RT Journal Article
SR Electronic
T1 Competition of Charge-Mediated and Specific Binding by Peptide-Tagged Cationic Liposome-DNA Nanoparticles <em>In Vitro</em> and <em>In Vivo</em>
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 156166
DO 10.1101/156166
A1 Emily Wonder
A1 Lorena Simón-Gracia
A1 Pablo Scodeller
A1 Ramsey Majzoub
A1 Venkata Ramana Kotamraju
A1 Kai K. Ewert
A1 Tambet Teesalu
A1 Cyrus R. Safinya
YR 2017
UL http://biorxiv.org/content/early/2017/06/26/156166.abstract
AB Cationic lipid vectors can be used as a modular gene delivery system that allows for easy tuning of the physicochemical properties that dictate cellular interactions and influence the delivery of exogenous nucleic acids. Cationic lipid-nucleic acid (CL–NA) complexes form spontaneously and can be sterically stabilized via PEGylation [PEG: poly(ethylene glycol)]. These PEGylated CL–NA nanoparticles (NPs) are also protected from opsonization in vivo and can be targeted to specific tissue and cell types via the conjugation of an affinity ligand. To achieve efficient targeting, it is necessary to maximize specific (receptor-ligand) binding and to suppress nonspecific (electrostatic) interactions. Here, we use our library of PEG–lipids targeted with a panel of tumor-homing peptides to assess the in vitro and in vivo targeting abilities of tunable CL–NA nanoparticles. With modular CL–NA NPs, we can easily adjust ligand properties (i.e., binding motif and density) as well as charge properties (i.e., charge ratio and density), allowing for modulation of specific and non-specific binding interactions. Flow cytometry was used to quantitatively assess binding and internalization of NPs in cultured cancer cells. In vivo tumor selectivity of selected NP formulations was evaluated in a mouse model of peritoneal carcinomatosis of gastric origin. CL–NA NPs targeted with iRGD and cyclic RGD, as well as non-targeted NPs, were injected intraperitoneally, and biodistribution and tumor penetration were assessed by ex vivo macroscopic imaging and confocal microscopy. The CL–NA NPs showed tumor binding and minimal accumulation in healthy control tissues. The NPs preferentially bound to and penetrated the smaller tumor nodules, most similar to those known to drive recurrence of the peritoneal cancer in human patients. This study provides a starting point for tuning charge and ligand properties of CL–NA NPs to minimize off-target electrostatic binding and maximize ligand-receptor binding for efficient solid tumor targeting.