In the drug delivery system utilizing nanoparticle as carrier, sizes of the particles have been shown to influent the effectiveness of the delivery. However, the effects of the particle shapes have received little attention. In this work, we investigated particles with same volume but with different shapes, namely spherical nanoparticles (SNPs) and hexagonal nanoprisms (HNPs), and observed their behaviors in vitro and in vivo. The nanoparticles were constructed with the multifunctional block copolymer component, mPEG-b-P(HEMA-co-histidine-PLA). This multifunctional copolymer was synthesized via free-radical copolymerization and through solvent exchange process that induced self-assembling to the desired structures. We have shown that the different shapes of nanoparticles could be formed by adjusting the copolymer property and the formulation parameters. From this work, it was demonstrated that the morphology of the nanoparticles played an important role in mitigating macrophage responses, and the phagocytosis by macrophage measured by flow cytometry was 91.6±0.8% of SNPs and 68.1±2.4% of HNPs at the 48h co-incubation. The functional group of copolymer, histidine, is a biodegradable and pH-sensitivity molecule, being readily protonated at intracellular pH change after cancer cell uptake. In addition, histidine is characterized as a good chelator to [99mTc(H2O)3(CO)3]+ for forming radiotracer for imaging studies. To understand the in vivo pharmacokinetics and biodistributions of these nanoparticles, these particles were labeled with 99mTc or the fluorescent moiety Cy5.5 and studied in animals. With longer circulation in the blood, the 99mTc-labeled HNPs accumulated better in the tumor site than did the SNPs with the same radiolabel. The tumor to liver uptake ratio of HNPs was two-fold higher than that of SNPs (1.176 of HNPs, 0.604 of SNPs). In the optical image, the Cy5.5-labeled HNPs were excreted mainly from the renal clearance and Cy5.5-labeled SNPs were eliminated through the hepatic metabolism. In this thesis, in vitro and in vivo studies have investigated the dual stealth characters including the pegylation and the structure of hexagonal prism for the mPEG-b-P(HEMA-co-histidine-PLA) formed nanoparticles. The dual stealth characters of the nanocarriers could be adopted in clinical application for in safe and efficient delivery for cancer therapy.

Champion, J. A. & Mitragotri, S. Role of target geometry in phagocytosis. Proc Natl Acad Sci U S A 103, 4930-4934, doi:0600997103 [pii] 10.1073/pnas.0600997103 (2006).
2 Mitragotri, S. & Lahann, J. Physical approaches to biomaterial design. Nat Mater 8, 15-23, doi:nmat2344 [pii] 10.1038/nmat2344 (2009).
3 Egli, A. et al. Organometallic 99mTc-aquaion labels peptide to an unprecedented high specific activity. J Nucl Med 40, 1913-1917 (1999).
4 Mandal, N. P. P. a. T. K. Engineered Nanoparticles in Cancer Therapy. Recent Patents on Drug Delivery & Formulation 1, 37-51 (2007).
5 Surendiran, A., Sandhiya, S., Pradhan, S. C. & Adithan, C. Novel applications of nanotechnology in medicine Indian J Med Res 130, 689-701 (2009).
6 Segal, E. & Satchi-Fainaro, R. Design and development of polymer conjugates as anti-angiogenic agents. Advanced Drug Delivery Reviews 61, 1159-1176 (2009).
7 Strebhardt, K. & Ullrich, A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nat Rev Cancer 8, 473-480 (2008).
8 Haag, R. & Kratz, F. Polymer Therapeutics: Concepts and Applications. Angew. Chem. Int. Ed. 45, 1198 - 1215 (2006).
9 Y, M. & H, M. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Research 46, 6387-6392 (1986).
10 Yuan F Fau - Dellian, M. et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size.
11 Skinner, S. A., Tutton, P. J. & O'Brien, P. E. Microvascular architecture of experimental colon tumors in the rat. Cancer Res 50, 2411-2417 (1990).
12 Maeda, H., Bharate, G. Y. & Daruwalla, J. Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eur J Pharm Biopharm 71, 409-419, doi:S0939-6411(08)00450-5 [pii] 10.1016/j.ejpb.2008.11.010 (2009).
13 Grislain, L. et al. Pharmacokinetics and distribution of a biodegradable drug-carrier. Int. J. Pharm. 15 335–345 (1983).
14 Storm, G., Belliot, S. O., Daemen, T. & Lasic, D. D. Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system. Advanced Drug Delivery Reviews 17, 31-48 (1995).
15 Fang, C. et al. In vivo tumor targeting of tumor necrosis factor-alpha-loaded stealth nanoparticles: effect of MePEG molecular weight and particle size. Eur J Pharm Sci 27, 27-36, doi:S0928-0987(05)00247-2 [pii] 10.1016/j.ejps.2005.08.002 (2006).
16 Rijcken, C. J., Soga, O., Hennink, W. E. & van Nostrum, C. F. Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: an attractive tool for drug delivery. J Control Release 120, 131-148, doi:S0168-3659(07)00190-3 [pii] 10.1016/j.jconrel.2007.03.023 (2007).
17 Vonarbourg, A., Passirani, C., Saulnier, P. & Benoit, J. P. Parameters influencing the stealthiness of colloidal drug delivery systems. Biomaterials 27, 4356-4373, doi:S0142-9612(06)00294-8 [pii] 10.1016/j.biomaterials.2006.03.039 (2006).
18 Lee, J. H., Kopeckova, P., Kopecek, J. & Andrade, J. D. Surface properties of copolymers of alkyl methacrylates with methoxy (polyethylene oxide) methacrylates and their application as protein-resistant coatings. Biomaterials 11, 455-464 (1990).
