A biocompatible delivery platform for photodynamic therapy (PDT), the phospholipid-functionalized, protoporphyrin IX-loaded mesoporous silica nanocarriers (Lipo-PpIX-MSNs), is presented herein. With derivatization of folate onto phospholipid-capped MSNs (denoted as FA-Lipo-PpIX-MSNs), we are able to demonstrate the selective-targeting treatment in vitro using the pair cell models, HeLa (cells with overexpressed folic acid receptor, FR+) and A549 (cells without overexpressed folic acid receptor, FR-). We have successfully confirmed the selective binding/entry of such nanocarriers toward FR+ cells by cell viability study and confocal microscopic analysis. The reduced dark-toxicity of FA-Lipo-PpIX-MSNs enabled the delivery of higher concentration of PpIX into cells; moreover, higher cellular uptake of such drug-loaded nanocarriers was also found comparing with the treatment of free PpIX. The singlet oxygen production, which is the crucial factor in determining the therapeutic effectiveness of PDT treatment, from irradiated FA-Lipo-PpIX-MSNs was examined by iodometric reagent. The result suggests the successful introduction of 1O2 in aqueous environment by our system. This integrated system should provide the advantages of (i) prolonged shelf-life and circulation time due to the enhanced water dispersibility of MSN nanocarriers, (ii) better specific selectivity due to the targeting ligands (DSPE-PEG2000-FA), and therefore leading to (iii) improved therapeutic efficacy. Furthermore, the photosensitizer-loaded nanocarriers offer the feasibility of being cellular trackers while monitoring under confocal microscope, which leads to the understanding of their possible bio-distribution profile.

於此篇研究中，我們利用修飾有葉酸分子之磷脂質來包覆中孔洞奈米矽球的表面，使其形成一個具有生物相容性和靶向能力之藥物載體，並將疏水的光敏劑藥物protoporphyrin IX裝載入奈米矽球的中孔洞裡，以展現本藥物載體於光動力治療的應用性。
由於中孔洞奈米矽球載體表面修飾有帶葉酸分子之磷脂質，此載體系統（FA-Lipo-PpIX-MSNs）的標靶對象為過度表現葉酸受體之癌細胞；當我們將此載體系統與HeLa細胞（有葉酸受體過度表現）和A549細胞（無葉酸受體過度表現）共培養後，透過共軛聚焦顯微鏡觀察可發現表面有葉酸受體過度表現的HeLa細胞明顯攝入較多的中孔洞奈米矽球。此外，在使用相同濃度光敏劑藥物的條件下，比起直接施以光敏劑分子，本系統（FA-Lipo-PpIX-MSNs）不但能增加光敏劑進入細胞內的量，並能明顯降低光敏劑藥物的暗毒性。透過iodometric method，我們也已經證實了本系統在接受光源照射後能成功地在水溶液中產生單氧，得以進行光動力治療，毒殺標靶癌細胞。
本載體系統的優點包含：（1）能增加中孔洞奈米矽球在含鹽水溶液中的分散性和循環時間，（2）對於具標靶葉酸受體表現的細胞有較佳的選擇性，（3）增加治療效率。

1. Zhang, Y.; Zhi, Z.; Jiang, T.; Zhang, J.; Wang, Z.; Wang, S., Spherical Mesoporous Silica Nanoparticles for Loading and Release of the Poorly Water-Soluble Drug Telmisartan. J. Controlled Release 2010, 145 (3), 257-263.
2. Neuse, E. W., Synthetic Polymers as Drug-Delivery Vehicles in Medicine. Met.-Based Drugs 2008, 2008.
3. Shi, J.; Votruba, A. R.; Farokhzad, O. C.; Langer, R., Nanotechnology in Drug Delivery and Tissue Engineering: From Discovery to Applications. Nano Lett. 2010, 10 (9), 3223-3230.
4. Venturoli, D.; Rippe, B., Ficoll and Dextran vs. Globular Proteins as Probes for Testing Glomerular Permselectivity: Effects of Molecular Size, Shape, Charge, and Deformability. Am. J. Physiol. Renal Physiol. 2005, 288 (4), F605-13.
5. Yuan, F., Transvascular Drug Delivery in Solid Tumors. Semin. Radiat. Oncol. 1998, 8 (3), 164-75.
6. Cho, K.; Wang, X.; Nie, S.; Chen, Z.; Shin, D. M., Therapeutic Nanoparticles for Drug Delivery in Cancer. Clin. Cancer. Res. 2008, 14 (5), 1310-1316.
7. Adiseshaiah, P. P.; Hall, J. B.; McNeil, S. E., Nanomaterial Standards for Efficacy and Toxicity Assessment. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2010, 2 (1), 99-112.
