RHAMM^B-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

Abstract

The incidence of pancreatic neuroendocrine tumor (PNET) has continued to rise. Due to their indolent feature, PNET patients often present with incurable, metastatic diseases. Novel therapies are urgently needed. We have previously shown that Receptor for Hyaluronic Acid-Mediated Motility isoform B (RHAMMB) and Bcl-xL are upregulated in PNETs and both of them promote PNET metastasis. Because RHAMM protein is undetectable in most adult tissues, we hypothesized that RHAMMB could be a gateway for nanomedicine delivery into PNETs. To test this, we developed RHAMMB-targeting nanoparticle. Inside this nanoparticle, we assembled siRNA against Bcl-xL (siBcl-xL) and mitochondria-fusing peptide KLA. We demonstratsed that RHAMMB-positive PNETs picked up the RHAMMB-targeting nanoparticles. siBcl-xL or KLA alone only killed 30% of PNET cells. In contrast, a synergistic killing effect was achieved with the co-delivery of siBcl-xL and KLA peptide in vitro. Unexpectedly, siBcl-xL induced cell death before reducing Bcl-xL protein levels. The systemically-injected RHAMMB-targeting nanoparticles carrying siBcl-xL and KLA peptide significantly reduced tumor burden in mice bearing RHAMMB-positive PNETs. Together, these findings indicate that the RHAMMB-targeting nanotherapy serves as a promising drug delivery system for PNET and possibly other malignancies upregulating RHAMMB. The combination of siBcl-xL and KLA peptide can be a therapy for PNET treatment.

Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration

“…Finally, we examined whether the TME modulation by vorinostat can impact T cell recruitment in vivo. We have recently developed a syngeneic mouse model of PNET immunocompetent mice (48). Here, we subcutaneously implanted a mouse PNET cell line, N134 (derived from a mouse model, RIP-Tag; RIP-tva (49) into the flanks of syngeneic RIP-tva mice (C57BL6 background) (Figure 7A).…”

“…N134 cells (5 x 10 6 cells mixed with DMEM with 2% FBS in a total volume of 100 µl) were subcutaneously injected into RIP-TVA (C57BL6 background) mice on the bilateral flanks (48).…”