Surface functionalized nanoparticles for proximity-activated detection and imaging of breast cancer.

Abstract

Abstract Abstract #6002 Site directed therapy of metastatic and primary breast cancer promises to minimize systemic toxicity associated with chemotherapy agents that have no specificity for pathologic tissues. We have developed a multifunctionalized nanoparticle specifically designed to target breast cancer, including metastases.
 Quantum dots (QDs) were functionalized with a matrilysin (MMP-7) cleavable, proximity activated substrate, PEG-peptide-PEG (PA construct), where cleavage occurs at the peptide bridge. The QDs were further functionalized with folic acid, a strong breast cancer cell targeting ligand with well-known binding to some normal tissues. The construct initially conceals the folate ligand and reduces binding to non-target tissues. MMP-7 activated cleavage of the PA construct and subsequent unmasking of the folate ligand occurs only at the site of the breast tumor, resulting in a proximity activated targeting (PAT) system. The activity of QDs functionalized with both the PA construct and folic acid (FA-QD-PA) was compared to QDs functionalized with only folic acid (QD-FA).
 Cellular association of QD-FA nanoparticles with the human breast cancer cell line MDA-MB-231 revealed that 61.9 ± 6.5% of the cells were fluorescently labeled. Addition of the PA construct reduced QD-FA recognition by MDA-MB-231 cells to 2.1 ± 0.4%. MMP-7 cleavage of the protected FA-QD-PA construct restored MDA-MB-231 recognition to 21.9 ± 5.4 %, a significant increase compare to the uncleaved multifunctional nanoparticle construct (one-way ANOVA, p*<0.001, n=3). This in vitro data suggests that the PAT nanoparticle model could function effectively in vivo for specific targeting of breast cancer and metastasis. In the next phase of research, the ability of the FA-QD-PA and FA-QD nanoparticles to detect breast cancer in vivo will be tested using murine models of human breast cancer.
 This work was funded by the US Army Medical Research and Material Command CDMRP under award BC043908. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6002.