8. Lembo, D.; Cavalli, R., Nanoparticulate Delivery Systems for Antiviral Drugs. Antiviral Chem. Chemother. 2010, 21, 53-70.
9. Greish, K., Enhanced Permeability and Retention of Macromolecular Drugs in Solid Tumors: A Royal Gate for Targeted Anticancer Nanomedicines. J. Drug Targeting 2007, 15 (7-8), 457-464.
10. Maeda, H., Tumor-Selective Delivery of Macromolecular Drugs via the EPR Effect: Background and Future Prospects. Bioconjugate Chem. 2010, 21 (5), 797-802.
11. Matsumura, Y.; Maeda, H., A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs. Cancer Res. 1986, 46 (12 Part 1), 6387-6392.
12. Dvorak, H. F., Vascular Permeability Factor/Vascular Endothelial Growth Factor: A Critical Cytokine in Tumor Angiogenesis and a Potential Target for Diagnosis and Therapy. J. Clin. Oncol. 2002, 20 (21), 4368-4380.
13. Guidi, A. J.; Schnitt, S. J.; Fischer, L.; Tognazzi, K.; Harris, J. R.; Dvorak, H. F.; Brown, L. F., Vascular Permeability Factor (Vascular Endothelial Growth Factor) Expression and Angiogenesis in Patients with Ductal Carcinoma In Situ of the Breast. Cancer 1997, 80 (10), 1945-1953.
14. Maeda, H.; Wu, J.; Sawa, T.; Matsumura, Y.; Hori, K., Tumor Vascular Permeability and the EPR Effect In Macromolecular Therapeutics: A Review. J. Controlled Release 2000, 65 (1-2), 271-284.
15. Sharma, R.; Sharma, C. L., Macromolecular Drugs: Novel Strategy In Target Specific Drug Delivery. Journal of Clinical and Diagnostic Research [serial online] 2008, 2 (4), 1020-1023.
16. Torchilin, V. P., Recent Advances with Liposomes as Pharmaceutical Carriers. Nat Rev Drug Discov 2005, 4 (2), 145-160.
17. Nakanishi, T.; Fukushima, S.; Okamoto, K.; Suzuki, M.; Matsumura, Y.; Yokoyama, M.; Okano, T.; Sakurai; Kataoka, K., Development of the Polymer Micelle Carrier System for Doxorubicin. J. Controlled Release 2001, 74 (1), 295-302.
18. Yokoyama, M.; Okano, T.; Sakurai, Y.; Suwa, S.; Kataoka, K., Introduction of Cisplatin into Polymeric Micelle. J. Controlled Release 1996, 39 (2), 351-356.
19. Yokoyama, M.; Opanasopit, P.; Okano, T.; Kawano, K.; Maitani, Y., Polymer Design and Incorporation Methods for Polymeric Micelle Carrier System Containing Water-Insoluble Anti-Cancer Agent Camptothecin. J. Drug Targeting 2004, 12 (6), 373-84.
20. Kim, S. H.; Jeong, J. H.; Lee, S. H.; Kim, S. W.; Park, T. G., Local and Systemic Delivery of VEGF siRNA using Polyelectrolyte Complex Micelles for Effective Treatment of Cancer. J. Controlled Release 2008, 129 (2), 107-116.
21. Al-Abd, A. M.; Lee, S. H.; Kim, S. H.; Cha, J.-H.; Park, T. G.; Lee, S. J.; Kuh, H.-J., Penetration and Efficacy of VEGF siRNA using Polyelectrolyte Complex Micelles in a Human Solid Tumor Model In-Vitro. J. Controlled Release 2009, 137 (2), 130-135.
22. Kim, S. H.; Jeong, J. H.; Lee, S. H.; Kim, S. W.; Park, T. G., LHRH Receptor-Mediated Delivery of siRNA Using Polyelectrolyte Complex Micelles Self-Assembled from siRNA-PEG-LHRH Conjugate and PEI. Bioconjugate Chem. 2008, 19 (11), 2156-2162.
23. Ponta, A.; Bae, Y., PEG-poly(amino acid) Block Copolymer Micelles for Tunable Drug Release. Pharm. Res. 2010, 27 (11), 2330-2342.
24. Murakami, Y.; Yokoyama, M.; Okano, T.; Nishida, H.; Tomizawa, Y.; Endo, M.; Kurosawa, H., A Novel Synthetic Tissue-Adhesive Hydrogel using a Crosslinkable Polymeric Micelle. Journal of Biomedical Materials Research Part A 2007, 80A (2), 421-427.
