the lymphocyte, the erythroid cell line may also be infected by the AIDS-related retrovirus.

Acquired Immunodeficiency Syndrome↗
PubMed1985

In vivo alteration of RES phagocytosis by magnetic albumin microspheres.

The effect of non-localized magnetically responsive albumin microspheres (MR-AMS) on RES phagocytic function was investigated. MR-AMS and MR-AMS containing Adriamycin (MR-AMS-ADR) were injected intravenously in rats at a dose which saturated all RES phagocytes. The ability of the RES to clear the bloodstream of a subsequent suspension of MR-AMS or streptococci was then analyzed over a three day period. MR-AMS clearance was enhanced after initial RES saturation with MR-AMS but depressed when the saturating agent was MR-AMS-ADR. Bloodstream clearance of streptococci was depressed by MR-AMS and MR-AMS-ADR. Localization of MR-AMS in the RES might depress RES phagocytosis by physical saturation of phagocytes or by a direct toxic effect of encapsulated chemotherapeutic agents.

Animals↗
PubMed1984

Magnetic targeting of microspheres in blood flow.

Magnetically responsive albumin microspheres can be targeted to the vasculature of specific organs, using extracorporeal magnetic sources. Experiments have been performed on targeting these microspheres to specific regions of normal and tumorous rat tails. This paper quantitatively analyzes the relationship between magnetic forces and the observed microsphere holding. The magnetic forces are determined by the magnetic responsiveness of the microspheres, and by the spatial field of the magnet; both of these are measured. The microsphere holding is defined as that fraction of the microspheres perfusing the tail which are held at a particular site; this is measured at various positions in the tail. The holding as a function of magnetic force is thereby established. To interpret the data, the dynamics of microspheres in blood flow is considered, including motion to a vessel wall, shear forces at the wall, and intersphere attraction. Overall, the method appears favorable for targeting therapeutic drugs to tumor sites in humans.

Animals↗
PubMed1983

Selective targeting of magnetic albumin microspheres containing low-dose doxorubicin: total remission in Yoshida sarcoma-bearing rats.

Magnetically responsive albumin microspheres containing doxorubicin hydrochloride were selectively localized in Yoshida sarcoma tumors. Tumors were implanted subcutaneously in the tail of Holtzman rats and allowed to grow to at least 200 mm2 size before initiation of experimental treatment. Drug-bearing microspheres at a dose level of either 0.5 or 2.5 mg/kg were infused proximal to the tumor via the ventral caudal artery. A bipolar permanent magnet was placed adjacent to the tumor during the infusion to effect localization. Control animals were treated with free doxorubicin infused intra-arterially at 5.0 mg/kg or 0.5 mg/kg. In other test groups animals received placebo microspheres localized in the tumor via influence of the external magnetic field, or drug-containing microspheres were infused without utilization of the magnet to effect localization. Of the 22 animals receiving magnetically localized doxorubicin microspheres 17 had total histological remission of the tumor. The remaining animals demonstrated marked tumor regression representing as much as 500-600 mm2 decrease in tumor size. While no deaths or metastases occurred in the groups receiving localized drug, animals treated with free doxorubicin, placebo microspheres or non-localized doxorubicin microspheres exhibited a significant increase in tumor size with metastases and subsequent death in 90-100% of the animals. No significant differences were noted in tumor regression/remission data between the 0.5 and 2.5 mg/kg dose levels of magnetically localized doxorubicin spheres. These results represent a significant advance in targeted chemotherapy in that 77% of the animals in the magnetically localized doxorubicin microsphere treatment groups exhibited total remission after only one regimen of drug therapy.

Animals↗
PubMed1983

Selective targeting of magnetic albumin microspheres to the Yoshida sarcoma: ultrastructural evaluation of microsphere disposition.

Magnetic albumin microspheres (1 micron average diameter) were selectively targeted to subcutaneous solid Yoshida sarcoma tumors (average size 450 mm2) in Holtzman rats. This was accomplished by placing an external magnet adjacent to the tumor while the microspheres were infused. Microspheres contained ultra-fine particles of Fe3O4 and no drug (placebo). Placebo microspheres were used due to the previously demonstrated rapid tumoricidal effect of targeted low-dose doxorubicin microspheres. Animals were killed 10 min, 60 min, 30 min, 24 hr and 72 hr after microsphere administration and tumors were examined by transmission electron microscopy to determine the in vivo disposition of the magnetically targeted microspheres. Using placebo microspheres, we have demonstrated microspheres endocytosed in endothelial cells as early as 10 min after infusion. By 30 min microspheres can be seen in the extravascular compartment, sitting adjacent to tumor cells and occasionally in tumor cells. By 24 hr the majority of microspheres have been endocytosed by tumor cells. Microspheres were still observed within tumor cells as late as 72 hr after administration. The rapid extravasation and cellular uptake of magnetically focused microspheres explains the extremely rapid tumoricidal effect previously observed when doxorubicin-containing microspheres were targeted to the tumor.

Animals↗
PubMed1981

Specific cell binding using staphylococcal protein A magnetic microspheres.

