Significant Increase in Antitumor Potency of Doxorubicin Hc1 by its Encapsulation in Pegylated Liposomes

Abstract

Pegylated liposomal doxorubicin (PL-DOX or DoxiP ) is currently being used in the clinic to treat solid tumors in humans (ovarian and breast cancer and Kaposi's sarcoma). Previous preclinical studies comparing the antitumor activity of nonliposomal doxorubicin and PL-DOX have shown that PL-DOX has significantly greater antitumor activity at equivalent doses, but these studies have not reported the degree of increase in antitumor potency associated with liposome encapsulation at lower doses of PL-DOX. The studies presented here were designed to determine the dose of PL-DOX that produces the same antitumor activity as the maximum tolerated dose (MTD) of nonliposomal doxorubicin. Conventional mice were inoculated with Lewis lung or C26 colon cells, and nude mice were inoculated with BT474 or MCF7 human breast cancer cells. Tumor-bearing mice were treated with nonliposomal doxorubicin at the MTD or with PL-DOX at the same or lower doses. As in previously published studies, PL-DOX had significantly greater antitumor activity than nonliposomal doxorubicin at the same dose levels (p < 0.05). In Lewis Lung and C26 Colon carcinoma, antitumor activity of nonliposomal doxorubicin (9 Journal of Liposome Research Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 08/11/15For personal use only. COLBERN ET AL.mg/kg, the MTD for conventional mice) was equivalent to antitumor activity of PL-DOX at 2 mg/kg, a 4.5-fold increase in antitumor potency. In human breast cancer xenografts (BT474 and MCF7) in nude mice, antitumor activity of nonliposomal doxorubicin (4 mg/kg, the MTD for nude mice) was equivalent to PL-DOX at 2 mg/kg, a 2-fold increase in potency. Based on results of these studies, the potency of PL-DOX is increased from 2to 4.5-fold conipared to nonliposomal doxorubicin.

Antimetastatic activities of pegylated liposomal doxorubicin in a murine metastatic lung cancer model

“…In accordance with previous reports (Cabanes et al 1998;Colbern et al 1999), the results of the present study indicated that PLD was able to dramatically retard the primary tumor growth. As shown in Figure 3, the tumor growth of LLC was virtually arrested.…”

Can Anthracycline Therapy for Pediatric Malignancies Be Less Cardiotoxic?

“…1) [17]. Liposomal doxorubicin was found to be more efficacious than doxorubicin in preclinical studies, with the activity of 1 to 2 mg/kg of liposomal doxorubicin being approximately equivalent to 9 mg/kg of doxorubicin [18]. Preclinical studies in beagles and rabbits also showed liposomal doxorubicin to be less cardiotoxic [19].…”

Antiangiogenic Targeting Liposomes Increase Therapeutic Efficacy for Solid Tumors

“…For example, PEGylated liposome-encapsulated doxorubicin has been reported to significantly improve the therapeutic index of doxorubicin in preclinical (10,12,13) and clinical studies (14 -16). Many of these drug delivery systems have entered the clinic and have been shown to improve the pharmacokinetics and pharmacodynamics of the drugs they deliver (6).…”