We report a method of synthesis and optimization of amino-functionalized silica nanoparticles (SiNPs) and their in vitro evaluation as targeted delivery vehicles for the potential treatment of pancreatic cancer. SiNPs can efficiently encapsulate doxorubicin and can be attached to a targeting moiety such as anti-Claudin-4 (CLN4). The preferential uptake in pancreatic cancer cells, where CLN4 is overexpressed, of SiNPs when conjugated to CLN4 antibody (compared to nonconjugated SiNPs) was confirmed by confocal microscopy. SiNPs encapsulating doxorubicin had greater efficacy in MTT assays than free doxorubicin, and when conjugated to CLN4, the efficacy was dramatically increased (at 1？μM). No apparent carrier toxicity was observed when void SiNPs were used. SiNPs carrying a chemotherapeutic drug have the potential to be used as a targeted therapy for lethal cancers, such as pancreatic cancer. Also, incorporation of fluorescent probes in these SiNPs creates the possibility of their use as an imaging probe for diagnostic purposes. 1. Introduction Cancer is still one of the most lethal diseases and one of the leading causes of death worldwide. Although there have been significant improvements in treating many cancers including breast, prostate, and lung with advances in medical technology, improvements in pancreatic cancer treatment have lagged behind. In the United States, pancreatic cancer is the fourth leading cause of cancer-related death. Aggressive disease progression and difficulties in early detection (before it metastasizes) are the two major factors that contribute to the ~95% death rate for patients suffering from pancreatic cancer. In most cancer treatments, the key to success relies mainly on early diagnosis, but in the case of pancreatic cancer currently available diagnosis technology is largely ineffective until the cancer progresses to late stages [1]. According to the American Association for Cancer Research, in 2012 there were an estimated 43,920 new cases of pancreatic cancer expected to occur, with 37,390 deaths [1]. Conventional treatment, which relies mainly on highly invasive chemotherapy, radiation, and surgery, has failed to impact the pancreatic cancer death rate because pancreatic cancer is resistant to most of the currently available chemo- and radiation therapies, and surgical removal of the primary tumor is fruitless owing to its high tendency to metastasize to distant organs. This is particularly true for individuals known to be “at risk” for developing pancreatic cancer because they have an inherited predisposition to it [2–5].
References
[1]
American Cancer Society, Cancer Facts & Figures 2012, pp. 19, http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012.
[2]
R. T. Greenlee, M. B. Hill-Harmon, T. Murray, and M. Thun, “Cancer statistics, 2001,” A Cancer Journal for Clinicians, vol. 51, no. 1, pp. 15–36, 2001.
[3]
T. P. Yeo, R. H. Hruban, S. D. Leach et al., “Pancreatic cancer,” Current Problems in Cancer, vol. 26, no. 4, pp. 176–275, 2002.
[4]
R. H. Hruban, G. M. Petersen, M. Goggins et al., “Familial pancreatic cancer,” Annals of Oncology, vol. 10, supplement 4, pp. 69–73, 1999.
[5]
G. M. Petersen and R. H. Hruban, “Familial pancreatic cancer: where are we in 2003?” Journal of the National Cancer Institute, vol. 95, no. 3, pp. 180–181, 2003.
[6]
D. F. Emerich and C. G. Thanos, “Nanotechnology and medicine,” Expert Opinion on Biological Therapy, vol. 3, no. 4, pp. 655–663, 2003.
[7]
T. Kubik, K. Bogunia-Kubik, and M. Sugisaka, “Nanotechnology on duty in medical applications,” Current Pharmaceutical Biotechnology, vol. 6, no. 1, pp. 17–33, 2005.
[8]
S. E. Leucuta, “Nanotechnology for delivery of drugs and biomedical applications,” Current Clinical Pharmacology, vol. 5, no. 4, pp. 257–280, 2010.
[9]
D. J. Bharali and S. A. Mousa, “Emerging nanomedicines for early cancer detection and improved treatment: current perspective and future promise,” Pharmacology & Therapeutics, vol. 128, no. 2, pp. 324–335, 2010.
[10]
M. Ferrari, “Cancer nanotechnology: opportunities and challenges,” Nature Reviews Cancer, vol. 5, no. 3, pp. 161–171, 2005.
[11]
S. Nie, Y. Xing, G. J. Kim, and J. W. Simons, “Nanotechnology applications in cancer,” Annual Review of Biomedical Engineering, vol. 9, pp. 257–288, 2007.
[12]
S. Singhal, S. Nie, and M. D. Wang, “Nanotechnology applications in surgical oncology,” Annual Review of Medicine, vol. 61, pp. 359–373, 2010.
[13]
G. S. Kwon, “Polymeric micelles for delivery of poorly water-soluble compounds,” Critical Reviews in Therapeutic Drug Carrier Systems, vol. 20, no. 5, pp. 357–403, 2003.
[14]
C. M. Walko and H. McLeod, “Pharmacogenomic progress in individualized dosing of key drugs for cancer patients,” Nature Clinical Practice Oncology, vol. 6, no. 3, pp. 153–162, 2009.
[15]
I. Brigger, C. Dubernet, and P. Couvreur, “Nanoparticles in cancer therapy and diagnosis,” Advanced Drug Delivery Reviews, vol. 54, no. 5, pp. 631–651, 2002.