Protein A, a protein derived from Staphylococcus aureus, was incorporated into the matrix of magnetic albumin microspheres. Because staphylococcal protein A binds most subclasses of immunoglobulin G through their Fc portions, immunoglobulin may be rapidly bound to microspheres without chemical coupling agents or a diamino-heptane spacer group. Microspheres so prepared bind specifically to a given cell type when incubated in vitro with a heterogeneous cell population. The use of these microspheres as a drug carrier capable of cellular specificity as well as their ability to isolate homogeneous cell populations rapidly is discussed.

Animals↗
PubMed1981

In vivo kinetics of magnetically targeted low-dose doxorubicin.

The in vivo kinetics of low-dose doxorubicin (0.05 mg/kg), entrapped in a carrier and magnetically targeted, were characterized in a rat tail model. Tissue concentrations of doxorubicin at a preselected target site and in various organs were followed over time. As late as 60 min postinjection, 3.7 microgram/g of drug was found at the target site with no detectable drug levels found in any organ. In comparison, a 100-fold higher dose (5.0 mg/kg iv) of free doxorubicin yielded drug concentrations of 1.8 microgram/g at the target site and 15.0 microgram/kg in the pooled organs. Therefore, 1% of the free intravenous dose targeted magnetically yielded approximately twice the local doxorubicin concentration at a preselected target site with no detectable systemic distribution. Magnetic targeting of particulate drug carriers to localized disease sites is suggested as an efficient method of obtaining high local drug concentrations and may reduce many unwanted side effects from unrestricted systemic circulation.

Animals↗
PubMed1981

Tumor remission in Yoshida sarcoma-bearing rts by selective targeting of magnetic albumin microspheres containing doxorubicin.

Magnetically responsive albumin microspheres containing doxorubicin and magnetite (Fe3O4) were selectively targeted to Yoshida sarcoma tumors in rats by utilizing an extracorporeal magnet. Tumor cells were inoculated subcutaneously in the tail of rats, and the tumors were allowed to grow to an average size of 9 X 45 mm prior to initiating treatment. Drug-bearing microspheres (0.5 mg of doxorubicin per kg of body weight) were infused proximal to the tumor through the ventral caudal artery while the tumor was exposed to an external magnetic field of 5500 Oe for 30 min. Control animals received free doxorubicin administered either intravenously (5 mg/kg) or infused intraarterially (5 and 0.5 mg/kg), drug-bearing microspheres infused intraarterially (0.5mg/kg), without the external magnet, or placebo microspheres with magnetic localization. Of the 12 animals treated with a single dose in the experimental group, 9 exhibited total remission of the tumor, representing a disappearance of tumors as large as 60 mm in length. Marked tumor regression was observed in the remaining three rats, and no deaths or metastases occurred in the experimental group. In contrast, significant increases in tumor size with widespread metastases occurred in all control groups and most rats died. These experiments indicate that targeting of oncolytic agents to solid neoplasms by magnetic microspheres may be a means of increasing the efficacy and decreasing the toxicity of antitumor agents.

Albumins↗
PubMed1981

A rapid method for immunofluorescent staining of paraffin sections using iron-containing protein A microspheres.

A method to rapidly perform immunofluorescence or light microscopic staining on formalin-fixed paraffin sections has been devised utilizing magnetic albumin microspheres containing Staphylococcal protein A. Because the protein A constituent of the microspheres has the property of binding the Fc portion of immunoglobulin G (IgG) class antibodies, the microspheres can be used to rapidly bind antigen-antibody complexes by the Fc portion of the antibody. Deparaffinized sections were stained with fluorescein isothiocyanate-conjugated antibody (IgG fractions) by standard techniques, after which the protein A microspheres were layered over the sections. Distinct fluorescence of sections was noted with the addition of the microspheres, whereas only autofluorescence was present with direct staining alone. The microspheres were also visualized by light microscopy by a subsequent Prussian blue reaction, staining the Fe3O4 within the microsphere matrix. This method represents a more rapid method for identifying antigens in tissues embedded in paraffin than has previously been reported.

Fluorescent Antibody Technique↗
PubMed1980

In vitro release of biologically active adriamycin by magnetically responsive albumin microspheres.

The kinetic release of therapeutically active Adriamycin from two different heat-stabilized preparations of magnetically responsive albumin microspheres (1 micron) has been evaluated using a rapid in vitro bioassay-harvesting system. Release products are added to freshly plated monolayers of a malignant Fisher 344 rat fibrosarcoma cell line, and the inhibition of [3H]uridine incorporation into trichloroacetic acid-precipitable material (RNA) and whole cells is determined in a 6-hr microtiter assay. The latter harvesting technique utilizes semiautomated cell collection using a multiple sample harvester. Standard fluorometric drug analyses are used to quantitate the chemical release rates of Adriamycin and related degradation products (aglycones). By altering the temperature of albumin matrix stabilization from 22 to 135 degrees, the half-time for the release of therapeutically active drug has been varied from 15 min to 9 hr. The biological activity of drug products released by the highest temperature (135 degrees) preparation is 78% of that for the native free drug. These in vitro antitumor assays are used to predict the maximal rates of release that could occur at the tissue level under optimal conditions of in vivo targeting.

Albumins↗