Improved distribution and reduced toxicity of adriamycin bound to albumin-heparin microspheres

Abstract

Adriamycin (ADR) was formulated in albumin-heparin conjugate microspheres (AHCMS) to improve site-specific delivery and to reduce the toxicity of the drug. The effect of formulating ADR in AHCMS was investigated upon intrahepatic administration to male Wag/Rij rats. After intraveno-portal (i.v.p.) administration of ADR-AHCMS, ADR peak plasma concentrations were reduced 10-fold and ADR tissue levels of non-target tissues were significantly reduced, as compared to i.v.p, administration of the free drug. At an i.v.p, administered drug dose of 7.5 mg/kg, free ADR showed distinct signs of acute toxicity. At the same dose of ADR-AHCMS, signs of toxicity were absent. Cardiac function parameters which were determined using an isolated working heart model did not change as a result of i.v.p, administration of free ADR or ADR-AHCMS at a dose of 7.5 mg/kg. Heart weights of animals in the ADR-AHCMS or the free ADR groups, however, were significantly lower than controls. Dose tolerance studies after intrahepatic-arterial (i.h.a.) administration of free ADR, empty AHCMS and ADR-AHCMS in rats demonstrated that empty AHCMS are tolerated at a dose of 45 mg/kg. Free ADR was tolerated at a dose of 4 mg/kg, whereas ADR-AHCMS were tolerated up to a dose of 10 mg ADR/kg, as indicated by the survival.

Additive effect of concomitant multiple low-dose doxorubicin and thoracic irradiation on ex vivo cardiac performance of the rat heart

“…At drug doses that were well tolerated by the rat, single injections with doxorubicin alone (sd-DXR; up to 5 mg/kg) did not lead to a change in cardiac performance whereas multiple injections with low-dose doxorubicin alone (mld-DXR; cumulative dose of 10±20 mg/kg) led to a dose-dependent decrease in cardiac function. Using a similar technique to evaluate ex vivo cardiac function, Cremers et al (1995) could not detect a decrease in the heart function of rats after a single bolus injection (intraveno-portal administration of 7.5 mg/kg DXR) either, in spite of the . 2 Relation between cardiac output (ml kPa min A1 g heart A1 ) and cumulative dose of doxorubicin (mld-DXR; mg/kg).…”

“…Tables 1, 2). Besides dose and the number of injections, factors such as route of administration, rat strain and gender are reported to play a role in the development of extracardiac toxicities (Bertani et al 1982;Cremers et al 1995;van Hoesel et al 1986;Young et al 1989). van Hoesel et al (1986), for example, showed that male rats are more susceptible to DXR-induced kidney damage than female rats; moreover, the rat strain used in their study (LOU/M/Wsl) developed DXR-induced kidney damage in spite of multiple drug injections.…”

“…Experimental research on the combined eects of thoracic irradiation with doxorubicin has put much emphasis on the identi®cation of pathological changes in the heart (Eltringham et al 1975(Eltringham et al , 1979Fajardo et al 1976;Klmler et al 1984). However, prediction and/or quanti®cation of doxorubicin cardiotoxicity based only on morphological studies are questionable as morphological and light-microscopic changes do not always correlate with loss of cardiac function (Cremers et al 1995;Isner et al 1983;Reeves et al 1990) or electrocardiographic alterations (Zbinden and BraÈ ndle 1975). Data on cardiac function after combined treatment are limited (Kitahara et al 1993).…”

Biodegradable ion-exchange microspheres based on modified polylysines

“…If biodegradable, biocompatible ion-exchange microspheres are used, however, this may not be a problem anymore. Recently ion-exchange albumin-heparin conjugate microspheres (AHCMS) were developed, which were shown to be biodegradable and biocompatible and which could be loaded with ADR up to payloads of 34% [10][11][12][13]. The AHCMS are prepared from a soluble conjugate of albumin and heparin.…”