Gastrointestinal and gynecological
malignancies disseminate in the peritoneal cavity - a condition known as
peritoneal carcinomatosis (PC). Intraperitoneal (IP) administration can be used to improve therapeutic index of anticancer drugs used for PC treatment. Activity of IP anticancer drugs can be further potentiated by encapsulation in nanocarriers and/or affinity targeting with
tumor-specific affinity
ligands, such as
tumor homing
peptides. Here we evaluated a novel
tumor penetrating
peptide, linTT1 (AKRGARSTA), as a PC targeting
ligand for nanoparticles. We first demonstrated that the primary homing receptor for linTT1, p32 (or gC1qR), is expressed on the cell surface of peritoneal
carcinoma cell lines of gastric (MKN-45P), ovarian (SKOV-3), and colon (CT-26) origin, and that peritoneal
tumors in mice and clinical peritoneal
carcinoma explants express p32
protein accessible from the IP space.
Iron oxide nanoworms (NWs) functionalized with the linTT1
peptide were taken up and routed to mitochondria in cultured PC cells. NWs functionalized with linTT1
peptide in tandem with a pro-apoptotic [D(
KLAKLAK)2]
peptide showed p32-dependent cytotoxicity in MKN-45P, SKOV-3, and CT-26 cells. Upon IP administration in mice bearing MKN-45P, SKOV-3, and CT-26
tumors, linTT1-functionalized NWs showed robust homing and penetration into malignant lesions, whereas only a background accumulation was seen in control tissues. In
tumors, the linTT1-NW accumulation was seen predominantly in CD31-positive blood vessels, in LYVE-1-positive lymphatic structures, and in CD11b-positive
tumor macrophages.
Experimental therapy of mice bearing peritoneal MKN-45P xenografts and CT-26 syngeneic
tumors with IP linTT1-D(KLAKLAK)2-NWs resulted in significant reduction of weight of peritoneal
tumors and significant decrease in the number of metastatic
tumor nodules, whereas treatment with untargeted D(KLAKLAK)2-NWs had no effect. Our data show that targeting of p32 with linTT1
tumor-penetrating
peptide improves
tumor selectivity and antitumor efficacy of IP pro-apoptotic NWs. P32-directed intraperitoneal targeting of other
anticancer agents and nanoparticles using
peptides and other affinity
ligands may represent a general strategy to increase their therapeutic index.