(3il) Peptide Coatings to Improve Diffusive Transport of Drug Carriers in Tumor Microenvironment

One in every six deaths in the world is due to cancer, making it the second leading cause of death globally. To effectively treat cancers, therapies must reach as many cancer cells as possible. However, current therapies against solid cancers fail in part due to their inability to penetrate through the extracellular matrix (ECM) of tumors and reach the cancer cells at therapeutic concentrations. The tumor ECM forms a net negative charged network that hinders the transport of molecules based on their size, shape, and intermolecular interactions. Traditionally, the focus of drug delivery to solid tumors has been to develop delivery systems smaller than the pore size of the tumor ECM and/or with neutral charge coatings to minimize interactions with the ECM for improved transport. Recently, literature suggests that there is an association between the surface charge of carriers with their transport through the tumor ECM—however, the mechanism of how charge-based interactions impact transport and penetration within the tumor microenvironment is not well understood. Here, we used genetically engineered T7 bacteriophage (phage) as a model biological nanoparticle system to display peptides of different charges on its surface and investigated the effect of charge-based transport through tumor ECM.

In contrast to most studies, we found a positively charged peptide “surface” enhanced the penetration, uptake, and retention of T7 phage in tumor-like ECM and tumor tissue when compared to neutral and negatively charged peptides. Transport studies with systematic alanine mutagenesis of T7 show that electrostatic interactions are likely responsible for the higher tumor tissue uptake and retention. Mechanistically, the positively charged particle partitioned into the tumor tissue (with an equilibrium partition coefficient of ~6) due to electrostatic interactions. Further, weak and reversible binding of the phage solute with the tumor bed (with an equilibrium dissociation constant of ~230 nM) allowed for deep penetration within the tumor tissue.

Additionally, the positively charged peptide-presenting phage has a high number of intra-tissue binding sites in the tumor microenvironment (~4 μM) that enables almost 100% retention in the tumor tissue up to 24 hours. These results indicate that the net negative tumor ECM can act as a depot for positively charged particles to improve drug penetration and enhance tumor retention. We will also discuss the role of positively charged peptides as anchors to improve intratumor penetration and retention of therapeutics for antitumor efficacy. This work can potentially transform the current paradigm regarding the design of drug delivery systems to ultimately improve therapeutic index and therapeutic outcomes in solid cancers.

Keywords: Electrostatic interaction, peptide, tumor ECM, partitioning, penetration, uptake, and retention

Research Interests:
My current research primarily focuses on developing therapeutic moieties that can overcome the transport barrier of the tumor microenvironment for improved drug delivery. From my work with cell culture, ex vivo tissue culture, and animal model development, I have realized there is an unmet gap to develop disease models that can more easily recapitulate the dynamic and transport features of cancers. For my postdoctoral study, I am interested in designing disease models that better reflect the tumor environment to accelerate the progress of cancer drug discovery. I believe that modeling cancer in human organ chips will provide engineering solutions to understand the interactions within the cancer microenvironment, and provide high throughput platforms for noninvasive diagnostics, rapid drug discovery and drug delivery applications.