Tumor antivascular effects of liposome-incorporated drugs

The effective treatment of malignant brain tumors, as with many solid tumors, represents a difficult therapeutic challenge. Drug deposition and penetration is hindered by the physiological properties of the tumor and the physicochemical properties of the drug or its formulation. Formulations based on liposome drug carriers can deposit large fractions of the administered dose in model tumors and significantly alter drug pharmacokinetics (PK).; The goal of this work was to investigate the effect of repetitive dosing with long-circulating doxorubicin containing liposomes (SSL-DXR) on tumor vascular permeability and develop new strategies for combination therapies that may exploit tumor vascular permeability changes. In order to quantify the amount of DXR in limited plasma and tissue samples, a rapid extraction procedure and sensitive liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method were developed (Chapter 1). In Chapter 2, PK analysis was performed in order to investigate the effect of formulation and dosing on the biodisposition of free versus SSL-DXR. Repetitive administration of SSL-DXR, but not free DXR, resulted in a significant increase in the plasma half-life of DXR, and altered drug deposition in organs responsible for the clearance of liposomes, namely the liver and spleen. A descriptive PK model was developed and used test the hypothesis that repetitive administration of SSL-DXR altered plasma PK and mediated an increase in the permeability of the rat 9L gliosarcoma brain tumor vasculature (Chapter 3).; The effect of repetitive treatment on the barrier properties of the brain tumor was investigated (Chapter 3). Evans Blue dye and DXR deposition in tumor were significantly increased following repetitive dosing with SSL-DXR, but not after free drug.; An additional aim was to determine the feasibility of developing liposome formulations containing TNP-470, one of a new class of oncolytic agents that inhibit endothelial development related to angiogenesis (Chapter 4). Biophysical techniques, (circular dichroism and differential scanning calorimetry) and a newly developed LC-MS/MS method were used to examine drug-lipid interactions and screen prototype liposome formulations. The data suggest that TNP-470 can be associated with liposomes at concentrations appropriate for in vivo use.