Mesoporous silica nanoparticle (MSN) as a drug delivery system (DDS) has attracted great attention in the last decade. The natural features of MSNs such as high surface area, uniform pores, and easily tunable structures serve MSN as a versatilenanocarrier for drug delivery. Moreover, the three topologically different domains of MSN as of silica framework, hexagonal nanochannels/pores, and the outermost surface can be independently functionalized for different yet synergistic biomedical applications. In this thesis, I summarize our works in use of MSN as a nanodelivery system for comprehensive cancer theranostics on three main research themes: (1) Theranostic MSN for in vivo photodynamic therapy; (2) Biocompatibility and excretability of MSN in vivo especially with the hepatobiliary route; and (3) Biological-responsive MSN for interactive drug delivery, such as intracellular pH-sensitive controlled release of anticancer chemotherapeutics.
In the first theme, we used MSN to carry the photosensitizer (PS), Pd-porphyrin (PdTPP) that is well-known in use of tissue oxygenation measurements. The PS loading with MSN can enhance its PDT efficiency significantly via the increases of PS solubility, cell uptake and on-site PS concentration and availability. We further developed the tri-functionalized MSN that orchestratesoptical contrast for tracing, cancer-specific motif for targeted delivery, and PS for PDT, all in a single particle. This theranostic MSN demonstrates highly selective PDT effect in specific cancer cells which overexpress □v□3 integrin. In parallel, to increase the tissue penetration depth of excitation light for PDT via two-photon excitation, we designed a MSN functionalized with two-photon antenna molecule and PS performing highly efficient intra-particle energy transfer relay for two-photon activated PDT. The pronounced PDT efficacies were manifested and validated both in vitro and in vivo.
In the second theme, the governing factors of MSN biocompatibility and excretability in vivo were intensively studied. We first reported the MSN loaded with FDA-approved near- infrared fluorescence dye indocyanine green (ICG) for optical diagnosis. Then we managed to guide different bio-distributions of MSN with different surface charges. We attested that the highly positive surface charge mediates rapid hepatobiliary excretion of MSN evident by measurements with in vivo fluorescence imaging and subsequent inductively coupled plasma-mass spectroscopy of harvested tissues, urine, and feces. Our findings suggest that charge-dependent adsorption of serum proteins greatly facilitates the hepatobiliary excretion of silica nanoparticles, and that nanoparticle residence time in vivo can be regulated by manipulation of surface charge. In order to further indentify the hepatobiliary excretion of MSNs, we utilized the intravital multiphoton fluorescence microscopy to visualize the dynamics of sub-hepatic distribution of MSN. We observed significant hepatocyte uptake of positively charged MSN. Conversely, in vivo imaging of negatively charged MSN reveals an overwhelming propensity for rapid Kupffer cell uptake in liver sinusoids.
In the third theme, we developed the pH-sensitive MSN (MSN-Hydrazone-Dox) for controlled release of doxorubicin (Dox) via hydrolysis. This drug delivery platform offers features included (1) Intracellular drug release is triggered by acid environment of endosomes/lysosomes in tumor cells and (2) preventing non specific release from enzymatic hydrolysis.
Given all these efforts, our results are encouraging from the perspective of possessing great potential of functionalizing MSN as an effective drug nanodelivery system for nanomedicine translation. With further decrease of the size of MSN (less than 50 nm) for better tumor EPR effect, appropriate surface modification of MSN for targeting and following excretion, as well as pH-responsive drug loading of MSN for controlled release, we are likely to forward such a theranostic nanoplatform with on-demand drug release mechanism into the phase of clinical trial in the near future.

