On 18 April at 15 Hedi Hunt will defend her doctoral thesis „Precision targeting of intraperitoneal tumors with peptide-guided nanocarriers“.
Professor Tambet Teesalu (PhD), Institute of Biomedicine and Translational Medicine, University of Tartu
Professor Pirjo Laakkonen (PhD), Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Gastrointestinal and gynecological malignancies often disseminate in the peritoneal cavity and cause severe complications such as bowel obstruction and the formation of ascites- a condition known as peritoneal carcinomatosis (PC). PC results from the dissemination of the primary tumor or seeding after surgical intervention and is a cause for incurability of intra-abdominal cancers. In the treatment of peritoneal tumor lesions, intraperitoneal chemotherapy can be used to improve delivery of drugs into peritoneal tumors by providing direct contact and higher local concentration, but this approach as well is not harmless and can cause side effects in the normal organs residing in the IP cavity.
IP chemotherapy is an attractive strategy to improve the outcome of PC. During the last decades, substantial amount of work has been dedicated into improving the therapeutic outcome of PC by applying different therapeutic approaches that maximize selectivity and limit side effects. Nanoparticles in the context of direct targeting of IP tumors are actively being evaluated in preclinical studies due to their potential of increasing the retention time in the IP cavity and to target drugs specifically to the tumor site compared to the conventional drugs. A few nanoparticle formulations of chemotherapeutic drugs have reached human trials, but there are no approved drug formulations for the specific use in the IP cavity. Novel strategies such as development of precision nanomedicines to specifically target cancerous lesions and development of drugs/nanoparticles with extended residence time in the IP cavity may help to increase efficacy of IP chemotherapy.
The tissue selectivity and efficacy of nanoparticles and chemotherapeutic drugs can be increased by conjugating affinity ligands (i.e. antibodies, peptides, aptamers) on their surface. Our lab focuses on tumor penetrating peptides (TPP), such as iRGD and TT1. The iRGD peptide is recruited to integrins expressed on endothelial cells and other cells in tumors. After recruitment to integrins, iRGD is proteolytically cleaved to expose c-terminally CRGDK CendR motif, and the truncated peptide loses most of its integrin-binding capacity and gains affinity for neuropilin-1 (NRP-1). Binding to NRP-1 mediates penetration to cells and tissues.
The primary homing receptor for TT1 is p32, a mitochondrial protein aberrantly expressed on the cell surface of activated malignant and stromal cells in solid tumors. TT1 peptide is after binding to p32 proteolytically cleaved to expose C-terminally the RGAR peptide that interacts with tissue penetration receptor NRP-1.
Current preclinical study focused on intraperitoneal (IP) tumors (i.e. gastric, colon and ovarian cancer) in exploring new imaging and therapeutic strategies by using different nanoparticles coated with tumor penetrating peptides. Specific focus was on polymeric and iron oxide nanoparticles and their selectivity towards IP tumor lesions following IP administration. We used different IP tumor cell lines and mouse models in animal experimentations.
The results from the study show that by conjugating TPP on the surface on nanoparticles the accumulation in the tumor tissue is increased. IP administered TPP-nanoparticles accumulate in the tumor tissue by direct binding as well as indirectly via systemic circulation. Importantly, peptide targeted nanoparticles increased therapeutic efficacy of nanoparticles loaded with anticancer drugs.