Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin

Abstract

Numerous studies have demonstrated that liposomal encapsulation decreases the life-threatening chronic and acute toxicities of doxorubicin in the face of unaltered or improved antitumor activity. Minimal attention has been paid to the encapsulation effect on the lesser toxicities of the drug, specifically the vesicant properties. In this report we assess the effect of the encapsulation of doxorubicin in an egg-yolk phosphatidylcholine (EPC) cholesterol liposome on the drug's topical toxicity. In addition, to ensure acceptable activity and reduction in toxicity comparable with those of previously assessed formulations, the cardiac and acute toxicities and antitumor activity of the liposomal doxorubicin complex were also investigated. Antitumor efficacy was assessed using the metastatic murine P815 mastocytoma model. Equivalent doses of free and encapsulated doxorubicin possessed the same antitumor activity in the prolongation of animal survival in 14-day survival studies conducted to assess the effect of liposomal encapsulation on the acute toxicity of this drug. The LD50 of liposomal doxorubicin was found to be 40 mg/kg, 53% higher than that of free doxorubicin (26 mg/kg). Histologic examination of cardiac sections taken from DBA/2J mice 7 days after a single i.v. injection of free or liposomal doxorubicin (25 mg/kg) revealed that the liposomal preparation was much less cardiotoxic. In animals receiving the free drug, edema, monocytic infiltration, and cell necrosis were evident. In contrast, those receiving the liposomal preparation demonstrated slight cellular edema but showed no evidence of cellular necrosis. To assess vesicant properties, DBA/2J mice were given a single s.c. injection (0.2 ml) of free or liposomal doxorubicin (2 mg/ml). Those receiving the free drug immediately developed erythema and edema at the injection site, which progressed to ulceration. Those receiving the liposomal complex developed slight erythema and edema but did not ulcerate at any time. All signs of irritation in this group had subsided 3 weeks postinjection. In summary, the liposomal complex used eliminated the vesicant properties of doxorubicin as well as significantly decreasing its cardiac and acute toxicities in the face of unaltered antitumor activity.

Strategy for the treatment of acute myelogenous leukemia based on folate receptor β–targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid

“…by guest www.bloodjournal.org From (5 mg/kg DOX). The free DOX dose (3 mg/kg) was chosen to correspond to a value below (at approximately 10% of) its previously reported LD 50 value 47 of approximately 26 mg/kg. The L-DOX or f-L-DOX dose (5 mg/kg) used was equitoxic to 3 mg/kg free DOX, based on previous findings showing that the LD 50 of L-DOX was between 1.5 and 2 times higher than that of free DOX in mice.…”

“…The L-DOX or f-L-DOX dose (5 mg/kg) used was equitoxic to 3 mg/kg free DOX, based on previous findings showing that the LD 50 of L-DOX was between 1.5 and 2 times higher than that of free DOX in mice. 47,48 Median survival time for the 4 groups of mice were 25.5, 28.5, 35, and more than 80 days, respectively (Figure 4). The data clearly indicated that L-DOX was more effective than free DOX in prolonging animal survival (P ϭ .0159; log-rank test), presumably because of the prolonged systemic circulation time of L-DOX compared to free DOX.…”

Amphotericin B Lipid Complex or Amphotericin B Multiple-Dose Administration to Rabbits with Elevated Plasma Cholesterol Levels: Pharmacokinetics in Plasma and Blood, Plasma Lipoprotein Levels, Distribution in Tissues, and Renal Toxicities

“…Despite the development of a number of new antifungal agents (10), amphotericin B (AmB) formulated as a micelle suspension with deoxycholate (Doc-AmB) remains one of the most effective agents in the treatment of systemic fungal infections (18). However, Doc-AmB use is often limited by the development of kidney toxicity manifested by renal vasoconstriction with a significant decrease in the glomerular filtration rate and renal plasma flow and by renal potassium and magnesium wasting (10,18,39).Incorporation of many drugs, including chemotherapeutic and antifungal agents, into liposomes minimizes toxicity without a loss of the pharmacological effect (2,15,22,29). In addition, when AmB was complexed with lipid to form AmB lipid complex (ABLC), AmB was selectively taken up by mononuclear phagocytes and delivered principally to the liver and the lung (16,28).…”

“…Incorporation of many drugs, including chemotherapeutic and antifungal agents, into liposomes minimizes toxicity without a loss of the pharmacological effect (2,15,22,29). In addition, when AmB was complexed with lipid to form AmB lipid complex (ABLC), AmB was selectively taken up by mononuclear phagocytes and delivered principally to the liver and the lung (16,28).…”

Release of Drugs from Liposomes Varies with Particle Size

“…[3][4][5] For example, liposomes are widely used to improve the delivery of many anticancer, antibiotic and antifungal drugs, such as doxorubicin, epirubicin, vincristine and ciprofloxacin. [6][7][8][9][10] The effectiveness of this formulation approach is dependent on the rate of drug release from the liposomes.…”