In vivo characterization of activatable cell penetrating peptides for targeting protease activity in cancer

• Published in: Integrative biology (Cambridge) 2009-06, Vol.1 (5-6), p.382-393
• Main Authors: Olson, Emilia S, Aguilera, Todd A, Jiang, Tao, Ellies, Lesley G, Nguyen, Quyen T, Wong, Edmund H, Gross, Larry A, Tsien, Roger Y
• Format: Article
• Language: English
• Subjects: Animals; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacokinetics; Cell Line, Tumor; Drug Delivery Systems - methods; Enzyme Activation; Humans; Matrix Metalloproteinases - metabolism; Metabolic Clearance Rate; Mice; Neoplasms - metabolism; Organ Specificity; Tissue Distribution
• ISSN: 1757-9708; 1757-9694; 1757-9708
• DOI: 10.1039/b904890a

Activatable cell penetrating peptides (ACPPs) are novel in vivo targeting agents comprised of a polycationic cell penetrating peptide (CPP) connected via a cleavable linker to a neutralizing polyanion (). Adsorption and uptake into cells are inhibited until the linker is proteolyzed. An ACPP cleavable by matrix metalloproteinase-2 (MMP-2) in vitro was the first one demonstrated to work in a tumor model in vivo, but only HT-1080 xenografts and resected human squamous cell carcinomas were tested. Generality to other cancer types, in vivo selectivity of ACPPs for MMPs, and spatial resolution require further characterization. We now show that ACPPs can target many xenograft tumor models from different cancer sites, as well as a thoroughly studied transgenic model of spontaneous breast cancer (mouse mammary tumor virus promoter driving polyoma middle T antigen, MMTV-PyMT). Pharmacological inhibitors and genetic knockouts indicate that current ACPPs are selective for MMP-2 and MMP-9 in the above in vivo models. In accord with the known local distribution of MMP activity, accumulation is strongest at the tumor-stromal interface in primary tumors and associated metastases, indicating better spatial resolution (