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«COLLOIDAL GOLD NANOPARTICLES FOR CANCER THERAPY: EFFECTS OF PARTICLE SIZE ON TREATMENT EFFICACY, TOXICOLOGY, AND BIODISTRIBUTION A Dissertation ...»

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COLLOIDAL GOLD NANOPARTICLES FOR CANCER THERAPY: EFFECTS

OF PARTICLE SIZE ON TREATMENT EFFICACY, TOXICOLOGY, AND

BIODISTRIBUTION

A Dissertation

Presented to

The Academic Faculty

By

Kate Y.J. Lee

In Partial Fulfillment

Of the Requirements for the Degree

Doctor of Philosophy in the

Wallace H. Coulter Department of Biomedical Engineering

Georgia Institute of Technology Emory University May 2011 Copyright © Kate Y.J. Lee 2011

COLLOIDAL GOLD NANOPARTICLES FOR CANCER THERAPY: EFFECTS

OF PARTICLE SIZE ON TREATMENT EFFICACY, TOXICOLOGY, AND

BIODISTRIBUTION

Approved by:

Dr. Shuming Nie, Advisor Dr. Mark Prausnitz School of Biomedical Engineering School of Chemical and Biomolecular Engineering Georgia Institute of Technology Georgia Institute of Technology Dr. Ravi Bellamkonda Dr. Lily Yang School of Biomedical Engineering College of Medicine Georgia Institute of Technology Emory University Dr. Niren Murthy School of Biomedical Engineering Georgia Institute of Technology Date Approved: [January 19, 2011] To Mom, Dad, King, and Mark

ACKNOWLEDGEMENTS

First of all, I would like to thank my advisor Dr. Shuming Nie, who has provided me tremendous support and continuous guidance throughout the years. I still remember his words when I first met him: “In our lab, you have the freedom to succeed, but also the freedom to fail.” These words have been my motto for the past five years, constantly challenging myself to be a better scientist. I greatly admire Dr. Nie’s passion for science, especially for nanotechnology. Through him, I learned no statement can be made without any scientific reasoning or proofs, allowing me to pursue false-proof and meticulous research studies. Also, through the numerous talks and conferences hosted by Dr. Nie, I got to meet world-class scientists, who further motivated my studies. Thank you very much for the invaluable insights and advice for my research. Thank you again for always motivating me and believing in me to prove myself to be the scientist as I am today.

I am also very fortunate to be surrounded by such kind, intellectual people in the Nie Lab. Without the help and support from Dr. Yiqing Wang, Dr. Ximei Qian, and Dr.

Aaron Mohs, I could not have been here. Thank you Dr. Yiqing Wang for numerous research ideas and support-your encouragement and guidance has been invaluable for the success of my research. Also, thank you for always entertaining me with your wonderful stories. Thank you Dr. Ximei Qian for introducing me to the world of gold nanoparticles.

I have learned so much about research in general from you, and you have been a great role model for me in the Nie lab. Thank you Dr. Aaron Mohs for your advice in research and life. Your life lessons always kept me motivated and focused on my research. I am also lucky to interact with other group members, especially Dr. Brad Kairdolf, Michael

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would like to thank them for their friendship, collaboration, and support. Because of you, my days in the Nie lab have been more pleasant and enjoyable. I would like to thank our administrator Ms. Michelle Denney for her hardwork and friendship. Lastly, I also like to thank past Nie lab members Dr. Tushar Sathe, Dr. Matthew Rhyner, Dr. Gang Ruan, Dr.

Jun Li, Dr. Min Kuang, Dr. Hongwei Duan, Dr. Tao Liu, Dr.Jian Liu, Dr. Gloria Kim, Dr. Dominic Ansari, Dr. Debatosh Majumdar, Dr. Xiaohua Huang, Ryan Jowers, and Shefaet Raman for all their support and friendship.

Next, I would like to convey my appreciation to Dr. Gee Young Lee. She has been a great collaborator, who helped me to overcome my fear of mice. I have learned so much about in vivo work, and without her, I couldn’t have completed my in vivo studies.

She is like an elder sister that I have never had. She has been of great help and influence in my professional and personal life.

