Electrostatic driven transport enhances penetration of positively charged peptide surfaces through tumor...

Drug carriers achieve poor and heterogeneous distribution within solid tumors due to limited transport through the tumor extracellular matrix (ECM). The tumor ECM forms a net negatively charged network that interacts with and hinders the transport of molecules in part due to electrostatic interactions. Traditionally, the surfaces of drug delivery systems are passivated to minimize these interactions, but the mechanism of how charge interactions impact transport and penetration within the tumor microenvironment (TME) is not well understood. Here, we used T7 bacteriophage as a model biological nanoparticle to display peptides of different charges on its surface and elucidate how charge-based binding drives transport, uptake, and retention within tumor tissue. In contrast to current studies with neutrally charged surfaces, we discovered that a positively charged peptide displayed on T7 enhanced its penetration through a tumor-like ECM when compared to neutrally and negatively charged peptides. The positively charged peptide displayed on T7 facilitated weak and reversible binding with the TME to achieve Donnan partitioning and deep penetration into ex vivo tumor tissue. Additionally, the positively charged peptide-presenting T7 has a high number of intra-tissue binding sites in the TME (~4 µM) that enables almost 100% retention in the tumor tissue for up to 24 h. These results, coupled with transport studies of systematically mutated T7, show that electrostatic interactions can be responsible for uptake and retention of the positively charged peptide-presenting T7 within the net negatively charged TME. STATEMENT OF SIGNIFICANCE: The TME selectively hinders the transport of drugs and drug delivery systems due to their size, shape, and intermolecular interactions. Typically, the focus in drug delivery has been to develop delivery systems smaller than the pore size of the tumor ECM and/or develop inert surface coatings that have negligible interactions with the tumor ECM for diffusive transport. While there is an association of the surface charge of carriers with their transport through the tumor ECM, the mechanism of charge-driven transport is poorly understood. In this work, we elucidate the mechanism and find that interestingly, particles with a weakly positive surface charge interact with the net negatively charged tumor ECM to significantly improve their uptake, penetration, and retention in tumor tissue.