title: A computational framework for identifying design guidelines to increase the penetration of targeted nanoparticles into tumors.
abstract: Targeted nanoparticles are increasingly being engineered for the treatment of cancer. By design, they can passively accumulate in tumors, selectively bind to targets in their environment, and deliver localized treatments. However, the penetration of targeted nanoparticles deep into tissue can be hindered by their slow diffusion and a high binding affinity. As a result, they often localize to areas around the vessels from which they extravasate, never reaching the deep-seeded tumor cells, thereby limiting their efficacy. To increase tissue penetration and cellular accumulation, we propose generalizable guidelines for nanoparticle design and validate them using two different computer models that capture the potency, motion, binding kinetics, and cellular internalization of targeted nanoparticles in a section of tumor tissue. One strategy that emerged from the models was delaying nanoparticle binding until after the nanoparticles have had time to diffuse deep into the tissue. Results show that nanoparticles that are designed according to these guidelines do not require fine-tuning of their kinetics or size and can be administered in lower doses than classical targeted nanoparticles for a desired tissue penetration in a large variety of tumor scenarios. In the future, similar models could serve as a testbed to explore engineered tissue-distributions that arise when large numbers of nanoparticles interact in a tumor environment.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hauert
authors.affiliation: Mechanical and Aerospace Engineering, Arizona State University, Tempe, AZ 85287, USA.
authors.forename: Spring
authors.initials: S
authors.lastname: Berman
authors.affiliation: Computer Science, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Nagpal
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA ; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA ; Division of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA ; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sangeeta N
authors.initials: SN
authors.lastname: Bhatia
keywords: Cancer; Modeling; Nanoparticle; Systems Nanotechnology; Targeting; Tissue Penetration