I also like to thank my committee members. I was lucky to interact with each of my committee members personally. I first met Dr. Ravi Bellamkonda and Dr. Mark Prausnitz when I was an undergraduate. I visited Georgia Institute of Technology for Research Experience for Undergraduate program, and I had a great opportunity to work in Dr. Mark Prausnitz lab over the summer. Dr. Ravi Bellamkonda, who happened to be a close friend of my undergraduate research advisor Dr. Christine Schmidt, gave me invaluable advice for getting into Georgia Tech’s prestigious Biomedical Engineering program. Dr. Lily Yang has been a great collaborator of our lab, and I got to personally interact with her through her research. Finally, I got to interact with Dr. Niren Murthy by working as a teaching assistant for his biotransport class.

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Ngangan, Brandon Kitchel, Adam Martinez, Marly Martinez, Fred Sieling, Steve Feng, Jaemin Shin, Jeeyun Yoon, Nick Willet, Kelly Brink, Stacie Chvatal, Hajira Ahmad, and Nola Li will be treasured forever.

I would like to thank my family for their tireless support and love. My parents have given me indefinite support and encouragement throughout my time here in Atlanta.





Despite being thousands of miles apart, my parents always cared and wished the best for me. Without your nurture and patience, I would have not been here today. I also thank my parents for giving me a wonderful younger brother, King, who always rooted for me throughout my journey in Atlanta. Finishing PhD degree was one of my dad’s top lists, since he had to stop at Masters due to birth of me and my brother in his graduate school years. Today, I am very proud to follow my dad’s footsteps and pursue my PhD degree in biomedical engineering.

Last but not least, I would like to thank my charming and magnificent fiancé, Mark Aramwattananont, who has been patiently waiting for me to finish my degree in Seattle, WA. I first met Mark in college as a sophomore, and he has been my best fan and supporter for the past ten years. Without your love and support, I would have not been here. You mean so much to me and I am very excited to start a new chapter of our lives together. Seattle, here I come!

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Maximum Loading of doxorubicin-PDPH onto Gold Nanoparticle 43 PEGylation of doxorubicin-PDPH-gold Nanoparticle Complex 44

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Characterization of doxorubicin-gold nanoparticle system 47 Characterization of PEGylated doxorubicin-gold nanoparticle system 51

–  –  –

PEGylation of Gold Nanoparticle and Blood Circulation Time 109 Biodistribution of Gold Nanoparticle in Skin and Pigmentation 111

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Table 1.2: Biodistribution of Various Size, Shape, and Dosage of Gold Nanoparticles 12 Table 2.

1: Summary of Selected Cytotoxicity for Gold Nanoparticles 26

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Figure 3.3: Fluorescence Spectra of Au-dox-PEG with Various Concentrations of PEG Indicate No Detectable Replacement of Bound Doxorubicin-PDPH on Gold Surface Compared to Au-dox and Pure Dox-PDPH.

54

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Figure 3.4: Surface Enhanced Raman Scattering (SERS) Spectra of Doxorubicin-PDPH on Non-Aggregated Gold Nanoparticle (Au-DOX and Au-DOX-PEG) Compared to SERS for Pure Doxorubicin and Gold Nanoparticle Mixture 55

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Figure 5.1: Blood Circulation Half Life of 5nm Gold Nanoparticle (~1.

6 days) 111 Figure 5.2: Gold Nanoparticle Induced Skin Pigmentation and Qualitative Monitoring of Distribution of 5nm versus 60nm Gold Nanoparticle 114

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Figure B.1: Darkfield Imaging of Liver, Spleen, Kidney, Lung, and Heart after 16 Days of 5nm Gold Nanoparticle Drug Delivery System Au-DOX-PEG Treatment

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The complexity and heterogeneity nature of cancer makes it difficult to successfully diagnose and treat cancer. Advances in cancer research have been focused on studying the molecular level of the disease, and nanotechnology plays a critical role in overcoming the obstacles in cancer biology. The size-scale (1-100nm) of nanotechnology provides a powerful tool to easily manipulate the cancer environment by distinctively size-tuning the nanomaterial to interact with biological molecules in tumor.

