PEGylation strategies for enhanced nanoparticle delivery to tumor associated immune cells

Barriers to nanoparticle drug delivery to the tumor microenvironment such as ECM deposition and clearance by the mononuclear phagocyte system have necessitated strategies for more effective tumor penetration. Adding polyethylene glycol (PEG) chains to the surface of nanoparticles (PEGylation) has been widely used to both enhance accumulation at the tumor site and increase blood circulation time. Recent work has also shown that immune cells (e.g. macrophages, dendritic cells, neutrophils) play an important role in the ability of NPs to effectively target and spread within a tumor. PEG chain characteristics such as size and branching affects how nanoparticles interact with tissues; however, it is unclear how PEGylation type affects NP uptake and cellular distribution in the tumor microenvironment. In this study, we evaluated the influence of both linear and branched PEGylation on nanoparticle biodistribution and uptake in tumor cells as well as tumor-infiltrating immune cells. As compared to conventional surface coatings with linear PEG, we show that modifying PEG structure to a branched conformation increases nanoparticle accumulation in the spleen of tumor-bearing mice, primarily due to significantly enhanced uptake by leukocytes. As compared to uncoated particles, we also found that nanoparticles densely coated with linear or branched PEG accumulated to a greater extent in tumors showing ≥8-fold increases in uptake by tumor-associated macrophages and dendritic cells. These studies provide insight into PEG architecture as a design parameter in nanomedicine that can facilitate the design of more effective cancer therapies. Translational Impact This work uncovers immune-mediated mechanisms and design strategies to enhance NP delivery to tumors via PEGylation which provide a foundation for clinical development of cancer therapeutics. The PEGylation strategies described could be readily integrated into clinically relevant nanoparticle delivery systems (e.g. lipid nanoparticles) with minimal effort making this a highly appealing approach to address the current limitations of cancer nanomedicine.