# CHOLESTEROL METABOLISM IN THE PHARMACOLOGY OF LIPOSOMAL THERAPEUTICS

> **NIH NIH R01** · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · 2024 · $463,889

## Abstract

ABSTRACT
Drug delivery using liposomes increases tumor drug accumulation while sparing normal tissue. Several liposomal
chemotherapies are approved to treat cancer. Unfortunately, lipid nanoparticles such as liposomes interact with
the immune system and their impact on the tumor immunologic milieu is largely unknown. We have reported that
liposomes composed of phospholipids and cholesterol, similar to those used in patients, doubled tumor size in
mice by suppressing the immune response against tumors. We recently identified macrophages as the cells that
are responsible for these detrimental effects. In this proposal, we seek to identify the precise molecular
mechanisms. Our preliminary data show that liposomal cholesterol is metabolized into oxysterols that are known
to alter the function of macrophages. Based on this, we theorize that liposomal oxysterols cause macrophages
to suppress antitumor immunity and enhance tumor growth. Notably, oxidized metabolites of beta-sitosterol (a
plant sterol) lack the protumoral inflammatory activity of oxysterols, suggesting that more efficacious liposomal
drug formulations can be developed using analogs of cholesterol. The objectives of this proposal are to
understand the metabolism of liposomal cholesterol and to develop cholesterol analogs without tumorigenic
effects for liposomal drug formulation. We will dissect the metabolism pathways by conducting time-dependent
studies in immune cells and in mouse models. To identify the metabolic and cell signaling pathways that are
involved, we will conduct mechanistic studies in wildtype and knockout mice, and donor human immune cells.
Finally, we will design and test the immunological and anticancer effects of cholesterol analogs in immune cells
and in mouse models of cancer. Our team has unique combined expertise necessary for successful completion
of this project. This proposal is expected to have a positive impact by addressing critical gaps in current
understanding of the role of the immune system in liposomal drug pharmacology and the role of oxidized sterols
in cancer. This is likely to lead to new therapeutic targets and drug formulation strategies with potential to
significantly advance both cancer drug delivery and immunotherapy.

## Key facts

- **NIH application ID:** 10931425
- **Project number:** 5R01CA282339-02
- **Recipient organization:** TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
- **Principal Investigator:** Ninh La-Beck
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $463,889
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931425

## Citation

> US National Institutes of Health, RePORTER application 10931425, CHOLESTEROL METABOLISM IN THE PHARMACOLOGY OF LIPOSOMAL THERAPEUTICS (5R01CA282339-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10931425. Licensed CC0.

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