Treatment > Immunotherapy

Meeting Abstract

Development of immunoliposomes for brain tumor treatment

Christoph Mamot, Daryl C Drummond, Keelung Hong, Dmitri B Kirpotin, James D Marks, John Nguyen, Krys Bankiewicz, Mitchel Berger, John W Park

UCSF Cancer Center, San Francisco, CA; CPMCRI, San Francisco, CA

Purpose. We have developed immunoliposomes (ILs) that bind EGFR or EGFRvIII and internalize in tumor cells, enabling intracellular delivery of potent anticancer agents.
ILs were further developed in conjunction with convection-enhanced delivery (CED) for integrated targeting of brain tumors.

Methods. ILs were constructed modularly with various MAb fragments covalently linked to liposomes containing various drugs.
MAb fragments included cetuximab-Fab´, which binds to both EGFR and EGFRvIII, and novel human scFvs from phage antibody libraries.

Results. Flow cytometry and fluorescence microscopy showed that anti-EGFR ILs efficiently bound and internalized in EGFR-overexpressing cells, including glioma (U87), carcinoma (A431, MDA-468), and stable transfectants.
Furthermore, anti-EGFR ILs did not bind to control cells (SKBR-3, MCF-7).
ILs containing cetuximab-Fab´ showed >1000-fold increased accumulation in NR6-EGFRvIII stable transfectants vs. parental NR6 cells.
Quantitative internalization studies indicated binding of anti-EGFR ILs to MDA-468 cells within 5 min, followed by intracellular accumulation beginning at 15 min; total uptake reached ~13,000 ILs/cell.
In contrast, uptake of non-targeted liposomes in MDA-468 cells and anti-EGFR ILs in MCF-7 cells was >40-fold less.
Anti-EGFR ILs were used to deliver various encapsulated drugs including doxorubicin, vinorelbine, methotrexate, and aminoellipticine to EGFR/EGFRvIII-overexpressing target cells.
In each case, the immunoliposome drug was markedly more cytotoxic than the same non-targeted liposomal drug in target cells, while equivalent against non-EGFR/EGFRvIII-overexpressing cells.
In vivo, fluorescence-labeled liposomes administered via CED into mouse striatum showed extensive distribution throughout the brainstem.
With CED into intracranial U87 glioma xenografts in nude rats, liposomes penetrated throughout tumor tissue with extension into surrounding normal brain.

Conclusion. Immunoliposomes provide efficient and targeted drug delivery to EGFR or EGFRvIII-overexpressing tumor cells, and can be used in conjunction with CED for combined molecular and regional targeting of brain tumors.

© Copyright 2002 American Society of Clinical Oncology