19 Kingshott, P., Thissen, H. & Griesser, H. J. Effects of cloud-point grafting, chain length, and density of PEG layers on competitive adsorption of ocular proteins. Biomaterials 23, 2043-2056 (2002).
20 Johnstone, S. A., Masin, D., Mayer, L. & Bally, M. B. Surface-associated serum proteins inhibit the uptake of phosphatidylserine and poly(ethylene glycol) liposomes by mouse macrophages. Biochimica et Biophysica Acta (BBA) - Biomembranes 1513, 25-37, doi:Doi: 10.1016/s0005-2736(01)00292-9 (2001).
21 Bae, Y., Fukushima, S., Harada, A. & Kataoka, K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew Chem Int Ed Engl 42, 4640-4643, doi:10.1002/anie.200250653 (2003).
22 Lee, E. S., Shin, H. J., Na, K. & Bae, Y. H. Poly(L-histidine)-PEG block copolymer micelles and pH-induced destabilization. J Control Release 90, 363-374, doi:S0168365903002050 [pii] (2003).
23 Tsai, H. C. et al. Graft and diblock copolymer multifunctional micelles for cancer chemotherapy and imaging. Biomaterials, doi:S0142-9612(09)01303-9 [pii] 10.1016/j.biomaterials.2009.11.059 (2009).
24 Whitesides, G. M. & Grzybowski, B. Self-assembly at all scales. Science 295, 2418-2421, doi:10.1126/science.1070821 295/5564/2418 [pii] (2002).
25 Lin, K. J. SMTP-1: The First Functionalized Metalloporphyrin Molecular Sieves with Large Channels. Angew Chem Int Ed Engl 38, 2730-2732, doi:10.1002/(SICI)1521-3773(19990917)38:18<2730::AID-ANIE2730>3.0.CO;2-9 [pii] (1999).
26 Hu, J. S., Guo, Y. G., Liang, H. P., Wan, L. J. & Jiang, L. Three-dimensional self-organization of supramolecular self-assembled porphyrin hollow hexagonal nanoprisms. J Am Chem Soc 127, 17090-17095, doi:10.1021/ja0553912 (2005).
27 Douglas, S. J., Davis, S. S. & Illum, L. Nanoparticles in drug delivery. Crit Rev Ther Drug Carrier Syst 3, 233-261 (1987).
28 Tabata, Y. & Ikada, Y. Drug delivery systems for antitumor activation of macrophages. Crit Rev Ther Drug Carrier Syst 7, 121-148 (1990).
29 Choi, H. S. et al. Renal clearance of quantum dots. Nat Biotechnol 25, 1165-1170, doi:nbt1340 [pii] 10.1038/nbt1340 (2007).
30 Perrault, S. D., Walkey, C., Jennings, T., Fischer, H. C. & Chan, W. C. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett 9, 1909-1915, doi:10.1021/nl900031y (2009).
31 Mmitragotri, s. & Llahann, J. Physical approaches to biomaterial design. nature materials 8, 15-23 (2009).
32 Geng, Y. et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nano 2, 249-255, doi:http://www.nature.com/nnano/journal/v2/n4/suppinfo/nnano.2007.70_S1.html (2007).
33 Berg, K. & Moan, J. Optimization of wavelengths in photodynamic therapy. J.G. Moser edn, 151– 168 (Harwood Academic Publishers, 1998).
34 Moan, J., Berg, K. & Iani, V. Action spectra of dyes relevant for photodymanic therapy. J.G. Moser edn, 169– 181 (Harwood Academic Publishers, 1998).
35 Dougherty, T. J. et al. Photodynamic therapy. J. Natl. Cancer Inst 90 889-905 (1998).
36 Oleinick, N. L., Morris, R. L. & Belichenko, I. The role of apoptosis in response to photodynamic therapy:what, where, why, and how. Photochem. Photobiol. Sci. 1, 1-21 (2005).
37 Castano, A. P., Mroz, P. & Hamblin, M. R. Photodynamic therapy and anti-tumour immunity. NATURE REVIEWS : CANCER, 353-545 (2006).
38 M, H. & FR, M. Characterization of rapid membrane internalization and recycling. J Biol Chem 275, 15279-15286 (2000).
39 Lo, C. L., Huang, C. K., Lin, K. M. & Hsiue, G. H. Mixed micelles formed from graft and diblock copolymers for application in intracellular drug delivery. Biomaterials 28, 1225-1235, doi:S0142-9612(06)00855-6 [pii] 10.1016/j.biomaterials.2006.09.050 (2007).
40 Moore, J. S. & Stupp, S. I. Room temperature polyesterification. Macromolecules 23, 65-70, doi:10.1021/ma00203a013 (1990).
41 Schibli, R., Katti, K. V., Higginbotham, C., Volkert, W. A. & Alberto, R. In vitro and in vivo evaluation of bidentate, water-soluble phosphine ligands as anchor groups for the organometallic fac-[99mTc(CO)3]+-core. Nucl Med Biol 26, 711-716, doi:S0969805199000281 [pii] (1999).
42 Lo, C. L., Lin, K. M. & Hsiue, G. H. Preparation and characterization of intelligent core-shell nanoparticles based on poly(D,L-lactide)-g-poly(N-isopropyl acrylamide-co-methacrylic acid). J Control Release 104, 477-488, doi:S0168-3659(05)00110-0 [pii] 10.1016/j.jconrel.2005.03.004 (2005).
43 Lo, C.-L., Lin, K.-M. & Hsiue, G.-H. Preparation and characterization of intelligent core-shell nanoparticles based on poly(d,l-lactide)-g-poly(N-isopropyl acrylamide-co-methacrylic acid). Journal of Controlled Release 104, 477-488 (2005).