Computational Modeling of Tumor Response to Drug Release from Vasculature-Bound Nanoparticles.

Louis T Curtis,Paolo Decuzzi,Hermann B Frieboes,Min Wu,John Lowengrub,Efstathios Karathanasis

doi:10.1371/journal.pone.0144888

Abstract

Systemically injected nanoparticle (NPs) targeting tumor vasculature offer a venue for anti-angiogenic therapies as well as cancer detection and imaging. Clinical application has been limited, however, due to the challenge of elucidating the complex interplay of nanotechnology, drug, and tumor parameters. A critical factor representing the likelihood of endothelial adhesion is the NP vascular affinity, a function of vascular receptor expression and NP size and surface-bound ligand density. We propose a theoretical framework to simulate the tumor response to vasculature-bound drug-loaded NPs and examine the interplay between NP distribution and accumulation as a function of NP vascular affinity, size, and drug loading and release characteristics. The results show that uniform spatial distribution coupled with high vascular affinity is achievable for smaller NPs but not for larger sizes. Consequently, small (100 nm) NPs with high vascular affinity are predicted to be more effective than larger (1000 nm) NPs with similar affinity, even though small NPs have lower drug loading and local drug release compared to the larger NPs. Medium vascular affinity coupled with medium or larger sized NPs is also effective due to a more uniform distribution with higher drug loading and release. Low vascular affinity hampered treatment efficacy regardless of NP size, with larger NPs additionally impeded by heterogeneous distribution and drug release. The results further show that increased drug diffusivity mainly benefits heterogeneously distributed NPs, and would negatively affect efficacy otherwise due to increased wash-out. This model system enables evaluation of efficacy for vascular-targeted drug-loaded NPs as a function of critical NP, drug, and tumor parameters.

Highlights

It is well known that chemotherapy success is hindered by cancerous tissue not following normal biological development
We evaluate drug release coupled to the accumulated NPs, and analyze the relative tumor response for each NP group
A two-dimensional model for the growth of a vascularized tumor was integrated with a mesoscale formulation for the vascular adhesion of systemically injected NPs [13], showing that a nonlinear relationship exists between NP size and affinity to achieve homogeneous intra-tumoral distribution

Summary

Introduction

It is well known that chemotherapy success is hindered by cancerous tissue not following normal biological development. Even if drug were to be available in cytotoxic concentrations, quiescent cells in tumor hypoxic regions would remain largely unresponsive to cell-cycle dependent chemotherapeutics. These cells would regain access to adequate oxygen and nutrients once the overall population was thinned out by therapy, resuming the tumor growth. Encapsulation of chemotherapeutic drugs into liposomal molecules is an active research area. These nanoparticles offer potential benefits over chemotherapeutic agents alone, including increased drug bioavailability, decreased drug degradation and inactivation, as well as decreased off-site toxicity [4, 5]. Mathematical and computational approaches have recently been developed as complementary tools to assist in this endeavor [6,7,8,9,10,11,12,13,14,15,16,17,18,19]

Methods

Results

Conclusion