25. Patil, M. L.; Zhang, M.; Taratula, O.; Garbuzenko, O. B.; He, H.; Minko, T., Internally Cationic Polyamidoamine PAMAM-OH Dendrimers for siRNA Delivery: Effect of the Degree of Quaternization and Cancer Targeting. Biomacromolecules 2009, 10 (2), 258-266.
26. Tomalia, D. A.; Reyna, L. A.; Svenson, S., Dendrimers as Multi-Purpose Nanodevices for Oncology Drug Delivery and Diagnostic Imaging. Biochem. Soc. Trans. 2007, 35, 61-67.
27. Duncan, R., Polymer Conjugates as Anticancer Nanomedicines. Nat Rev Cancer 2006, 6 (9), 688-701.
28. Cartiera, M. S.; Johnson, K. M.; Rajendran, V.; Caplan, M. J.; Saltzman, W. M., The Uptake and Intracellular Fate of PLGA Nanoparticles in Epithelial Cells. Biomaterials 2009, 30 (14), 2790-2798.
29. Kocbek, P.; Obermajer, N.; Cegnar, M.; Kos, J.; Kristl, J., Targeting Cancer Cells using PLGA Nanoparticles Surface Modified with Monoclonal Antibody. J. Controlled Release 2007, 120 (1-2), 18-26.
30. Zhang, L.; Chan, J. M.; Gu, F. X.; Rhee, J.-W.; Wang, A. Z.; Radovic-Moreno, A. F.; Alexis, F.; Langer, R.; Farokhzad, O. C., Self-Assembled Lipid−Polymer Hybrid Nanoparticles: A Robust Drug Delivery Platform. ACS Nano 2008, 2 (8), 1696-1702.
31. Chan, J. M.; Zhang, L.; Yuet, K. P.; Liao, G.; Rhee, J.-W.; Langer, R.; Farokhzad, O. C., PLGA–Lecithin–PEG Core–Shell Nanoparticles for Controlled Drug Delivery. Biomaterials 2009, 30 (8), 1627-1634.
32. Schmid, M. H.; Korting, H. C., Therapeutic Progress with Topical Liposome Drugs for Skin Disease. Adv. Drug Del. Rev. 1996, 18 (3), 335-342.
33. Bangham, A. D.; Standish, M. M.; Watkins, J. C., Diffusion of Univalent Ions across the Lamellae of Swollen Phospholipids. J. Mol. Biol. 1965, 13 (1), 238-IN27.
34. Bangham, A. D.; Standish, M. M.; Weissmann, G., The Action of Steroids and Streptolysin S on the Permeability of Phospholipid Structures to Cations. J. Mol. Biol. 1965, 13 (1), 253-IN28.
35. Sessa, G.; Weissmann, G., Phospholipid Spherules (Liposomes) as a Model for Biological Membranes. J. Lipid Res. 1968, 9 (3), 310-318.
36. Cˇeh, B.; Winterhalter, M.; Frederik, P. M.; Vallner, J. J.; Lasic, D. D., StealthR Liposomes: From Theory to Product. Adv. Drug Del. Rev. 1997, 24 (2-3), 165-177.
37. Immordino, M.; Dosio, F.; Cattel, L., Stealth Liposomes: Review of the Basic Science, Rationale, and Clinical Applications, Existing and Potential. Int. J. Nanomed. 2006, 1 (3), 297-315.
38. Pirollo, K. F.; Chang, E. H., Does a Targeting Ligand Influence Nanoparticle Tumor Localization or Uptake? Trends Biotechnol. 2008, 26 (10), 552-558.
39. Owens Iii, D. E.; Peppas, N. A., Opsonization, Biodistribution, and Pharmacokinetics of Polymeric Nanoparticles. Int. J. Pharm. 2006, 307 (1), 93-102.
40. Modi, S.; Prakash Jain, J.; Domb, A. J.; Kumar, N., Exploiting EPR in Polymer Drug Conjugate Delivery for Tumor Targeting. Curr. Pharm. Des. 2006, 12, 4785-4796.
41. Iyer, A. K.; Khaled, G.; Fang, J.; Maeda, H., Exploiting the Enhanced Permeability and Retention Effect for Tumor Targeting. Drug Discovery Today 2006, 11 (17-18), 812-818.
42. Khalid, M.; Simard, P.; Hoarau, D.; Dragomir, A.; Leroux, J.-C., Long Circulating Poly(Ethylene Glycol)-Decorated Lipid Nanocapsules Deliver Docetaxel to Solid Tumors. Pharm. Res. 2006, 23 (4), 752-758.
43. Gabizon, A. A.; Shmeeda, H.; Zalipsky, S., Pros and Cons of the Liposome Platform in Cancer Drug Targeting*. J. Liposome Res. 2006, 16 (3), 175-183.
