Tuning Nanoparticle Interactions with Ovarian Cancer through Layer-by-Layer Modification of Surface Chemistry

Abstract

Nanoparticle surface chemistry is a fundamental engineering parameter that governs tumor-targeting activity. Electrostatic assembly generates controlled polyelectrolyte complexes through the process of adsorption and charge overcompensation utilizing synthetic polyions and natural biomacromolecules; it can yield films with distinctive hydration, charge, and presentation of functional groups. Here, we used electrostatic layer-by-layer (LbL) assembly to screen 10 different surface chemistries for their ability to preferentially target human ovarian cancer in vitro. Our screen identified that poly-Laspartate, poly-L-glutamate, and hyaluronate-coated LbL nanoparticles have striking specificity for ovarian cancer, while sulfated poly(β-cyclodextrin) nanoparticles target noncancerous stromal cells. We validated top candidates for tumor-homing ability with a murine model of metastatic disease and with patient-derived ovarian cancer spheroids. Nanoparticle surface chemistry also influenced subcellular trafficking, indicating strategies to target the cell membrane, caveolae, and perinuclear vesicles. Our results confirm LbL is a powerful tool to systematically engineer nanoparticles and achieve specific targeting.

Massively parallel pooled screening reveals genomic determinants of nanoparticle-cell interactions

“…To this end, we selected liposomes electrostatically coated with poly-L-glutamate (Lipo-PLE), which we have previously established to remain extracellularly associated on a number of ovarian cancer cell lines, for further study. 9,53 In agreement with our prior findings, we observed that Lipo-PLE NPs remain predominantly extracellularly associated with the T47D vector control cells (Figure 4F, upper panels). However, we observed a stark difference in Lipo-PLE trafficking in the T47D-SLC46A3 knockout cells, where in addition to some extracellular association, a significant portion of particles appear to be internalized in vesicles distributed uniformly throughout the cytoplasm (Figure 4F, bottom panels).…”

Lipidome-based Targeting of STAT3-driven Breast Cancer Cells Using Poly-l-glutamic Acid–coated Layer-by-Layer Nanoparticles

“…The LbL nanoparticle library was synthesized and characterized as previously described (7,8). Passive loading was employed for cisplatin (CDDP) encapsulation as described in the Supplementary Materials and Methods (9,10).…”

Polymeric Nanoparticle Delivery of Combination Therapy with Synergistic Effects in Ovarian Cancer

“…Nanoparticles with folic acid conjugated to the surface have shown enhanced cytotoxic activity compared to non-targeted particles in human ovarian cancer cells (Ovcar-5) [ 145 ]. Nanoparticles functionalized with poly-L-aspartate, poly-L-glutamate, and hyaluronate-coated nanoparticles demonstrated highly specific association with ovarian cancer tissue (using patient derived ovarian cancer spheroids) compared to conventional PEGylated nanoparticles [ 19 ]. In active targeting, the surface of the nanoparticle is functionalized with one or more targeting moieties to interact specifically with antigens or receptors that are uniquely expressed or overexpressed on the tumor cells compared to normal tissues.…”

“…Specifically, polymer nanoparticles offer control over parameters including size and material selection i.e., drug combinations. Therefore, polymer nanoparticles are an especially attractive approach for improving delivery of chemotherapeutic agents [ 18 , 19 ]. With appropriate selection of the polymer, nanocarriers can facilitate high loading of hydrophobic drugs and tunable release of the payload.…”