In vivo bone marrow microenvironment siRNA delivery using lipid-polymer nanoparticles for multiple myeloma therapy

Pedro P.G. Guimarães, Christian G. Figueroa-Espada, Rachel S. Riley, Ningqiang Gong, Lulu Xue, Tomasz Sewastianik, Peter S. Dennis, Claudia Loebel, Amanda Chung, Sarah J. Shepherd, Rebecca M. Haley, Alex G. Hamilton, Rakan El-Mayta, Karin Wang, Robert Langer, Daniel G. Anderson, Ruben D. Carrasco, Michael J. Mitchell

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference (RNAi) and lipid-polymer nanoparticles to engineer a potential MM therapy, which targets CyPA within blood vessels of the bone marrow. We used combinatorial chemistry and high-throughput in vivo screening methods to engineer a nanoparticle platform for small interfering RNA (siRNA) delivery to bone marrow endothelium. We demonstrate that our strategy inhibits CyPA in BMECs, preventing MM cell extravasation in vitro. Finally, we show that siRNA-based silencing of CyPA in a murine xenograft model of MM, either alone or in combination with the Food and Drug Administration (FDA)-approved MM therapeutic bortezomib, reduces tumor burden and extends survival. This nanoparticle platform may provide a broadly enabling technology to deliver nucleic acid therapeutics to other malignancies that home to bone marrow.

Original languageEnglish (US)
Article numbere2215711120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number25
DOIs
StatePublished - Jun 20 2023

All Science Journal Classification (ASJC) codes

  • General

Fingerprint

Dive into the research topics of 'In vivo bone marrow microenvironment siRNA delivery using lipid-polymer nanoparticles for multiple myeloma therapy'. Together they form a unique fingerprint.

Cite this