44. Riehemann, K.; Schneider, S. W.; Luger, T. A.; Godin, B.; Ferrari, M.; Fuchs, H., Nanomedicine—Challenge and Perspectives. Angew. Chem. Int. Ed. 2009, 48 (5), 872-897.
45. Hilgenbrink, A. R.; Low, P. S., Folate Receptor-Mediated Drug Targeting: From Therapeutics to Diagnostics. J. Pharm. Sci. 2005, 94 (10), 2135-2146.
46. Sudimack, J.; Lee, R. J., Targeted Drug Delivery via the Folate Receptor. Adv. Drug Del. Rev. 2000, 41 (2), 147-162.
47. Lu, Y.; Sega, E.; Low, P. S., Folate Receptor-Targeted Immunotherapy: Induction of Humoral and Cellular Immunity against Hapten-Decorated Cancer Cells. Int. J. Cancer 2005, 116 (5), 710-719.
48. Chen, H.; Ahn, R.; Van den Bossche, J.; Thompson, D. H.; O'Halloran, T. V., Folate-Mediated Intracellular Drug Delivery Increases the Anticancer Efficacy of Nanoparticulate Formulation of Arsenic Trioxide. Mol. Cancer Ther. 2009, 8 (7), 1955-1963.
49. Xia, W.; Low, P. S., Folate-Targeted Therapies for Cancer. J. Med. Chem. 2010, 53 (19), 6811-6824.
50. Cheng, S.-H.; Lee, C.-H.; Chen, M.-C.; Souris, J. S.; Tseng, F.-G.; Yang, C.-S.; Mou, C.-Y.; Chen, C.-T.; Lo, L.-W., Tri-Functionalization of Mesoporous Silica Nanoparticles for Comprehensive Cancer Theranostics-The Trio of Imaging, Targeting and Therapy. J. Mater. Chem. 2010, 20 (29), 6149-6157.
51. Odrljin, T. M.; Haidaris, C. G.; Lerner, N. B.; Simpson-Haidaris, P. J., Integrin αvβ3-Mediated Endocytosis of Immobilized Fibrinogen by A549 Lung Alveolar Epithelial Cells. Am. J. Respir. Cell Mol. Biol. 2001, 24 (1), 12-21.
52. Lu, J.; Shi, M.; Shoichet, M. S., Click Chemistry Functionalized Polymeric Nanoparticles Target Corneal Epithelial Cells through RGD-Cell Surface Receptors. Bioconjugate Chem. 2008, 20 (1), 87-94.
53. Goutayer, M.; Dufort, S.; Josserand, V.; Royere, A.; Heinrich, E.; Vinet, F.; Bibette, J.; Coll, J.-L.; Texier, I., Tumor Targeting of Functionalized Lipid Nanoparticles: Assessment by In Vivo Fluorescence Imaging. Eur. J. Pharm. Biopharm. 2010, 75 (2), 137-147.
54. Pike, D. B.; Ghandehari, H., HPMA Copolymer–Cyclic RGD Conjugates for Tumor Targeting. Adv. Drug Del. Rev. 2010, 62 (2), 167-183.
55. Mitra, A.; Mulholland, J.; Nan, A.; McNeill, E.; Ghandehari, H.; Line, B. R., Targeting Tumor Angiogenic Vasculature using Polymer–RGD Conjugates. J. Controlled Release 2005, 102 (1), 191-201.
56. Shukla, R.; Thomas, T. P.; Peters, J.; Kotlyar, A.; Myc, A.; Baker, J. J. R., Tumor Angiogenic Vasculature Targeting with PAMAM Dendrimer-RGD Conjugates. Chem. Commun. 2005, (46), 5739-5741.
57. Chen, W.; Jarzyna, P. A.; van Tilborg, G. A. F.; Nguyen, V. A.; Cormode, D. P.; Klink, A.; Griffioen, A. W.; Randolph, G. J.; Fisher, E. A.; Mulder, W. J. M.; Fayad, Z. A., RGD Peptide Functionalized and Reconstituted High-Density Lipoprotein Nanoparticles as a Versatile and Multimodal Tumor Targeting Molecular Imaging Probe. The FASEB Journal 2010, 24 (6), 1689-1699.
58. Garanger, E.; Boturyn, D.; Dumy, P., Tumor Targeting with RGD Peptide Ligands-Design of New Molecular Conjugates for Imaging and Therapy of Cancers. Anticancer Agents Med. Chem. 2007, 7, 552-558.
59. de Bruin, K.; Ruthardt, N.; von Gersdorff, K.; Bausinger, R.; Wagner, E.; Ogris, M.; Brauchle, C., Cellular Dynamics of EGF Receptor-Targeted Synthetic Viruses. Mol Ther 2007, 15 (7), 1297-1305.
