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RHAMMB-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor
Xiang Chen1, Seung Koo Lee2, Mei Song3
1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
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 a RHAMMB-targeting nanoparticle (NP). Inside this NP, we assembled small interfering RNA (siRNA) against Bcl-xL (siBcl-xL) and mitochondria-fusing peptide KLA. We demonstrated that RHAMMB-positive PNETs picked up the RHAMMB-targeting NPs. siBcl-xL or KLA alone killed only 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 NPs 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 with upregulated RHAMMB. The combination of siBcl-xL and KLA peptide can be a therapy for PNET treatment.
Insights
Novel nanomedicine targets pancreatic neuroendocrine tumors (PNETs) by delivering therapies that reduce metastasis. This RHAMM-targeting nanoparticle effectively reduced PNET tumor burden in mice.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Pancreatic neuroendocrine tumors (PNETs) are increasing, often presenting as metastatic disease.
- Receptor for Hyaluronic Acid-Mediated Motility isoform B (RHAMMB) and Bcl-xL are upregulated in PNETs, promoting metastasis.
- RHAMMB presents a potential target for selective nanomedicine delivery due to its limited expression in normal tissues.
Purpose of the Study:
- To develop and evaluate a RHAMMB-targeting nanoparticle for PNET therapy.
- To co-deliver small interfering RNA against Bcl-xL (siBcl-xL) and KLA peptide for synergistic effects.
- To assess the efficacy of this nanotherapy in reducing PNET tumor burden in vivo.
Main Methods:
- Engineered RHAMMB-targeting nanoparticles encapsulating siBcl-xL and KLA peptide.
- Demonstrated uptake of nanoparticles by RHAMMB-positive PNET cells.
- Evaluated the in vitro cytotoxicity of combined siBcl-xL and KLA peptide.
- Assessed in vivo tumor reduction in a mouse model after systemic nanoparticle injection.
Main Results:
- RHAMMB-positive PNETs efficiently internalized the targeted nanoparticles.
- Co-delivery of siBcl-xL and KLA peptide demonstrated synergistic cell killing in vitro.
- siBcl-xL induced cell death preceding significant Bcl-xL protein reduction.
- Systemic administration of nanoparticles significantly reduced PNET tumor burden in mice.
Conclusions:
- RHAMMB-targeting nanotherapy is a promising drug delivery system for PNETs.
- The combination of siBcl-xL and KLA peptide offers a potential therapeutic strategy for PNET treatment.
- This approach may be applicable to other malignancies expressing RHAMMB.
