Protamine enhances uptake of cationic liposomes in angiogenic microvessels.
BACKGROUND
Cationic liposomes have been shown to target angiogenic endothelial cells of solid tumours. Supposing a charge-related mechanism might be responsible for liposome-endothelial interaction, we investigated the effect of intravenous pre-injection of the charged molecules protamine, a polycationic protein, and fucoidan, a polyanionic polysaccharide on the accumulation of cationic liposomes within the blood vessels of a solid tumour.


METHODS
Experiments were performed using the amelanotic hamster melanoma A-Mel-3 growing in a dorsal skinfold chamber of hamsters. Accumulation of fluorescently-labelled cationic liposomes was quantified by intravital macroscopy and digital image analysis of tumour (t) and surrounding normal host tissue (n) over an observation period of 6 h. All animals received an i.v. injection of cationic liposomes. Animals of the control group were pre-treated with an i.v. injection of 0.9% saline, while animals of group 2 received positively charged protamine and animals of group 3 negatively charged fucoidan prior to liposome injection.


RESULTS
In control animals i.v. injection of cationic liposomes revealed a preferential targeting of the tumour vessels, indicated by a maximal t/n ratio of 2.2 +/- 0.24 and a maximal fluorescence intensity (fmax) corresponding to the tumour of 66 +/- 12 [% standard]. While there were no significant differences of liposome accumulation within normal host tissue, accumulation of cationic liposomes within the tumour was significantly enhanced after the pre-administration of protamine (fmax: 117 +/- 12 [% standard]). The t/n ratio was significantly increased in protamine pre-treated animals (5.3 +/- 1.7) in comparison to control and fucoidan treated animals. In contrast, pre-injection of fucoidan resulted in reduced maximal fluorescence intensities in tumour (47 +/- 8 [% standard]) and normal surrounding host tissue.


CONCLUSIONS
Pre-administration of protamine increases the accumulation of cationic liposomes in a solid tumour animal model causing an increased selectivity of cationic liposomes in targeting angiogenic microvessels.
Eichhorn
M E
ME
Department of Surgery, Klinikum Grosshadern, University of Munich, Germany.
Strieth
S
S
Krasnici
S
S
Sauer
B
B
Teifel
M
M
Michaelis
U
U
Naujoks
K
K
Dellian
M
M
D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D002412:Cations; D006224:Cricetinae; D016503:Drug Delivery Systems / Q000379:methods*; D008081:Liposomes / Q000493:pharmacokinetics*; D008297:Male; D008647:Mesocricetus; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011134:Polysaccharides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011479:Protamines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D002412:Cations; D008081:Liposomes; D011134:Polysaccharides; D011479:Protamines; C007789:fucoidan