# Functionalized Lipid Carriers for Nucleic-Acid and Drug Therapeutics

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2021 · $295,265

## Abstract

Project Summary/Abstract
The current level of research activity involving gene therapy with either synthetic vectors (carriers) or engineered viruses
is unprecedented. Liposomes are the most widely studied nonviral carriers worldwide for nucleic acid (NA) and drug
delivery applications. Cationic liposomes (CLs) are relatively safe nonviral vectors used in ongoing clinical trials. CLs
may either be complexed via electrostatic interactions with therapeutic NAs (anionic DNA or short interfering RNA) for
gene delivery and silencing, or used as vectors of potent cytotoxic hydrophobic drugs, encapsulated within their lipid
bilayer, in cancer therapeutics. Among the biggest advantages of nonviral vectors (over viral vectors which are currently
more efficient in in vivo settings) are their safety, their low immunogenicity and their ability to transfer entire genes
(containing coding and noncoding sequences) and regulatory sequences into cells (currently not feasible with engineered
viruses because of capsid size limitations). The development of nonviral lipid-based vectors with efficacy competitive
with viral vectors in vivo will require a mechanistic understanding of how synthetic vectors may be functionalized to
overcome the major intracellular hurdle of endosomal escape. Successful endosomal escape is required for release of
therapeutic nucleic acid within the cell cytosol and therefore maximum efficacy. The first aim of this research application
is to employ modern biophysical and synthetic approaches to the rational design of functionalized CL–NA nanoparticles
(NPs) with synergistic, complementary dual-function PEG-lipid and fusogenic components for optimized endosomal
escape. Modern methods of organic and solid phase chemistry will be employed to synthesize dual-function PEG-lipids
with cell targeting and endosome escaping properties. The second aim of this research application is to optimize efficacy
of a new class of CL-based carriers of the hydrophobic drug paclitaxel (PTXL) for cancer therapeutics. This will be
achieved by developing a mechanistic understanding of the relation between physical and chemical properties of the
carrier (i.e. size of the functionalized CL carrier, membrane spontaneous curvature, and lipid tail structure) and functional
efficacy (i.e. PTXL membrane solubility, cell uptake of vector and PTXL delivery leading to cytotoxicity against human
cancer cells). The structures of CL-based vectors of NAs and hydrophobic drugs will be characterized using cryogenic
electron microscopy and synchrotron x-ray diffraction techniques. The interactions between CL vectors and cell
organelles will be directly visualized with spinning disk confocal fluorescence microscopy. Their structures will be
correlated to their biological activity in human cancer cells. The broad, long-term objective of our research is to develop a
fundamental science base through mechanistic studies that will lead to the design and synthesis of nonviral vectors of
n...

## Key facts

- **NIH application ID:** 10242074
- **Project number:** 5R01GM130769-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** CYRUS R SAFINYA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $295,265
- **Award type:** 5
- **Project period:** 2018-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242074

## Citation

> US National Institutes of Health, RePORTER application 10242074, Functionalized Lipid Carriers for Nucleic-Acid and Drug Therapeutics (5R01GM130769-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242074. Licensed CC0.

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