Computational analysis of drug transport in tumor microenvironment as a critical compartment for nanotherapeutic pharmacokinetics

Abstract

Over the last decade, nanotherapeutics gained increasingly important role in drug delivery because of their frequently beneficial pharmacokinetics (PK) and lower toxicity when compared to classical systemic drug delivery. In view of therapeutic payload delivery, convective transport is crucial for systemic distribution via circulatory system, but the target domain is tissue outside vessels where transport is governed by diffusion. Here, we have computationally investigated the understudied interplay of physical transports to characterize PK of payload of nanotherapeutics. The analysis of human vasculature tree showed that convective transport is still 5 times more efficient than diffusion suggesting that circulating and payload releasing drug vectors can contribute mostly to systemic delivery. By comparing payload delivery using systemic circulation and drug vectors to microenvironment, internalized vectors were the most efficient and showed Area under the Curve almost 100 higher than in systemic delivery. The newly introduced zone of influence parameter indicated that vectors, especially internalized, lead to the largest tissue fraction covered with therapeutically significant payload concentration. The internalization to microenvironment minimizes effects of plasma domain on payload extravasation from nanotherapeutics. The computed results showed that classical PK, which mostly relies on concentration profiles in plasma, sometimes might be inadequate or not sufficient in explaining therapeutic efficacy of nanotherapeutics. These results provide a deeper look into PK of drug vectors and can help in the design of better drug delivery strategies.

Keywords:

• Capillaries
• diffusion
• local concentration
• pharmacokinetics
• zone of influence

Declaration of interest

The authors acknowledge support from the Houston Methodist Research Institute, Ministry of Education and Science of Serbia (OI 174028, III 41007), City of Kragujevac, and EU grant FP7-ICT-2007 project (224297, ARTreat); the National Institute of Health (U54CA143837 – M.F., K.Y., U54CA151668 – M.F.), the Ernest Cockrell Jr. Distinguished Endowed Chair (M.F.), and the US Department of Defense (W81XWH-09-1-0212) (M.F.).

M.F. serves on the Board of Directors of NanoMedical Systems, Inc., ArrowHead Research Corporation, and discloses potential financial interest in the companies. All other authors declare no competing financial interests.

Supplementary material available online

Supplementary Figures S1 and S2 and Table S.