1. D. A. LaVan et al., Nat. Rev. Drug Discov., 2002, 1, 77.
2. M. Ferrari, Nat. Rev. Cancer, 2005, 5, 161.
3. G. M. Whitesides, Nat. Biotech. 2003, 21, 1161
4. B. Y. S. Kim, J. T. Rutka, and W. C. W. Chan, N. Engl. J. Med . 2010,363,2434-43.
5. Y. Xia, Y. J. Xiong, B. Lim, S. E.Skrabalak Angew Chem Int Ed Engl 2009,48,60-103.
6. D. Peer, J. M. Karp, S. Hong, O. C. Farokhzad, R. Margalit, R. Langer. Nat Nanotechnol 2007,2, 751-60.
7. M. E. Davis, J. E. Zuckerman, C. H. J. Choi, et al. Nature 2010,464, 1067-70.
8. R. A. Sperling, P. R. Gil, F. Zhang, M. Zanella, W. J. Parak. Chem Soc Rev 2008, 37, 1896-908.
9. Z. A. Liu, X. L. Li, S. M. Tabakman, K. L. Jiang, S. S. Fan, H. J. Dai, J Am Chem Soc 2008, 130, 13540-1.
10. U. Resch-Genger, M. Grabolle, S. Cavaliere-Jaricot, R. Nitschke, T. Nann. Nat Methods 2008,5, 763-75.
11. S. K. Hobbs, W. L. Monsky, F. Yuan, et al. Proc Natl Acad Sci U S A 1998, 95, 4607-12.
12. G. Prencipe, S. M. Tabakman, K. Welsher, et al. J Am Chem Soc 2009,131,4783-7.
13. F. Alexis, E. Pridgen, L. K. Molnar, O. C. Farokhzad. Mol Pharm 2008, 5, 505-15.
14. M. S. Shoichet, M. Shi and J. Lu, J Mater Chem 2009,19, 5485-5498.
15. J. Xie, S. Lee , X. Chen, Adv. Drug Deliv.Rev. 2010, 62, 1064–1079
16. S. Del Vecchio, A. Zannetti, R. Fonti, L. Pace, M. Salvatore, Q. J. Nucl. Med. Mol. Imaging 2007, 51, 152–163.
17. S. Nie, Y. Xing, G.J. Kim, J.W. Simons, Annu. Rev. Biomed. Eng. 2007, 9, 257–288.
18. Y. Liu, H. Miyoshi, M. Nakamura, Int. J. Cancer 2007, 120,2527–2537.
19. C. T. Kresge, M. E. Leonowicz, W. J. Roth, J. C. Vartuli and J. S. Beck, Nature, 1992, 359, 710–712.
20. I. I. Slowing, J. L. Vivero-Escoto, B. G. Trewyn and V. S. Y. Lin, J. Mater. Chem., 2010, 20, 7924–7937.
21. B. G. Trewyn, S. Giri, I. I. Slowing and V. S. Y. Lin, Chem. Commun., 2007, 3236–3245.
22. Q. He and J. Shi, J. Mater. Chem., 2011, 21, 5845–5855.
23. S. H. Wu, Y. Hung and C. Y. Mou, Chem. Commun. 2011, DOI: 10.1039/c1cc11760b
24. D. Bruhwiler, Nanoscale, 2010, 2, 887–892.
25. J. Vivero-Escoto, I.I Slowing, B. G. Trewyn and V. S. Y. Lin, Small, 2010. 6, 1952-1967.
26. S. P. Hudson, R. F. Padera, R. Langer and D. S. Kohane, Biomaterials, 2008, 29, 4045–4055.
27. T. H. Chung, S. H. Wu, M. Yao, C. W. Lu, Y. S. Lin, Y. Hung, C. Y. Mou, Y. C. Chen and D. M. Huang, Biomaterials, 2007, 28, 2959–2966.
28. C. H. Lee, T. S. Lin and C. Y. Mou, Nano Today, 2009, 4, 165–179.
29. M. Vallet-Regi, A. Ramila, R. P. del Real and J. Perez-Pariente, Chem. Mater., 2001, 13, 308–311.
30. D. R. Radu, C.-Y. Lai, K. Jeftinija, E. W. Rowe, S. Jeftinija, V. S. Y. Lin, J. Am. Chem. Soc. 2004, 126, 13216–13217.