60. Carlsson, J.; Blomquist, E.; Gedda, L.; Liljegren, A.; Malmstrom, P. U.; Sjostrom, A.; Sundin, A.; Westlin, J. E.; Zhao, Q.; Tolmachev, V.; Lundqvist, H., Conjugate Chemistry and Cellular Processing of EGF-Dextran. Acta oncologica (Stockholm, Sweden) 1999, 38 (3), 313-21.
61. Funatomi, H.; Itakura, J.; Ishiwata, T.; Pastan, I.; Thompson, S. A.; Johnson, G. R.; Korc, M., Amphiregulin Antisense Oligonucleotide Inhibits the Growth of T3M4 Human Pancreatic Cancer Cells and Sensitizes the Cells to EGF Receptor-Targeted Therapy. Int. J. Cancer 1997, 72 (3), 512-517.
62. von Gersdorff, K.; Ogris, M.; Wagner, E., Cryoconserved Shielded and EGF Receptor Targeted DNA Polyplexes: Cellular Mechanisms. Eur. J. Pharm. Biopharm. 2005, 60 (2), 279-285.
63. Park, J. W.; Mok, H.; Park, T. G., Epidermal Growth Factor (EGF) Receptor Targeted Delivery of PEGylated Adenovirus. Biochem. Biophys. Res. Commun. 2008, 366 (3), 769-774.
64. Xu, L.; Pirollo, K. F.; Tang, W.-H.; Rait, A.; Chang, E. H., Transferrin-Liposome-Mediated Systemic p53 Gene Therapy in Combination with Radiation Results in Regression of Human Head and Neck Cancer Xenografts. Hum. Gene Ther. 1999, 10 (18), 2941-2952.
65. Daniels, T. R.; Delgado, T.; Rodriguez, J. A.; Helguera, G.; Penichet, M. L., The Transferrin Receptor Part I: Biology and Targeting with Cytotoxic Antibodies for the Treatment of Cancer. Clin. Immunol. 2006, 121 (2), 144-158.
66. Xu, L.; Pirollo, K. F.; Chang, E. H., Transferrin–Liposome-Mediated p53 Sensitization of Squamous Cell Carcinoma of the Head and Neck to Radiation In Vitro. Hum. Gene Ther. 1997, 8 (4), 467-475.
67. Xu, L.; Tang, W. H.; Huang, C. C.; Alexander, W.; Xiang, L. M.; Pirollo, K. F.; Rait, A.; Chang, E. H., Systemic p53 Gene Therapy of Cancer with Immunolipoplexes Targeted by Anti-Transferrin Receptor scFv. Mol. Med. 2001, 7 (10), 723-734.
68. Xu, L.; Huang, C.-C.; Huang, W.; Tang, W.-H.; Rait, A.; Yin, Y. Z.; Cruz, I.; Xiang, L.-M.; Pirollo, K. F.; Chang, E. H., Systemic Tumor-targeted Gene Delivery by Anti-Transferrin Receptor scFv-Immunoliposomes 1 Mol. Cancer Ther. 2002, 1 (5), 337-346.
69. Pirollo, K. F.; Zon, G.; Rait, A.; Zhou, Q.; Yu, W.; Hogrefe, R.; Chang, E. H., Tumor-Targeting Nanoimmunoliposome Complex for Short Interfering RNA Delivery. Hum. Gene Ther. 2006, 17 (1), 117-124.
70. Lasic, D. D.; Needham, D., The "Stealth" Liposome: A Prototypical Biomaterial. Chem. Rev. 1995, 95 (8), 2601-2628.
71. Bartlett, D. W.; Su, H.; Hildebrandt, I. J.; Weber, W. A.; Davis, M. E., Impact of Tumor-Specific Targeting on the Biodistribution and Efficacy of siRNA Nanoparticles Measured by Multimodality In Vivo Imaging. Proceedings of the National Academy of Sciences 2007, 104 (39), 15549-15554.
72. Davis, M. E.; Chen, Z.; Shin, D. M., Nanoparticle Therapeutics: An Emerging Treatment Modality for Cancer. Nat Rev Drug Discov 2008, 7 (9), 771-782.
73. Antony, A. C., Folate Receptors Annu. Rev. Nutr. 1996, 16, 501-521.
74. Ball, E. W.; Giles, C., Folic Acid and Vitamin B12 Levels in Pregnancy and Their Relation to Megaloblastic Anaemia. J. Clin. Pathol. 1964, 17 (2), 165-174.
