Tumor Uptake and Therapeutic Effects of Drugs Encapsulated in Long-Circulating Pegylated Stealth® Liposomes

Abstract

In this study, tumor uptake and clearance of doxorubicin were determined for two formulations of the drug: the free form in aqueous solution and the encapsulated form in polyethylene glycol-coated (pegylated, STEALTH®) liposomes composed of cholesterol/hydrogenated soy phosphatidylcholine/ polyethylene glycol-distearoyl-phosphatidyl-ethanolamine (Doxil®). The determinations used confocal laser scanning microscopy in a pancreatic carcinoma model in nude mice. The movement of pegylated liposomes containing doxorubicin from blood vessels into tumors was studied using confocal microscopy combined with autoradiography of liposomes containing a tritium-labeled phospholipid. Laser microscopy measurements showed that the lipo-some-encapsulated doxorubicin remained in the tumor longer than the free drug and produced a six-fold increase in the area under the concentration-time curve (AUC). Autoradiography showed that the extravasated tritium-labeled lipid had entered the nuclei as well as the cytoplasm of tumor cells. The authors also compared the therapeutic effects of intravenous cisplatin, doxorubicin hydrochloride, vincristine sulfate, and vinorelbine tartrate, each in the aqueous free form or encapsulated in pegylated liposomes. In this pancreatic carcinoma model, the liposome-encapsulated drugs were all more effective than the free drugs in inhibiting tumor growth and in producing cures. Except for cisplatin, all of the free drugs had toxic systemic side effects indicated by an average weight loss of 3 to 5%, which was recovered by 2 to 4 weeks after the last treatment. The liposome-encapsulated drugs did not cause weight loss.

Keywords::

• Liposomes
• Drug uptake
• Therapeutic effects