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Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma.
Clin Cancer Res. 2005 May 01; 11(9):3465-74.CC

Abstract

In vitro tumor cell culture models have illuminated the potential therapeutic utility of elevating the intracellular concentration of the antimitogenic and proapoptotic sphingolipid, ceramide. However, although cell-permeable, short-chain ceramide is an effective apoptotic agent in vitro, its use as an in vivo, systemically delivered therapeutic is limited by its inherent lipid hydrophobicity and physicochemical properties. Here, we report that the systemic i.v. delivery of C6-ceramide (C6) in a pegylated liposomal formulation significantly limited the growth of solid tumors in a syngeneic BALB/c mouse tumor model of breast adenocarcinoma. Over a 3-week treatment period, a well-tolerated dose of 36 mg/kg liposomal-C6 elicited a >6-fold reduction in tumor size compared with empty ghost liposomes. Histologic analyses of solid tumors from liposomal-C6-treated mice showed a marked increase in the presence of apoptotic cells, with a coincident decrease in cellular proliferation and in the development of a microvessel network. Liposomal-C6 accumulated within caveolae and mitochondria, suggesting putative mechanisms by which ceramide induces selective cancer cell cytotoxicity. A pharmacokinetic analysis of systemic liposomal-C6 delivery showed that the pegylated liposomal formulation follows first-order kinetics in the blood and achieves a steady-state concentration in tumor tissue. Confirming the therapeutic utility of i.v. liposomal-C6 administration, we also shown diminution of solid tumor growth in a human xenograft model of breast cancer. Together, these results indicate that bioactive ceramide analogues can be incorporated into pegylated liposomal vehicles for improved solubility, drug delivery, and antineoplastic efficacy.

Authors+Show Affiliations

Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15867249

Citation

Stover, Thomas C., et al. "Systemic Delivery of Liposomal Short-chain Ceramide Limits Solid Tumor Growth in Murine Models of Breast Adenocarcinoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 11, no. 9, 2005, pp. 3465-74.
Stover TC, Sharma A, Robertson GP, et al. Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin Cancer Res. 2005;11(9):3465-74.
Stover, T. C., Sharma, A., Robertson, G. P., & Kester, M. (2005). Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 11(9), 3465-74.
Stover TC, et al. Systemic Delivery of Liposomal Short-chain Ceramide Limits Solid Tumor Growth in Murine Models of Breast Adenocarcinoma. Clin Cancer Res. 2005 May 1;11(9):3465-74. PubMed PMID: 15867249.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. AU - Stover,Thomas C, AU - Sharma,Arati, AU - Robertson,Gavin P, AU - Kester,Mark, PY - 2005/5/4/pubmed PY - 2005/8/2/medline PY - 2005/5/4/entrez SP - 3465 EP - 74 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 11 IS - 9 N2 - In vitro tumor cell culture models have illuminated the potential therapeutic utility of elevating the intracellular concentration of the antimitogenic and proapoptotic sphingolipid, ceramide. However, although cell-permeable, short-chain ceramide is an effective apoptotic agent in vitro, its use as an in vivo, systemically delivered therapeutic is limited by its inherent lipid hydrophobicity and physicochemical properties. Here, we report that the systemic i.v. delivery of C6-ceramide (C6) in a pegylated liposomal formulation significantly limited the growth of solid tumors in a syngeneic BALB/c mouse tumor model of breast adenocarcinoma. Over a 3-week treatment period, a well-tolerated dose of 36 mg/kg liposomal-C6 elicited a >6-fold reduction in tumor size compared with empty ghost liposomes. Histologic analyses of solid tumors from liposomal-C6-treated mice showed a marked increase in the presence of apoptotic cells, with a coincident decrease in cellular proliferation and in the development of a microvessel network. Liposomal-C6 accumulated within caveolae and mitochondria, suggesting putative mechanisms by which ceramide induces selective cancer cell cytotoxicity. A pharmacokinetic analysis of systemic liposomal-C6 delivery showed that the pegylated liposomal formulation follows first-order kinetics in the blood and achieves a steady-state concentration in tumor tissue. Confirming the therapeutic utility of i.v. liposomal-C6 administration, we also shown diminution of solid tumor growth in a human xenograft model of breast cancer. Together, these results indicate that bioactive ceramide analogues can be incorporated into pegylated liposomal vehicles for improved solubility, drug delivery, and antineoplastic efficacy. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/15867249/Systemic_delivery_of_liposomal_short_chain_ceramide_limits_solid_tumor_growth_in_murine_models_of_breast_adenocarcinoma_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15867249 DB - PRIME DP - Unbound Medicine ER -