Antitumor activity of an epithelial cell adhesion molecule–targeted nanovesicular drug delivery system

Abstract

Site-specific delivery of anticancer agents to tumors represents a promising therapeutic strategy because it increases efficacy and reduces toxicity to normal tissues compared with untargeted drugs. Sterically stabilized immunoliposomes (SIL), guided by antibodies that specifically bind to well internalizing antigens on the tumor cell surface, are effective nanoscale delivery systems capable of accumulating large quantities of anticancer agents at the tumor site. The epithelial cell adhesion molecule (EpCAM) holds major promise as a target for antibodybased cancer therapy due to its abundant expression in many solid tumors and its limited distribution in normal tissues. We generated EpCAM-directed immunoliposomes by covalently coupling the humanized single-chain Fv antibody fragment 4D5MOCB to the surface of sterically stabilized liposomes loaded with the anticancer agent doxorubicin. In vitro, the doxorubicin-loaded immunoliposomes (SIL-Dox) showed efficient cell binding and internalization and were significantly more cytotoxic against EpCAM-positive tumor cells than nontargeted liposomes (SL-Dox). In athymic mice bearing established human tumor xenografts, pharmacokinetic and biodistribution analysis of SIL-Dox revealed long circulation times in the blood with a half-life of 11 h and effective time-dependent tumor localization, resulting in up to 15% injected dose per gram tissue. These favorable pharmacokinetic properties translated into potent antitumor activity, which resulted in significant growth inhibition (compared with control mice), and was more pronounced than that of doxorubicin alone and nontargeted SL-Dox at low, nontoxic doses. Our data show the promise of EpCAM-directed nanovesicular drug delivery for targeted therapy of solid tumors.

A Novel Fusion Toxin Derived from an EpCAM-Specific Designed Ankyrin Repeat Protein Has Potent Antitumor Activity

“…The epithelial cell adhesion molecule (EpCAM) has also emerged as a promising structure for targeted therapy of solid tumors. One reason is that its efficient internalization promotes access of surface bound effector molecules to intracellular targets (11)(12)(13)(14). EpCAM is a homophilic cell adhesion molecule of 39 to 42 kDa, consisting of an extracellular domain with an epidermal growth factor-like and a human thyroglobulin-like domain, and a short cytoplasmic domain.…”

Predictive Models of Diffusive Nanoparticle Transport in 3-Dimensional Tumor Cell Spheroids

“…The second formulation comprised DOTAP:DPPC:DOPE:Chol: PEG-DSPE:Rhod-DOPE (20:5:19:50:5:1 molar ratio, referred to as C20-5 liposomes). Liposomes were prepared using the standard thin-film hydration method (15), with some modifications. Briefly, lipids were dissolved in chloroform, and Rhod-DOPE was added.…”

Endocytosis of PEGylated Agents Enhances Cancer Imaging and Anticancer Efficacy

“…Tumor-binding ligands such as peptides (8,9) and antibodies (10,11) may be conjugated to the distal terminus of PEGylated nanoparticles and macromolecules to increase targeting specificity. Thus far, various tumor-associated antigens or receptors have been validated as targets for PEGylated compounds, especially for immunoliposomes (10)(11)(12)(13)(14)(15). These tumor-associated antigens or receptors can be either endocytic or nonendocytic.…”