VIP receptors as molecular targets of breast cancer: implications for targeted imaging and drug delivery

• Published in: Journal of controlled release 2001-07, Vol.74 (1), p.129-134
• Main Authors: Dagar, S., Sekosan, M., Lee, B.S., Rubinstein, I., Önyüksel, H.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; BODIPY-Chol; Breast Neoplasms - diagnostic imaging; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Carcinogens; Drug Delivery Systems; DSPE–PEG–NHS; DSPE–PEG–VIP; Female; Fluorescent Dyes; General pharmacology; Liposomes; Mammary Neoplasms, Experimental - diagnostic imaging; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Methylnitrosourea; n-methyl nitrosourea; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; polyacrylamide; Polyethylene Glycols; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Receptors, Vasoactive Intestinal Peptide - biosynthesis; Receptors, Vasoactive Intestinal Peptide - drug effects; sodium dodecyl sulfate; Tumor targeting, VIP conjugation; vasoactive intestinal peptide; vasoactive intestinal peptide receptors
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(01)00326-1

Receptors for vasoactive intestinal peptide (VIP-R) are overexpressed in human breast cancer. This phenomenon may have important diagnostic and therapeutic implications because carrier systems loaded with imaging or therapeutic agents, and with surface ligands to VIP-R could potentially be actively targeted to breast cancer. Previously, we have prepared sterically stabilized liposomes (SSL) with VIP non-covalently associated on their surface. However, these liposomes were not able to actively target to breast cancer in rats in situ, most probably due to dissociation of non-covalently associated VIP from SSL. Hence, there is a need to conjugate VIP covalently to SSL. This study aims to begin to address this issue and to test the targeting ability of VIP–SSL to n-methyl nitrosourea (MNU)-induced rat breast cancer in vitro. First, VIP was conjugated to DSPE–PEG 3400–NHS [1,2-dioleoyl- sn-glycero-3-phosphoethanolamine- n-[poly(ethylene glycol)]- N-hydroxy succinamide, PEG M w 3400] under mild conditions to obtain a predominantly 1:1 conjugate of VIP and DSPE–PEG 3400 (DSPE–PEG 3400–VIP), as evidenced by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). Next, DSPE–PEG 3400–VIP was inserted into preformed fluorescent cholesterol (BODIPY-Chol) labeled SSL by incubation at 37°C. To test breast cancer targeting ability in vitro, these VIP–SSL were subsequently incubated with MNU-induced rat breast cancer tissue sections. The results showed that when compared to fluorescent SSL without VIP or non-covalently attached VIP, significantly more VIP–SSL were attached to rat breast cancer tissues indicating that SSL with covalently attached VIP can be actively targeted to rat breast cancer tissues. This targeted carrier system is currently being explored for functional imaging and targeted chemotherapy of breast cancer.