Direct measurement of the extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy

doi:10.1016/S0378-5173(96)04674-1

International Journal of Pharmaceutics

Volume 144, Issue 1, 1996, Pages 11-17

https://doi.org/10.1016/S0378-5173(96)04674-1 Get rights and content

Abstract

The extravasation of liposomes of different sizes into solid tumors after i.v. injection was visualized by in vivo fluorescence microscopy in mouse neuroblastoma C-1300-bearing mice. Liposomes composed of distearoylphosphatidylcholine/cholesterol (1/1 molar ratio) and 6 mol% distearoylphosphatidylethanolamine derivative of polyethyleneglycol (PEG) were prepared. The PEG-coated liposomes were fluorescently labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) as a liposome marker or with doxorubicin (DXR) as an aqueous-phase marker. Liposomes with an average diameter of 100–200 nm showed the greatest tumor accumulation. With time after injection of DiI-labeled liposomes, the tumor interstitial fluorescence intensity increased. Most fluorescent spots were located outside and around the vessel wall, indicating extravasation of intact liposomes. The perivascular distribution was heterogeneous. We also obtained the same fluorescence localization pattern with DXR released from extravasated liposomes after injection of DXR-encapsulated liposomes. No fluorescence from extravasated liposomes was detected in normal s.c. tissue; the fluorescent spots were observed only in the vessel wall. Our results indicate that small-size long-circulating liposomes are able to traverse the endothelium of blood vessels in tumors and extravasate into interstitial spaces. Moreover, encapsulated drug was released from extravasated liposomes in the tumor.

Reference (17)

AllenT.M. et al.
Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation halflives in vivo
Biochim. Biophys. Acta
(1991)
BlumeG. et al.
Liposomes for sustained drug release in vivo
Biochim. Biophys. Acta
(1990)
ClaassenE.
Post-formation fluorescent labeling of liposomal membranes
KlibanovA.L. et al.
Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes
FEBS Lett.
(1990)
KlibanovA.L. et al.
Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target
Biochim. Biophys. Acta
(1991)
MaruyamaK. et al.
Prolonged circulation time in vivo of large unilamellar liposomes composed of distearoylphosphatidylcholine and cholesterol containing amphipathic poly(ethylene glycol)
Biochim. Biophys. Acta
(1992)
MayerL.D. et al.
Uptake of adriamycin into large unilamellar vesicles in response to a pH gradient
Biochim. Biophys. Acta
(1986)
UnezakiS. et al.
Enhanced tumor targeting and improved antitumor activity of doxorubicin by long circulating liposomes containing amphipathic poly(ethylene glycol)
Int. J. Pharm.
(1995)

There are more references available in the full text version of this article.

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Direct measurement of the extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy

Abstract

Biochim. Biophys. Acta

Biochim. Biophys. Acta

FEBS Lett.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Int. J. Pharm.