75. Rasmussen, K.; Moller, J.; Lyngbak, M.; Pedersen, A.; Dybkjaer, L., Age- and Gender-Specific Reference Intervals for Total Homocysteine and Methylmalonic Acid in Plasma before and after Vitamin Supplementation. Clin. Chem. 1996, 42 (4), 630-636.
76. Antony, A., The Biological Chemistry of Folate Receptors. Blood 1992, 79 (11), 2807-2820.
77. Kamen, B. A.; Capdevila, A., Receptor-Mediated Folate Accumulation is Regulated by the Cellular Folate Content. Proceedings of the National Academy of Sciences 1986, 83 (16), 5983-5987.
78. Leamon, C. P.; Reddy, J. A., Folate-Targeted Chemotherapy. Adv. Drug Del. Rev. 2004, 56 (8), 1127-1141.
79. Elnakat, H.; Ratnam, M., Distribution, Functionality and Gene Regulation of Folate Receptor Isoforms: Implications in Targeted Therapy. Adv. Drug Del. Rev. 2004, 56 (8), 1067-1084.
80. Balamurugan, K.; Said, H. M., Role of Reduced Folate Carrier in Intestinal Folate Uptake. American Journal of Physiology - Cell Physiology 2006, 291 (1), C189-C193.
81. Salazar, M.; Ratnam, M., The Folate Receptor: What Does It Promise in Tissue-Targeted Therapeutics? Cancer Metastasis Rev. 2007, 26 (1), 141-152.
82. Leamon, C. P.; Low, P. S., Folate-Mediated Targeting: From Diagnostics to Drug and Gene Delivery. Drug Discovery Today 2001, 6 (1), 44-51.
83. Antony, A. C.; Kane, M. A.; Portillo, R. M.; Elwood, P. C.; Kolhouse, J. F., Studies of the Role of a Particulate Folate-Binding Protein in the Uptake of 5-Methyltetrahydrofolate by Cultured Human KB Cells. J. Biol. Chem. 1985, 260 (28), 14911-14917.
84. Leamon, C. P.; Low, P. S., Delivery of Macromolecules into Living Cells: A Method that Exploits Folate Receptor Endocytosis. Proceedings of the National Academy of Sciences 1991, 88 (13), 5572-5576.
85. Low, P. S.; Henne, W. A.; Doorneweerd, D. D., Discovery and Development of Folic-Acid-Based Receptor Targeting for Imaging and Therapy of Cancer and Inflammatory Diseases. Acc. Chem. Res. 2007, 41 (1), 120-129.
86. Muller, C.; Vlahov, I. R.; Santhapuram, H. K. R.; Leamon, C. P.; Schibli, R., Tumor Targeting Using 67Ga-DOTA-Bz-Folate — Investigations of Methods to Improve the Tissue Distribution of Radiofolates. Nucl. Med. Biol. 2011, 38 (5), 715-723.
87. Muller, C.; Forrer, F.; Schibli, R.; Krenning, E. P.; de Jong, M., SPECT Study of Folate Receptor-Positive Malignant and Normal Tissues in Mice Using a Novel 99mTc-Radiofolate. J. Nucl. Med. 2008, 49 (2), 310-317.
88. Parker, N.; Turk, M. J.; Westrick, E.; Lewis, J. D.; Low, P. S.; Leamon, C. P., Folate Receptor Expression in Carcinomas and Normal Tissues Determined by a Quantitative Radioligand Binding Assay. Anal. Biochem. 2005, 338 (2), 284-293.
89. Leamon, C. P.; Parker, M. A.; Vlahov, I. R.; Xu, L.-C.; Reddy, J. A.; Vetzel, M.; Douglas, N., Synthesis and Biological Evaluation of EC20:  A New Folate-Derived, 99mTc-Based Radiopharmaceutical. Bioconjugate Chem. 2002, 13 (6), 1200-1210.
90. Reddy, J. A.; Xu, L.-C.; Parker, N.; Vetzel, M.; Leamon, C. P., Preclinical Evaluation of 99mTc-EC20 for Imaging Folate Receptor–Positive Tumors. J. Nucl. Med. 2004, 45 (5), 857-866.
91. Fisher, R. E.; Siegel, B. A.; Edell, S. L.; Oyesiku, N. M.; Morgenstern, D. E.; Messmann, R. A.; Amato, R. J., Exploratory Study of 99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors. J. Nucl. Med. 2008, 49 (6), 899-906.
92. Galt, J. R.; Halkar, R. K.; Evans, C.-O.; Osman, N. A.; LaBorde, D.; Fox, T. H.; Faraj, B. A.; Kumar, K.; Wang, H.; Oyesiku, N. M., In Vivo Assay of Folate Receptors in Nonfunctional Pituitary Adenomas with 99mTc-Folate SPECT/CT. J. Nucl. Med. 2010, 51 (11), 1716-1723.