31. T. D. Nguyen, K. C. F. Leung, M. Liong, C. D. Pentecost, J. F. Stoddart, J. I. Zink, Org. Lett. 2006, 8, 3363–3366.
32. K. C. F. Leung, T. D. Nguyen, J. F. Stoddart, J. I. Zink, Chem. Mater. 2006, 18, 5919–5928.
33. C. Park, K. Oh, S. C. Lee, C. Kim, Angew. Chem., Int. Ed. 2007, 46, 1455–1457.
34. R. Casasus, E. Climent, M. D. Marcos, R. Martinez-Manez, F. Sancenon, J. Soto et al. J. Am. Chem. Soc. 2008, 130, 1903–1917.
35. S. Angelos, Y.-W. Yang, K. Patel, J. F. Stoddart, J. I. Zink, Angew. Chem., Int. Ed. 2008, 47, 2222–2226.
36. T. D. Nguyen, Y. Liu, S. Saha, K. C. F. Leung, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2007, 129, 626–634.
37. K. Patel, S. Angelos, W. R. Dichtel, A. Coskun, Y.-W. Yang, J. I. Zink, J. F. Stoddart, J. Am. Chem. Soc. 2008, 130, 2382–2383.
38. N. K. Mal, M. Fujiwara, Y. Tanaka, Nature 2003, 421, 350–353.
39. S. Angelos, E. Choi, F. Voegtle, L .De Cola, J. I. Zink, J. Phys. Chem. C 2007, 111, 6589–6592.
40. T. D. Nguyen, K. C. F. Leung, M. Liong, Y. Liu, F. Stoddart, J. I. Zink, Adv. Funct. Mater. 2007, 17, 2101–2110.
41. J. Lu, E. Choi, F. Tamanoi, J. I. Zink, Small 2008, 4, 421–426.
42. C. H. Lee, L. W. Lo, C. Y. Mou and C. S. Yang, Adv. Funct. Mater., 2008, 18, 3283–3292.
43. C. E. Ashley, E. C. Carnes, G. K. Phillips, D. Padilla, P. N. Durfee, P. A. Brown, et al. Nat. Mater., 2011, 10, 389–397.
44. J. Rosenholm, C. Sahlgren and M. Linden, J. Mater. Chem., 2010, 20, 2707–2713.
45. M. Vallet-Regi, M. Colilla and B. Gonzalez, Chem. Soc. Rev., 2011, 40, 596–607.
46. C.A. Robertson, D. H. Evans, H. J. Abrahamse Photochem. Photobiol. B 2009, 96(1), 1-8.
47. M. Triesscheijn, P. Baas, J. H. Schellens, F.A. Stewart, Oncologist 2006, 11(9), 1034-1044.
48. T. J. Dougherty, C. J. Gomer, B.W. Henderson et al.. J. Natl. Cancer Inst. 1998, 90(12), 889-905.
49. Q. J. He, J. L. Shi, M. Zhu, Y. Chen and F. Chen, Microporous Mesoporous Mater., 2010, 131, 314–320.
50. Y. S. Lin, N. Abadeer and C. L. Haynes, Chem. Commun., 2011, 47, 532–534.
51. He, X. X.; Nie, H. L.; Wang, K. M.; Tan, W. H.; Wu, X.; Zhang, P. F. Anal. Chem. 2008, 80, 9597–9603.
52. J. Lu, M. Liong, Z. X. Li, J. I. Zink and F. Tamanoi, Small, 2010, 6, 1794–1805.
53. X. Huang, L. Li, T. Liu, N. Hao, H. Liu, D. Chen,and F. Tang, ACS Nano, 2011, ASAP
54. H. Meng, M. Xue, T. Xia, Z. Ji, D. Y. Tarn, J. I. Zink, and A. E. Ne, ACS Nano, 2011,5, 4131-4144.