Antivascular and antitumor activities of liposome-associated drugs.
Particulate drug carriers offer unique opportunities to improve tumor therapy through several different mechanisms. Liposomes may (1) assist in formulation of poorly-soluble therapeutic agents, (2) provide a slow-release vehicle to achieve pharmacokinetic profiles that maximize the therapeutic index, or (3) behave as long-circulating nano-particulates that can extravasate in the hyperpermeable regions of tumor vasculature. For paclitaxel, liposomes provide an aid to formulation. In the intracranial rat 9L brain tumor model, paclitaxel liposomes reduced dose-limiting toxicity and mediated a 40% increase in median survival. Free drug did not extend survival. Doxorubicin entrapped within sterically-stabilized liposomes (SSL-DXR) represents a long-circulating formulation that can extravasate within tumors and enhance drug deposition. Repetitive dosing with SSL-DXR mediated a 30% extension in median lifespan of animals bearing advanced 9L tumors. Fluorescence microscopic imaging revealed non-uniform, sporadic deposition of liposomes within the tumor. Magnetic resonance imaging showed that repetitive dosing with SSL-DXR, but not free drug, resulted in vascular collapse and microhemorrhage within tumors. Exploiting this antivascular effect may provide a new means to enhance tumor therapy, and suggests the utility of combination therapy with agents such as paclitaxel that have antiangiogenic effects on tumors.
Straubinger
Robert M
RM
The Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260-1200, USA. rms@Buffalo.edu
Arnold
Robert D
RD
Zhou
Rong
R
Mazurchuk
Richard
R
Slack
Jeanine E
JE
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage* / Q000493:pharmacokinetics
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes