Multiple Myeloma (MM) is an incurable hematologic cancer characterized by the accumulation of abnormal plasma cells within bone marrow. We and others have shown that the bone marrow niche itself, specifically bone marrow endothelial cells (BMECs), provides the “soil” supportive of MM cell (the “seeds”) homing, colonization, and proliferation in marrow. Specifically, extracellular cyclophilin A (CyPA) secreted by BMECs promotes signaling changes in MM including enhanced expression of CD147, the receptor of CyPA, which enhances proliferation and homing of MM cells. Thus, inhibition of CyPA secretion from BMECs provides a potential therapeutic strategy via disrupting physical interactions between MM and the bone marrow niche. Herein, we have developed the first controlled release technology to deliver nucleic acids to the bone marrow microenvironment in vivo, as a paradigm-shifting MM therapy which disrupts interactions between MM and the marrow niche. We engineered novel lipid-polymer hybrid (PLH) gene delivery materials consisting of dendrimers conjugated to epoxide-terminated lipids. These materials, in combination with polyethylene glycol (PEG)-lipid conjugates and siRNA, assembled into NPs via microfluidic mixing. Through screening of a small library of materials we identified a NP formulation that induces potent gene silencing (~80%) of a target BMEC gene (Tie2) in bone marrow in vivo. NPs induced rapid RNA uptake in BMECs in vivo within 30 min, demonstrated using multiphoton intravital imaging of mouse BM. Cell populations targeted were primarily BMECs, with minimal RNA uptake in immune cells that reside in BM, identified using flow cytometry. We then screened a library of CyPA siRNAs in vitro, and identified a CyPA siRNA candidate that induced potent CyPA gene knockdown (~90%) at low dosages (10 nM) in BMECs in vitro. To assess if NP siCyPA treatment can be exploited therapeutically in animal models of MM, mice were treated with siCyPA NPs once per week (dose: 1.0 mg/kg). Strikingly, treatment of mice with NPs silencing CyPA largely reduced progression of MM in mice in vivo. Collectively, we have developed the first nucleic acid delivery technologies to therapeutically target MM and its interactions with the bone marrow niche in vivo. We envision that our microenvironment-targeted approach can be combined with chemo- and immunotherapies used in the clinic.

In vivo nucleic acid delivery systems for therapeutic targeting of multiple myeloma-microenvironment interactions

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.