93. Reddy, J. A.; Westrick, E.; Santhapuram, H. K. R.; Howard, S. J.; Miller, M. L.; Vetzel, M.; Vlahov, I.; Chari, R. V. J.; Goldmacher, V. S.; Leamon, C. P., Folate Receptor–Specific Antitumor Activity of EC131, a Folate-Maytansinoid Conjugate. Cancer Res. 2007, 67 (13), 6376-6382.
94. De Jonge, M. J.; Sleijfer, S.; Martin, L. P.; Marshall, J.; Deeken, J. F.; Konner, L. A.; Aghajanian, C., Phase I Pharmacokinetic and Safety Analysis of Epothilone Folate (BMS-753493): First-In-Human Clinical Experience of a Folate Receptor-Targeted Chemotherapeutic Agent Administered on Days 1, 4, 8, and 11 of a 21-Day Cycle. J. Clin. Oncol. 2010, 25 (15), 2607.
95. Leamon, C. P.; Reddy, J. A.; Klein, P. J.; Vlahov, I. R.; Dorton, R.; Bloomfield, A.; Nelson, M.; Westrick, E.; Parker, N.; Bruna, K.; Vetzel, M.; Gehrke, M.; Nicoson, J. S.; Messmann, R. A.; LoRusso, P. M.; Sausville, E. A., Reducing Undesirable Hepatic Clearance of a Tumor-Targeted Vinca Alkaloid via Novel Saccharopeptidic Modifications. J. Pharmacol. Exp. Ther. 2010.
96. Leamon, C. P.; Reddy, J. A.; Vlahov, I. R.; Westrick, E.; Parker, N.; Nicoson, J. S.; Vetzel, M., Comparative Preclinical Activity of the Folate-Targeted Vinca Alkaloid Conjugates EC140 and EC145. Int. J. Cancer 2007, 121 (7), 1585-1592.
97. Leamon, C. P.; Reddy, J. A.; Vlahov, I. R.; Westrick, E.; Dawson, A.; Dorton, R.; Vetzel, M.; Santhapuram, H. K.; Wang, Y., Preclinical Antitumor Activity of a Novel Folate-Targeted Dual Drug Conjugate. Mol. Pharm. 2007, 4 (5), 659-667.
98. Reddy, J. A.; Dorton, R.; Westrick, E.; Dawson, A.; Smith, T.; Xu, L.-C.; Vetzel, M.; Kleindl, P.; Vlahov, I. R.; Leamon, C. P., Preclinical Evaluation of EC145, a Folate-Vinca Alkaloid Conjugate. Cancer Res. 2007, 67 (9), 4434-4442.
99. Covello, K.; Flefleh, C.; Menard, K.; Wiebesiek, A.; McGlinchey, K.; Wen, M.; Westhouse, R.; Reddy, J.; Vlahov, I.; Hunt, J.; Rose, W.; Leamon, C.; Vite, G.; Lee, F., Preclinical Pharmacology of Epothilone-Folate Conjugate BMS-753493, a Tumor-Targeting Agent Selected for Clinical Development. AACR Meeting Abstracts 2008, 2008 (1_Annual_Meeting), 2326.
100. Konner, J. A.; Ahmed, S.; Gerst, S.; Vander Els, N.; Pezzuli, S.; Sabbatini, P.; Hensley, M.; Dupont, J.; Tew, W.; Aghajanian, C., Phase I Study of MORAb-003, a Humanized Anti-Folate Receptor-alpha Monoclonal Antibody, in Platinum Resistant Ovarian Cancer. J. Clin. Oncol. 2006, 24 (18S), 5027.
101. Sausville, E.; LoRusso, P.; Quinn, M.; Forman, K.; Leamon, C.; Morganstern, D.; Bever, S.; Messmann, R., A Phase I Study of EC145 Administered Weeks 1 and 3 of a 4-Week Cycle in Patients with Refractory Solid Tumors. J. Clin. Oncol. 2007, 25 (18S), 2577.
102. Messmann, R.; Amato, R.; Hernandez-McClain, J.; Conley, B.; Rogers, H.; Lu, J.; Low, P.; Bever, S.; Morgenstern, D., A Phase II Study of FolateImmune (EC90 with GP1-0100 Adjuvant Followed by EC17) with Low Dose Cytokines Interleukin-2 (IL-2) and Interferon-alpha (IFN-alpha) in Patients with Refractory or Metastatic Cancer. J. Clin. Oncol. 2007, 25 (18S), 13516.