[16]
J. Lu, M. Liong, J. I. Zink, and F. Tamanoi, “Mesoporous silica nanoparticles as a delivery system for hydrophobic anticancer drugs,” Small, vol. 3, no. 8, pp. 1341–1346, 2007.
[17]
T. Y. Ohulchanskyy, I. Roy, L. N. Goswami et al., “Organically modified silica nanoparticles with covalently incorporated photosensitizer for photodynamic therapy of cancer,” Nano Letters, vol. 7, no. 9, pp. 2835–2842, 2007.
[18]
R. Kumar, I. Roy, T. Y. Ohulchanskyy et al., “Covalently dye-linked, surface-controlled, and bioconjugated organically modified silica nanoparticles as targeted probes for optical imaging,” ACS Nano, vol. 2, no. 3, pp. 449–456, 2008.
[19]
H. Yan, C. Teh, S. Sreejith, L. Zhu, A. Kwok, W. Fang, et al., “Functional mesoporous silica nanoparticles for photothermal-controlled drug delivery in vivo,” Angewandte Chemie, vol. 51, no. 33, pp. 8373–8377, 2012.
[20]
M. Gary-Bobo, Y. Mir, C. Rouxel, D. Brevet, O. Hocine, M. Maynadier, et al., “Multifunctionalized mesoporous silica nanoparticles for the in vitro treatment of retinoblastoma: drug delivery, one and two-photon photodynamic therapy,” International Journal of Pharmaceutics, vol. 432, no. 1-2, pp. 99–104, 2012.
[21]
I. Roy, T. Y. Ohulchanskyy, H. E. Pudavar et al., “Ceramic-based nanoparticles entrapping water-insoluble photosensitizing anticancer drugs: a novel drug-carrier system for photodynamic therapy,” Journal of the American Chemical Society, vol. 125, no. 26, pp. 7860–7865, 2003.
[22]
P. Sharma, N. E. Bengtsson, G. A. Walter, H. B. Sohn, G. Zhou, N. Iwakuma, et al., “Gadolinium-doped silica nanoparticles encapsulating indocyanine green for near infrared and magnetic resonance imaging,” Small, vol. 8, no. 18, pp. 2856–2868, 2012.
[23]
P. Wang, X. Hu, S. Cook, and H. M. Hwang, “Influence of silica-derived nano-supporters on cellobiase after immobilization,” Applied Biochemistry and Biotechnology, vol. 158, no. 1, pp. 88–96, 2009.
[24]
D. J. Bharali, I. Klejbor, E. K. Stachowiak et al., “Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 32, pp. 11539–11544, 2005.
[25]
D. Luo and W. M. Saltzman, “Enhancement of transfection by physical concentration of DNA at the cell surface,” Nature Biotechnology, vol. 18, no. 8, pp. 893–895, 2000.
[26]
W. Tan, K. Wang, X. He et al., “Bionanotechnology based on silica nanoparticles,” Medicinal Research Reviews, vol. 24, no. 5, pp. 621–638, 2004.
[27]
S. Santra, P. Zhang, K. Wang, R. Tapec, and W. Tan, “Conjugation of biomolecules with luminophore-doped silica nanoparticles for photostable biomarkers,” Analytical Chemistry, vol. 73, no. 20, pp. 4988–4993, 2001.
[28]
L. M. Rossi, L. Shi, F. H. Quina, and Z. Rosenzweig, “Stober synthesis of monodispersed luminescent silica nanoparticles for bioanalytical assays,” Langmuir, vol. 21, no. 10, pp. 4277–4280, 2005.
[29]
H. Flachsbart and W. St？ber, “Preparation of radioactively labeled monodisperse silica spheres of colloidal size,” Journal of Colloid and Interface Science, vol. 30, no. 4, pp. 568–573, 1969.
[30]
K. Stalder and W. Stober, “Haemolytic activity of suspensions of different silica modifications and inert dusts,” Nature, vol. 207, no. 999, pp. 874–875, 1965.
[31]
D. J. Bharali, V. Pradhan, G. Elkin et al., “Novel nanoparticles for the delivery of recombinant hepatitis B vaccine,” Nanomedicine, vol. 4, no. 4, pp. 311–317, 2008.
[32]
H. Meng, M. Liong, T. Xia et al., “Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line,” ACS Nano, vol. 4, no. 8, pp. 4539–4550, 2010.
[33]
P. Michl, M. Buchholz, M. Rolke et al., “Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin,” Gastroenterology, vol. 121, no. 3, pp. 678–684, 2001.
[34]
C. A. Foss, J. J. Fox, G. Feldmann et al., “Radiolabeled anti-claudin 4 and anti-prostate stem cell antigen: initial imaging in experimental models of pancreatic cancer,” Molecular Imaging, vol. 6, no. 2, pp. 131–139, 2007.
[35]
H. Yamaguchi, T. Kojima, T. Ito, D. Kyuno, Y. Kimura, M. Imamura, et al., “Effects of Clostridium perfringens enterotoxin via claudin-4 on normal human pancreatic duct epithelial cells and cancer cells,” Cellular & Molecular Biology Letters, vol. 16, no. 3, pp. 385–397, 2011.