Recently, gold nanoparticle has emerged as an attractive platform for drug delivery applications by complementing the existing drug delivery carriers. Gold nanoparticles confer several advantages such as biocompatibility, size-tunability, and easy surface modification methods. Furthermore, due to its unique optical properties, multiple analytical chemistry methods such as UV-vis spectrophotometry, SERS, TEM, ICP-MS, darkfield microscopy, fluorescence can be used. Currently, only a few gold nanoparticle-based anticancer drug delivery systems have been reported, compared to the polymer-based delivery systems. Additionally, there is still a lack of understanding for the behavior and fate of the gold-drug conjugate in the body that further attention is required. The overall goal of this thesis is to investigate the in vivo behavior of colloidal gold nanoparticle and its therapeutic efficacy in an animal model, especially in a drug delivery application. To achieve this goal, we investigated the feasibility of using colloidal gold nanoparticle as an anticancer agent delivery vehicle for treatment of cancer. Then, long-term clearance, toxicity, and biodistribution of colloidal gold nanoparticle were studied to further aid in understanding of using colloidal gold nanoparticle as a drug delivery platform. In particular, two representative sizes of gold

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efficacy, toxicity, biodistribution, and clearance in cancer nanotherapy.

First, we report the development and characterization of multifunctional drug delivery system for simultaneously therapy and SERS spectroscopic detection of tumor.

Doxorubicin, serving a dual function of chemotherapeutic agent and SERS reporter molecule, was chemically conjugated to 60nm gold nanoparticle via pH-sensitive hydrazone linker, and then PEG was added to develop multifunctional delivery system.

The multifunctional delivery system demonstrated successful pH-dependent drug release profile, therapeutic effect on tumor cells, along with in vitro SERS spectroscopic detection. SERS spectra were detected for non-aggregated gold system at near-infrared wavelength. Thus, the development of multifunctional drug delivery system raises exciting opportunities for simultaneous spectroscopic detection and therapy for tumors.

Then, we report development of smaller-sized 5nm gold nanoparticle drug delivery system. Similar to 60nm gold system, 5nm gold nanoparticles were coated with doxorubicin, which was modified with pH-sensitive hydrazone linker, and then with PEG to give colloidal stability and biocompatibility. When tested in a tumor mouse model, 5nm gold drug delivery system resulted in therapeutic efficacy against tumor with no apparent systemic toxicity. In contrast, pure doxorubicin resulted in kidney, heart, and lung toxicity, along with insignificant therapeutic efficacy compared to other groups tested. The success of 5nm gold system resulted from (1) “high” accumulation at the tumor site compared to other non-tumor sites via EPR effect, (2) ideal spatial distribution and successful penetration at the tumor site, and (3) slow, controlled release of drug via pH-sensitive linker to result in no apparent systemic toxicity.

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colloidal gold nanoparticles that (1) increased circulation time for 5nm gold system (due to size and PEG) resulted in biodistribution of gold in various organs compared to 60nm gold system, (2) larger 60nm gold system was mostly uptaken in the liver and the spleen, whereas smaller sized 5nm gold system was visible in the various organs in the system, especially resulting in pigmentation in the skin and the lymph nodes, and (3) size dependent clearance was observed where 5nm gold system gets excreted via renal (urine) and hepatobiliary (feces) pathways, whereas 60nm gold was mostly retained in the spleen and liver after 6 months. Thus, 5nm gold system is a potential candidate for biomedical applications, where 5nm gold core displays inherently different biodistribution and clearance characteristics than 60nm or larger nanoparticles.

In summary, we believe that nanoparticle size plays a critical role for not only delivering the drug to the target site but also determining the in vivo behavior such as biodistribution and clearance in the system. By choosing an appropriate size scale for the system, we were able to successfully use gold nanoparticles for drug delivery applications along with desirable clearance from the biological system. This work is significant by providing an insight on a potential ideal candidate for drug delivery carrier for cancer nanotherapy.

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1.1 ABSTRACT Nanotechnology is an interdisciplinary research field that combines chemistry, engineering, biology, and medicine that allows early detection, accurate diagnosis, and personalized treatment of cancer. Nanotechnology adopts a size scale that is equivalent to biological molecules of 5-100 nm in diameter. The complexity and heterogeneity nature of cancer makes it difficult to successfully diagnose and treat cancer. Advances in cancer research have been focused on studying molecular level of the disease, and nanotechnology plays a critical role in overcoming the obstacles in cancer biology. In this chapter we will look at general characteristics of cancer and emphasizes the role of nanotechnology, particularly in terms of size effect, for successful detection, diagnosis, and treatment of cancer.

1.2 INTRODUCTION

According to the American Cancer Society, cancer is defined as the following:

“Cancer is a group of disease characterized by uncontrolled growth and

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