Date of Award

Summer 2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor

Pedro Derosa

Abstract

Determining the factors that influence the delivery of nanoparticles to tumors and understanding the relative importance of each of these factors is fundamental to optimize the drug delivery process. In this research, a model that combines random walk with the pressure driven flow of nanoparticles in a tumor vasculature is modeled. Nanoparticle movement in a cylindrical tube with dimensions similar to the tumor's blood capillary with a single pore is simulated. Nanoparticle velocities are calculated as a pressure driven flow over imposed to Brownian motion. During the study, the effect of red blood cells (RBC) is also studied by comparing the delivery with and without RBC. The number and percentage of nanoparticles leaving the blood vessel through the pore is obtained as a function of pore size, nanoparticle size and concentration, interstitial pressure, and blood pressure in the tumor vasculature. The model presented here is able to determine the relative importance of these controllable parameters and thus it can be used to understand the process and predict the best conditions for nanoparticle-based treatment. When RBC are not considered, the results indicate that the nanoparticle delivery gradually increases with pore size and decreases with nanoparticle size for tumors with high interstitial fluid pressure (in this work we found this behavior for head and neck carcinoma and for metastatic melanoma with interstitial pressures of 18 mmHg and 19 mmHg, respectively). For tumors with lower interstitial fluid pressure (rectal carcinoma with 15.3 mmHg) however, delivery is about constant for almost the entire nanoparticle size range. Though increase in nanoparticle concentration increases the number of nanoparticles being delivered, the efficiency of the delivery (percentage of nanoparticles delivered) is found to remain unaffected.

The motion of red blood cells in the capillary is also simulated and the velocity of nanoparticles between two red blood cells is obtained from the bolus flow of plasma, and the velocity between a red blood cell and the capillary wall is obtained from the lubrication theory. The results show that bolus flow of plasma in the presence of RBC pushes the NP's towards the capillary wall leading to an increased NP delivery to the tumor; however the delivery as a function of NP size, blood pressure and interstitial fluid pressure is qualitatively the same that when there are no red blood cells.

A study of nanoparticle movement through entire body is performed by considering that the nanoparticles are uniformly distributed throughout the blood circulation. The nanoparticle delivery to the tumor with time obtained from this study showed a very good to excellent agreement with the experimental results.

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