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Designing lipid nanoparticles toward targeted drug delivery: Fundamental studies identify key compositional properties to improve formulations for the hydrophobic cancer drug paclitaxel


In order to increase the efficacy of the cancer drug paclitaxel (PTX), scientists must develop more effective drug carriers that well solubilize PTX and achieve targeted delivery. Loading cytotoxic drugs like PTX into nanoparticles that are engineered to accumulate in cancer tissue by physical or chemical means is expected to increase local drug concentrations and minimize systemic side effects. Due to its hydrophobic nature, PTX loads into the actual membrane of lipid nanoparticles (LNPs)—closely associating with lipid tails—and has limited solubility in lipid membranes. In vitro cell viability experiments demonstrate a direct correlation between delivery efficacy and the duration of PTX solubility in LNPs. This study importantly reveals enhanced delivery when PTX is loaded below, rather than at, its drug-loading saturation level. Based on PTX loading into membranes, we expect and indeed observe that PTX solubility depends strongly on the types of lipids used in LNP formulations. Here we report the PTX-loading and delivery efficacy of a selection of lipids that enhance delivery of other therapeutics (hydrophilic drugs, nucleic acids) to see if they similarly improve PTX delivery: inverted cone-shaped lipids (DOPE, GMO), poly-unsaturated (18:2, 18:3) lipids, cationic lipids (DOTAP, MVL5), and polymer-conjugated lipids (2k and 5k PEG-lipids).

We developed a complementary approach using physical and cell biology characterization methods to elucidate structure-function relationships of LNP composition. DIC microscopy observations are used to generate kinetic phase diagrams to compare PTX solubility in different LNP formulations. Small-angle x-ray scattering (SAXS) shows that PTX-loading thins lipid membranes and determines the self-assembly structures of LNPs. The in vitro delivery efficacy of LNP formulations is determined by incubating PTX-loaded LNPs with PC3 (prostate) and M21 (melanoma) immortalized human cancer cell lines and measuring the resultant cell death. Fluorescent microscopy and flow cytometry provide qualitative and quantitative information about how LNPs interact with cells based on their composition. Finally, cryoTEM images offer important clues about how LNP structure and stability directly impact cell interactions and PTX delivery. In particular, we highlight how LNP vesicles transition to various disk, worm, and sphere micelles as the fraction of cationic or PEG-lipid increases. Using these methods, we have found several promising strategies to improve LNPs for PTX delivery. Studying fundamental LNP properties to determine composition-function relationships is a smarter strategy than empirical discovery because it identifies specific ways to thoughtfully design better drug delivery systems.

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