# Engineering Biomaterials to Modulate the Bone Marrow Microenvironment in Multiple Myeloma

> **NIH NIH F99** · UNIVERSITY OF PENNSYLVANIA · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Multiple myeloma (MM) accounts for ~23% of all hematologic malignancies with a 2.1% of cancer-related deaths
in the United States in 2022. Despite tremendous efforts to develop effective therapies, MM remains largely
incurable, and virtually all patients develop resistance to current therapies. Thus, there is an urgent clinical need
for innovative and improved MM therapeutics. It has been demonstrated that bone marrow endothelium is critical
to MM cell homing, progression, survival, and drug resistance. Specifically, cyclophilin A and E-selectin, a
homing factor and adhesion receptor, respectively, expressed by bone marrow endothelial cells, are critical to
MM survival. Thus, inhibition of cyclophilin A and E-selectin provides a potential therapeutic strategy to abolish
MM dissemination and resistance. However, direct- and specific-inhibition of cyclophilin A and E-selectin by
small molecules has been elusive. Thus, cyclophilin A and E-selectin are promising candidates for combination
RNA interference (RNAi) therapy, which inhibits traditionally undruggable targets by directly reducing their
messenger RNA (mRNA) expression. The challenge of utilizing small-interfering RNA (siRNA) is the need for
safe and effective delivery methods, as siRNA degrades in the bloodstream and does not readily cross
membranes. During my predoctoral studies, I have engineered a library of polymer-lipid hybrid biomaterials, that
in combination with polyethylene glycol (PEG)-lipid conjugates and siRNA, assembled into nanoparticles (NPs)
via microfluidic mixing. Through high-throughput in vivo screening, I identified a NP formulation with potent gene
silencing in bone marrow endothelial cells in vivo. This formulation was used to encapsulate cyclophilin A siRNA,
and showed inhibition of MM progression in vivo, and sensitized MM cells to the proteasome inhibitor bortezomib,
a current therapeutic modality to treat MM. During the F99 phase, I will improve our NP design by incorporating
bone marrow endothelial-targeting ligands on the NP’s surface to enhance their specificity to bone marrow
endothelium, minimizing off-target effects. I will use our targeted NP to co-encapsulate cyclophilin A and E-
selectin siRNA sequences, and evaluate their inhibition in vitro through adhesion and transendothelial migration
assays, to determine the invasive abilities of MM cells. Further, I will test our co-delivery siRNA nanotechnology
through a survival study in a validated mouse xenograft model of MM and quantify its effects either alone or in
combination with bortezomib. This technology is expected to provide with a broadly enabling platform to target
other bone marrow-homing cancers. For the K00 phase, I will identify a renowned cancer biology laboratory to
study cell-cell interactions in the bone marrow immune microenvironment utilizing high-dimensional single-cell
approaches and tissue-engineered models, with the aim to determine mechanisms that drive cancer progressi...

## Key facts

- **NIH application ID:** 10901933
- **Project number:** 5F99CA284294-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Christian Gabriel FIGUEROA-ESPADA
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-08-09 → 2024-08-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901933

## Citation

> US National Institutes of Health, RePORTER application 10901933, Engineering Biomaterials to Modulate the Bone Marrow Microenvironment in Multiple Myeloma (5F99CA284294-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901933. Licensed CC0.

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