Hyaluronan-binding peptide for targeting peritoneal carcinomatosis

Abstract

Peritoneal carcinomatosis results from dissemination of solid tumors in the peritoneal cavity, and is a common site of metastasis in patients with carcinomas of gastrointestinal or gynecological origin. Peritoneal carcinomatosis treatment is challenging as poorly vascularized, disseminated peritoneal micro-tumors are shielded from systemic anticancer drugs and drive tumor regrowth. Here, we describe the identification and validation of a tumor homing peptide CKRDLSRRC (IP3), which upon intraperitoneal administration delivers payloads to peritoneal metastases. IP3 peptide was identified by in vivo phage display on a mouse model of peritoneal carcinomatosis of gastric origin (MKN-45P), using high-throughput sequencing of the peptide-encoding region of phage genome as a readout. The IP3 peptide contains a hyaluronan-binding motif, and fluorescein-labeled IP3 peptide bound to immobilized hyaluronan in vitro. After intraperitoneal administration in mice bearing peritoneal metastases of gastric and colon origin, IP3 peptide homed robustly to macrophage-rich regions in peritoneal tumors, including poorly vascularized micro-tumors. Finally, we show that IP3 functionalization conferred silver nanoparticles the ability to home to peritoneal tumors of gastric and colonic origin, suggesting that it could facilitate targeted delivery of nanoscale payloads to peritoneal tumors. Collectively, our study suggests that the IP3 peptide has potential applications for targeting drugs, nanoparticles, and imaging agents to peritoneal tumors.

Tumor-penetrating peptide for systemic targeting of Tenascin-C

“…Highperformance liquid chromatography (HPLC) was used to purify the peptides with 0.1% trifluoroacetic acid (TFA) in acetonitrile-water mixtures to 90%-95% purity. The peptides were validated by quadrupole time-of-flight (Q-TOF) mass spectral analysis 18 . CF647 amine dye was purchased from Biotium (Hayward, CA, USA).…”

“…The eluted phages were titered and amplified for a next round of selection. After 5 rounds of selection, peptide-encoding DNA from a set of 48 phage clones was subjected to Sanger sequencing of peptide-encoding phage DNA 18,22 . For cell-free binding studies with individual phage clones were incubated with Ni-NTA magnetic beads coated with hexahistidine-tagged TNC-C as above.…”

Engineering Targeting Materials for Therapeutic Cancer Vaccines

“…Accordingly, GAG-binding peptides have been used to target materials into tumors. For instance, silver nanoparticles functionalized with the IP3 HA-binding peptide have successfully localized into peritoneal tumors (Ikemoto et al, 2017). In addition to being overexpressed, some tumoral GAGs also display differences in sulfation patterns, which can be further exploited to enhance targeting specificity (Vallen et al, 2014).…”

Peritoneal Carcinomatosis Targeting with Tumor Homing Peptides

“…Hyaluronic acid (HA) is a glycosaminoglycan component of the extracellular matrix present in epithelial, connective, and neural tissues. In peritoneal space, HA is present on mesothelial surface, prominently expressed in peritoneal tumors of gastrointestinal [33] and ovarian origin, where it is known to contribute to the peritoneal dissemination [88]. We have recently identified a hyaluronan-binding peptide that targets peritoneal tumors [33].…”

“…In peritoneal space, HA is present on mesothelial surface, prominently expressed in peritoneal tumors of gastrointestinal [33] and ovarian origin, where it is known to contribute to the peritoneal dissemination [88]. We have recently identified a hyaluronan-binding peptide that targets peritoneal tumors [33]. The 9-residue cyclic peptide CKRDLSRRC (IP3) was identified by in vitro and in vivo phage display in a mouse model of PC derived from MKN-45P gastric tumor.…”