Thomas A. Fritz

Liposomal mr contrast agents

AbstractLiposomes are spheres composed of relatively non-toxic and biodegradable lipids which are useful for entrapping a variety of drugs, decreasing drug toxicity and targeting. For a number of years we have evaluated the use of liposomes as MR contrast agents. We have prepared and tested contrast agents entrapped within the internal aqueous space of liposomes as well as liposomes incorporating lipophilic contrast agents in the lipid bilayer. When chelates such as Gd-DTPA are entrapped within the internal aqueous space of lipid vesicles, delivery is primarily to the Kupffer cells and clearance is slow. Manganese ions entrapped within lipid vesicles cause more enhancement per micromole of paramagnetic ion than gadolinium. Lipophilic derivatives of manganese EDTA chelates when incorporated into liposomes confer the greatest hepatic enhancement per micromole of metal ion and have favorable clearance kinetics. An apparently hepatocyte specific liposomal MR contrast agent has been prepared based upon a lipop...

Phase I clinical trials of MRX-115: A new ultrasound contrast agent

RATIONALE AND OBJECTIVES Stabilized microbubbles are under development as contrast agents for medical ultrasound. The authors report the results of Phase I clinical trials of a new ultrasound contrast agent based on lipidencapsulated perfluorocarbon gas microbubbles. METHODS Lipids encapsulating perfluoropropane gas (Aerosomes MRX-115, ImaRx Pharmaceutical Corp., Tucson, AZ) were evaluated in Phase I clinical trials. Two separate studies were performed. The first was a single escalating-dose study (n = 30 subjects), and the second was a multiple-dose study (n = 18 subjects) with rechallenge in several subjects (n = 4) after 21 days. Echocardiographic examinations were performed before and after contrast agent for each test drug administration for both studies, with the exception of the rechallenge group. Doses tested in the single-dose study ranged from 0.005 mL/kg to 0.100 mL/kg body weight. In the multiple-dose study, five doses of 0.005 mL/ kg to 0.030 mL/kg (0.025-0.150 mL/kg total dose) were evaluated. Studies were single-masked, placebo-controlled, and safety assessment and adverse events were monitored. RESULTS All doses in both studies were well tolerated with no treatment-related changes in safety measures for either study. Left ventricular cavity and myocardial enhancement were seen with all doses of MRX-115. CONCLUSIONS MRX-115 is a promising new intravascular ultrasound contrast agent that was safe and well tolerated at the doses evaluated in these studies.

Manganese-based liposomes. Comparative approaches.

RATIONALE AND OBJECTIVES.The purpose of this study was to further develop and compare manganese-based liposomes prepared by two different approaches wherein a manganese ion was entrapped within the internal aqueous space of the vesicles or into the bilayer surface via membrane bound complexes. METHODS.Small unilamellar liposomes (SUVs) were prepared entrapping manganese chloride. Alkylated complexes of manganese were prepared and also incorporated into SUVs. The two different manganese-based liposomes were compared for in-vitro relaxivity, stability, toxicity, and in-vivo imaging in rats with liver tumors. RESULTS.Liposomes entrapping manganese had a concentration-dependent change in relaxivity that was maximal at a several-fold molar excess of phospholipid relative to manganese ion. Liposomes bearing membrane-bound complexes showed relaxivity inversely proportional to vesicle size. In-vivo imaging showed greater and more specific hepatic enhancement with manganese liposomes bearing alkylated complexes than those entrapping manganese ion. CONCLUSIONS.Correlation effects likely explain the increased relaxivity of manganese entrapped in phospholipid vesicles. Greater efficacy, however, is afforded by liposomes bearing alkylated complexes.

Gas-filled lipid bilayers as ultrasound contrast agents

Unger E, Shen D, Fritz T, Kulik B, Lund P, Wu G-L, Yel-lowhair D, Ramaswami R, Matsunaga T. Gas-filled lipid bilayers as ultrasound contrast agents. Invest Radiol 1994;29: S134–S136.

Gas-filled liposomes as echocardiographic contrast agents in rabbits with myocardial infarcts.

RATIONALE AND OBJECTIVES The authors evaluated gas-filled liposomes as echocardiographic contrast agents in rabbits with myocardial infarcts. METHODS Ten rabbits underwent ligation of the left anterior descending coronary artery. Five animals underwent echocardiography before and after production of myocardial infarct (MI) and four animals had post-MI imaging only. In either case, images were obtained before and after injection of a single dose of 1 mL of gas-filed liposomes. Three radiologists blinded to clinical information reviewed the pre- and postcontrast images and assessed endomyocardial border definition, wall motion, confidence levels for normal versus abnormal wall motion and visualization of papillary muscle and mitral valve. RESULTS Postcontrast scans showed significant improvement (P < .05) in endomyocardial border definition, visualization of wall motion, papillary muscle and mitral valve as well as increased reader confidence level. CONCLUSIONS These results are encouraging and suggest that gas-filled liposomes may be a useful contrast agent for echocardiography.

Gas fIIIed lipid bilayers as imaging contrast agents

AbstractGas bubbles are highly efficient reflectors of sound and are therefore useful as contrast agents for diagnostic ultrasound. In general, in order to pass through the pulmonary circulation and provide contrast for the systemic circulation the gas bubbles must be of defined diameter and stabilized by a coating material. Our group has developed gas bubbles which are stabilized within lipid bilayers. These bubbles may be formed with stable size and gas content. In vivo studies in rabbit and porcine models show sustained ventricular enhancement, increased arterial doppler signal following intravenous injection and myocardial perfusion enhancement following injection into the aortic root of pigs. Preliminary toxicity studies suggest that the therapeutic index (LD50 dose divided by imaging dose) is greater than 400 to 1. For therapy, these agents may be used to increase the capture of ultrasonic energy for hyperthermia to augment local tissue heating. An exciting new class of agents based upon gas fIIIed ...

DETAILED TOXICITY STUDIES OF LIPOSOMAL GADOLINIUM-DTPA

Acute, subacute, and delayed toxicity testing was assessed in mice for liposomal gadolinium-DTPA (Gd-DTPA), blank liposomes, and nonliposomal Gd-DTPA. In the subacute experiments mice were injected intravenously (IV) with 0.3 mmol/kg Gd-DTPA per day for 30 days in the form of either free Gd-DTPA, liposomal Gd-DTPA, or an equivalent amount of lipid in blank liposomes without Gd-DTPA. The interpolated acute LD50 of liposomal and nonliposomal Gd-DTPA, estimated as a means of identifying the approximate level, was similar (LD50 = 5.7 mmol/kg Gd-DTPA). In subacute toxicity testing, prolonged high doses of liposomal Gd-DTPA caused splenomegaly, cardiomegaly, lymphocytopenia and hypergammaglobulinemia (P less than .05). Nonliposomal Gd-DTPA caused mild cardiomegaly and altered liver enzymes (P less than .05). Blank liposomes caused relatively mild splenomegaly (P less than .05) but few other changes. Delayed testing three months after the subacute testing showed that most of the changes caused by the liposomal Gd-DTPA were reversible.