| 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 nanoparticles, 5nm and 60nm, were investigated for the size effect on therapeutic 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.;Finally, we demonstrated the size-dependent biodistribution and clearance of 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. |
