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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Chemosensitization of carcinoma cells using epithelial cell adhesion molecule-targeted liposomal antisense against
Sajid Hussain1, Andreas Plückthun, Theresa M Allen
1Department of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Abstract:
Nanoscale drug delivery systems, such as sterically stabilized immunoliposomes binding to internalizing tumor-associated antigens, can increase therapeutic efficacy and reduce toxicity to normal tissues compared with nontargeted liposomes. The epithelial cell adhesion molecule (EpCAM) is of interest as a ligand for targeted drug delivery because it is abundantly expressed in solid tumors but shows limited distribution in normal tissues. To generate EpCAM-specific immunoliposomes for targeted cancer therapy, the humanized single-chain Fv antibody fragment 4D5MOCB was covalently linked to the exterior of coated cationic liposomes. As anticancer agent, we encapsulated the previously described antisense oligonucleotide 4625 specific for both bcl-2 and bcl-xL. The EpCAM-targeted immunoliposomes (SIL25) showed specific binding to EpCAM-overexpressing tumor cells, with a 10- to 20-fold increase in binding compared with nontargeted control liposomes. No enhanced binding was observed on EpCAM-negative control cells. On cell binding, SIL25 was efficiently internalized by receptor-mediated endocytosis, ultimately leading to down-regulation of both bcl-2 and bcl-xL expression on both the mRNA and protein level, which resulted in enhanced tumor cell apoptosis. In combination experiments, the use of SIL25 led to a 2- to 5-fold sensitization of EpCAM-positive tumor cells of diverse origin to death induction by doxorubicin. Our data show the promise of EpCAM-specific drug delivery systems, such as antisense-loaded immunoliposomes, for targeted cancer therapy.
Insights
Targeted cancer therapy using EpCAM-specific immunoliposomes loaded with antisense oligonucleotides effectively targets tumor cells. This novel drug delivery system enhances apoptosis and sensitizes cancer cells to chemotherapy, showing promise for improved treatment outcomes.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Nanoscale drug delivery systems, like immunoliposomes, offer improved therapeutic efficacy and reduced toxicity.
- Epithelial cell adhesion molecule (EpCAM) is a promising target for cancer therapy due to its high expression in tumors and limited presence in normal tissues.
Purpose of the Study:
- To develop and evaluate EpCAM-specific immunoliposomes for targeted cancer therapy.
- To encapsulate an antisense oligonucleotide targeting bcl-2 and bcl-xL within these immunoliposomes.
Main Methods:
- Covalent linkage of the humanized single-chain Fv antibody fragment 4D5MOCB to cationic liposomes to create EpCAM-targeted immunoliposomes (SIL25).
- Encapsulation of antisense oligonucleotide 4625 within SIL25.
- Assessment of SIL25 binding specificity and internalization via receptor-mediated endocytosis in EpCAM-positive and EpCAM-negative cells.
- Evaluation of bcl-2 and bcl-xL down-regulation at mRNA and protein levels.
- Combination experiments with doxorubicin to assess chemosensitization.
Main Results:
- SIL25 demonstrated 10- to 20-fold increased specific binding to EpCAM-overexpressing tumor cells compared to control liposomes.
- SIL25 was efficiently internalized by tumor cells, leading to down-regulation of bcl-2 and bcl-xL.
- This resulted in enhanced tumor cell apoptosis.
- SIL25 sensitized EpCAM-positive tumor cells to doxorubicin-induced death by 2- to 5-fold.
Conclusions:
- EpCAM-specific immunoliposomes loaded with antisense oligonucleotides represent a promising targeted drug delivery strategy for cancer therapy.
- This approach effectively targets tumor cells, induces apoptosis, and enhances sensitivity to conventional chemotherapy.
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