Lipo-Dox Mechanism of Action

Pharmacology: Lipo-Dox is a long-circulating pegylated liposomal formulation of doxorubicin HCl.
Pegylated liposomes contain surface-grafted segments of the hydrophilic polymer methoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surface forming a protective coating that reduces interactions between the liposomal lipid bilayer membrane and the plasma components, so the circulation time of pegylated liposomal doxorubicin is prolonged in the blood stream.
Pegylated liposomes are small enough (average diameter of approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumors. Evidence of penetration of pegylated liposomes from blood vessels and their entry and accumulation in tumors has been seen in mice with C-26 colon carcinoma tumors and in transgenic mice with Kaposi’s sarcoma-like lesions. The doxorubicin HCl could be encapsulated during liposome residence time in circulation, because of low permeability lipid matrix and internal liquid buffer system of the pegylated liposomes.
The plasma pharmacokinetics in humans are significant different between pegylated liposomal doxorubicin and standard doxorubicin HCl preparations. At lower doses (10 mg/m² - 20 mg/m²), pegylated liposomal doxorubicin displayed linear pharmacokinetics. However, the pharmacokinetics are displayed to be non-linear over the dose range of 10mg/m² to 60 mg/m².
The standard doxorubicin HCl displays extensive tissue distribution (volume of distribution, 700 to 1100 L/m²) and a rapid elimination clearance (24-73 L/h/m²). In contrast the pharmacokinetic profile of pegylated liposomal doxorubicin indicates that pegylated liposomal doxorubicin is confined mostly to the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. After the liposomes are extravasated and enter the tissue compartment, doxorubicin becomes available.
At equivalent doses, the plasma concentration and AUC values of pegylated liposomal doxorubicin which mostly exist as encapsulated in liposomeos (containing 90% to 95% of the measured doxorubicin) are significant higher than standard doxorubicin HCl.
Pharmacodynamics: Mechanism of action: The exact mechanism of the antitumor activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effect. This is probably the result of intercalation of the doxorubicin between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication.