Understanding the impact of ovarian cancer cell genomic properties on the uptake of hyaluronic acid coated nanoparticles

Abstract

High grade serous ovarian cancer (HGSOC) is one of the deadliest forms of cancer in women. Known as the silent killer, ovarian cancer is difficult to treat due to its subtle early-stage symptoms that lead to late stage diagnosis1. Current treatments utilize a combination of surgery and chemotherapy but can become ineffective following initial treatment2. Therefore, it is desired to enhance patient outcomes by developing alternative treatments that will improve accumulation of therapeutics in desired disease sites.One of the promising areas for future cancer treatments is nanoparticle (NP)-based therapeutics. An unmet need in NP research is a lack of a comprehensive understanding of the biological features that mediate the uptake and trafficking of these particles in tissues and target disease sites such as tumors. Progress has been made in this area of research by utilizing advancements in cancer genomics and machine learning. These advancements have allowed researchers to develop and conduct high throughput screening experiments that can be used to correlate NP characteristics with cell specific features. A notable finding from this work was the identification of an inverse relationship between the gene expression of biomarker SLC46A3, and uptake of lipid nanocarriers3. It was also shown that expression levels of SLC46A3 do not affect the uptake of polymeric NPs, such as those formulated from polystyrene (PS) or polylactide-co-glycolic acid (PLGA). This discovery is of significant interest because it highlights an alternative method to improve nanocarrier accumulation at desired tumor sites by taking advantage of cancer cell expression profiles. Separately, research has shown that NP delivery to disease sites can be enhanced by adding external ligands to the NP surface. This traditional approach to targeting uses ligands to coat NPs and target specific cell receptors overexpressed by diseased cells.4 One of the most prominent ligands is hyaluronic acid (HA). HA preferentially binds to a receptor known as CD44, which is overexpressed in numerous types of cancers, including ovarian5. It has been demonstrated that HA-modified NPs can preferentially bind to cells expressing CD44, thereby enhancing targetability of tumor cells using the HA-CD44 binding interaction5. Here, we sought to determine if SLC46A3 and CD44 expression levels could be used to increase lipid nanocarrier accumulation in malignant cells and decouple the role of nanocarrier core composition and surface chemistry in this process. This research lays the groundwork for enhancing tumor targeting by gaining an understanding of how levels of CD44 and SLC46A3 affect NP uptake. It will also further illuminate the impact NP core identity and presence of HA-coating has on NP uptake. We selected a panel of HGSOC cell lines with a range of CD44 and SLC46A3 expression levels. We observed that HA coated NPs exhibited enhanced uptake compared to uncoated NPs, in line with prior findings. Notably, we also observed that liposome uptake inversely correlated with SLC46A3 expression, both for NPs with and without HA coatings. This indicates that SLC46A3 has the ability to modulate cellular association of liposomal nanocarriers even in the presence of external NP coatings. A significant correlation was also observed between CD44 and HA coated PS NPs, but not HA coated liposomes. This indicates that SLC46A3 strongly mediates liposomal nanocarrier uptake in comparison to other cell receptors.