Tumour uptake of doxorubicin in polyethylene glycol-coated liposomes and therapeutic effect against a xenografted human pancreatic carcinoma

Abstract

Summary This study tested the therapeutic efficacy of doxorubicin hydrochloride in two formulations: free in saline suspension and encapsulated in polyethylene glycol-coated, long-circulating liposomes. The drug formulations at a dose level of 3 mg doxorubicin per kg body weight were injected intravenously to treat the human pancreatic carcinoma AsPC-1, implanted s.c. into nude Swiss mice. Liposomeencapsulated doxorubicin was significantly more effective in inhibiting tumour growth and in effecting cures, and had only minor systemic toxic side-effects, indicated by a transient weight loss. Confocal laser scanning microscopy was used to determine the tumour uptake and the clearance of doxorubicin in the free and in the liposomal forms. The liposome-encapsulated doxorubicin entered the tumour in greater quantity, and remained in the tumour longer, than the free drug. The liposome formulation produced a sixfold or greater increase in doxorubicin at the disease site. It is probable that increased penetration into the tumour, and long presence with slow drug release from liposomes in the tumour, account for the enhanced therapeutic effect when the drug was encapsulated in polyethylene glycol-coated liposomes.

Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx™) in human osteosarcoma xenografts

“…Although liposomal delivery of doxorubicin improves the tumour uptake compared to free doxorubicin, the drug distribution within the tumour tissue is still heterogeneous (Vaage et al, 1997;Davies et al, 2004). The present work showed that hyaluronidase increased the transcapillary pressure gradient in OHS xenografts, thereby improving the uptake and distribution of liposomal doxorubicin.…”

“…Hence, the toxicity to normal tissue is reduced considerably, especially cardiotoxicity (Harris et al, 2002). Although liposomal delivery of doxorubicin improves the tumour uptake compared to free doxorubicin, the drug distribution within the tumour tissue is still heterogeneous (Vaage et al, 1997;Davies et al, 2004).…”

A multicentre phase II study of carboplatin plus pegylated liposomal doxorubicin as first-line chemotherapy for patients with advanced or recurrent endometrial carcinoma: the END-1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) group

“…The use of carboplatin instead of cisplatin has been suggested to improve tolerability with the same efficacy (Santin et al, 2004). Pegylated liposomal doxorubicin (PLD) is an interesting formulation of doxorubicin, in which the anthracycline is encapsulated in liposomes to obtain pharmacokinetic properties not available with conventional formulation of the drug: lower plasma concentration peak, lower clearance, smaller distribution volume, longer half-life, and higher area under curve (AUC), resulting in a different toxicity profile (Vaage et al, 1993;Sakakibara et al, 1996;Vaage et al, 1997;Safra et al, 2001). Moreover, the size of the liposomes allows selective accumulation in the tumour vascular bed following extravasation through the leaky tumour vasculature (Vaage et al, 1997).…”

“…Pegylated liposomal doxorubicin (PLD) is an interesting formulation of doxorubicin, in which the anthracycline is encapsulated in liposomes to obtain pharmacokinetic properties not available with conventional formulation of the drug: lower plasma concentration peak, lower clearance, smaller distribution volume, longer half-life, and higher area under curve (AUC), resulting in a different toxicity profile (Vaage et al, 1993;Sakakibara et al, 1996;Vaage et al, 1997;Safra et al, 2001). Moreover, the size of the liposomes allows selective accumulation in the tumour vascular bed following extravasation through the leaky tumour vasculature (Vaage et al, 1997). Furthermore, the special coating (pegylation) of the liposomes is associated with reduced clearance by the mononuclear phagocyte system, thus helping to maintain active drug concentrations for a long time (Vaage et al, 1993;Sakakibara et al, 1996;Vaage et al, 1997;Safra et al, 2001).…”

“…Moreover, the size of the liposomes allows selective accumulation in the tumour vascular bed following extravasation through the leaky tumour vasculature (Vaage et al, 1997). Furthermore, the special coating (pegylation) of the liposomes is associated with reduced clearance by the mononuclear phagocyte system, thus helping to maintain active drug concentrations for a long time (Vaage et al, 1993;Sakakibara et al, 1996;Vaage et al, 1997;Safra et al, 2001).…”