Large anti-HER2/neu liposomes for potential targeted intraperitoneal therapy of micrometastatic cancer

Abstract

Effective targeting and killing of intraperitoneally disseminated micrometastases remains a challenge.

Objective/Methods: In this work, we evaluated the potential of antibody-labeled PEGylated large liposomes as vehicles for direct intraperitoneal (i.p.) drug delivery with the aim to enhance the tumor-to-normal organ ratio and to improve the bioexposure of cancer cells to the delivered therapeutics while shifting the toxicities toward the spleen. These targeted liposomes are designed to combine: (1) specific targeting to and internalization by cancer cells mediated by liposome-conjugated tumor-specific antibodies, (2) slow clearance from the peritoneal cavity, and (3) shift of normal organ toxicities from the liver to the spleen due to their relatively large size.

Results: Conjugation of anti-HER2/neu antibodies to the surface of large (approximately 600 nm in diameter) PEGylated liposomes results in fast, specific binding of targeted liposomes to cancer cells in vitro, followed by considerable cellular internalization. In vivo, after i.p. administration, these liposomes exhibit fast, specific binding to i.p. cancerous tumors. Large liposomes are slowly cleared from the peritoneal cavity, and they exhibit increased uptake by the spleen relative to the liver, while targeted large liposomes demonstrate specific tumor uptake at early times. Although tissue and tumor uptake are greater for cationic liposomes, the tumor-to-liver and spleen-to-liver ratios are similar for both membrane compositions, suggesting a primary role for the liposome’s size, compared to the liposome’s surface charge.

Conclusions: The findings of this study suggest that large targeted liposomes administered i.p. could be a potent drug-delivery strategy for locoregional therapy of i.p. micrometastatic tumors.

Keywords::

• Large liposomes
• targeted liposomes
• trastuzumab
• intraperitoneal therapy
• ovarian cancer

Acknowledgments

The authors thank Iwao Teraoka, PhD (Polytechnic Institute of NYU, Brooklyn, NY) for use of the DLS apparatus.

Declaration of interest

This study was supported by Concept and IDEA awards DAMD170010657 and DAMD170310755, respectively, from the U.S. Army Medical Research and Materiel Command, grant R01 CA55349 from the National Institutes of Health (Bethesda, Maryland, USA), the Doris Duke Charitable Foundation, the Experimental Therapeutics Center, the Goodwin Commonwealth Foundation for Cancer Research, and the Dr. Frederick E.G. Valergakis Graduate Research Grant of the Hellenic University Club of New York.