Publications (2)0 Total impact
Article: Direct measurement of the extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy[show abstract] [hide abstract]
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.International Journal of Pharmaceutics.
Article: Enhanced tumor targeting and improved antitumor activity of doxorubicin by long-circulating liposomes containing amphipathic poly(ethylene glycol)[show abstract] [hide abstract]
ABSTRACT: Enhanced delivery of doxorubicin (DXR) to colon 26 in mice was studied by the long-circulating liposomes (LCL) composed of distearoylphosphatidylcholine cholesterol (DSPC CH) (1 1. m m) and 6 mol° distearoyl phosphatidyl ethanolamine (DSPE) derivatives of poly(ethylene glycol) (PEG) with an average molecular weight of 1000. LCL was approximately 100 nm in mean diameter and encapsulated DXR with > 98% entrapping efficiency by the transmembrane pH gradient method. The control liposomes (LP) which had the same lipid composition, similar size and DXR entrapment as LCL. but did not have amphipathic PEG. were used for comparison. Liposomal DXR and free DXR were injected intravenously at a dose of 5 mg DXR kg to Balb c mice implanted subcutaneously with colon 26 carcinoma. DXR encapsulated in LCL showed high blood levels up to 24 h after injection, compared with the corresponding DXR-LP and free DXR. The value of the area under the curve (AUC) of blood was approximately 2.4-or 810-fold higher than that of DXR-LP or free DXR. respectively. LCL decreased the uptake amount of DXR by the reticuloendothelial system (RES) of liver and spleen. Both liposomal formulations effectively reduced the DXR concentrations in heart compared with free DXR. Compared with DXR-LP or free drug. DXR-LCL produced an approximately 3.6-or 10.5-fold increased DXR level in tumor. respectively, at 6 h after injection. The AUC value of tumor tissue for DXR-LCL was 3.4-or 9.4-fold higher than that of DXR-LP or free DXR. respectively. These high tumor levels of DXR by LCL corresponded to the prolonged residence feature of liposomes. Therapeutic experiments were performed with three different formulations of DXR. Administration of DXR-LCL at a dose of 10 mg DXR kg resulted in effective retardation of tumor growth and 2-fold prolongation of survival times compared with DXR-LP. free drug and saline. Our results indicate that DXR encapsulated in long-circulating liposomes is significantly more active against colon 26 carcinoma than the conventional liposome (DSPC CH. 1:1. m m) formulation of DXR and free drug. Thus long-circulating liposomes should be useful carriers of chemotherapeutic agents for the treatment of solid tumor.International Journal of Pharmaceutics.