103. Kim, H.; Lee, B.; Kim, T.; Nam, S.; Kim, B., Phase II Trial of Biweekly Reduced-Dose Combination Chemotherapy of Oxaliplatin/5-Fluorouracil/Folic Acid (Modified FOLFOX) as First-Line Chemotherapy in Elderly Patients with Metastatic or Rcurrent Gstric Cancer. American Society of Clinical Oncology 2009, 2009 Gastrointestinal Cancers Symposium (70).
104. Maddox, D.; Manlapat, A.; Roon, P.; Prasad, P.; Ganapathy, V.; Smith, S., Reduced-Folate Carrier (RFC) is Expressed in Placenta and Yolk Sac, as well as in Cells of the Developing Forebrain, Hindbrain, Neural Tube, Craniofacial Region, Eye, Limb Buds and Heart. BMC Dev. Biol. 2003, 3 (1), 6.
105. Weitman, S. D.; Lark, R. H.; Coney, L. R.; Fort, D. W.; Frasca, V.; Zurawski, V. R.; Kamen, B. A., Distribution of the Folate Receptor GP38 in Normal and Malignant Cell Lines and Tissues. Cancer Res. 1992, 52 (12), 3396-3401.
106. Toffoli, G.; Cernigoi, C.; Russo, A.; Gallo, A.; Bagnoli, M.; Boiocchi, M., Overexpression of Folate Binding Protein in Ovarian Cancers. Int. J. Cancer 1997, 74 (2), 193-198.
107. Bueno, R.; Appasani, K.; Mercer, H.; Lester, S.; Sugarbaker, D., The α Folate Receptor is Highly Activated in Malignant Pleural Mesothelioma. The Journal of Thoracic and Cardiovascular Surgery 2001, 121 (2), 225-233.
108. Kalli, K. R.; Oberg, A. L.; Keeney, G. L.; Christianson, T. J. H.; Low, P. S.; Knutson, K. L.; Hartmann, L. C., Folate Receptor Alpha as a Tumor Target in Epithelial Ovarian Cancer. Gynecol. Oncol. 2008, 108 (3), 619-626.
109. Ross, J. F.; Wang, H.; Behm, F. G.; Mathew, P.; Wu, M.; Booth, R.; Ratnam, M., Folate Receptor Type β is a Neutrophilic Lineage Marker and is Differentially Expressed in Myeloid Leukemia. Cancer 1999, 85 (2), 348-357.
110. Dixit, V.; Van den Bossche, J.; Sherman, D. M.; Thompson, D. H.; Andres, R. P., Synthesis and Grafting of Thioctic Acid−PEG−Folate Conjugates onto Au Nanoparticles for Selective Targeting of Folate Receptor-Positive Tumor Cells. Bioconjugate Chem. 2006, 17 (3), 603-609.
111. Osada, K.; Christie, R. J.; Kataoka, K., Polymeric Micelles from Poly(ethylene glycol)–Poly(amino acid) Block Copolymer for Drug and Gene Delivery. Journal of The Royal Society Interface 2009, 6 (Suppl 3), S325-S339.
112. Muller, C.; Schibli, R.; Krenning, E. P.; de Jong, M., Pemetrexed Improves Tumor Selectivity of 111In-DTPA-Folate in Mice with Folate Receptor–Positive Ovarian Cancer. J. Nucl. Med. 2008, 49 (4), 623-629.
113. Ke, C.-Y.; Mathias, C. J.; Green, M. A., The Folate Receptor as a Molecular Target for Tumor-Selective Radionuclide Delivery. Nucl. Med. Biol. 2003, 30 (8), 811-817.
114. Wang, X.; Li, J.; Wang, Y.; Koenig, L.; Gjyrezi, A.; Giannakakou, P.; Shin, E. H.; Tighiouart, M.; Chen, Z.; Nie, S.; Shin, D. M., A Folate Receptor-Targeting Nanoparticle Minimizes Drug Resistance in a Human Cancer Model. ACS Nano 2011, 5 (8), 6184-6194.
115. Low, P. S.; Kularatne, S. A., Folate-Targeted Therapeutic and Imaging Agents for Cancer. Curr. Opin. Chem. Biol. 2009, 13 (3), 256-262.
116. Paulos, C. M.; Turk, M. J.; Breur, G. J.; Low, P. S., Folate Receptor-Mediated Targeting of Therapeutic and Imaging Agents to Activated Macrophages in Rheumatoid Arthritis. Adv. Drug Del. Rev. 2004, 56 (8), 1205-1217.
117. Pinhassi, R. I.; Assaraf, Y. G.; Farber, S.; Stark, M.; Ickowicz, D.; Drori, S.; Domb, A. J.; Livney, Y. D., Arabinogalactan−Folic Acid−Drug Conjugate for Targeted Delivery and Target-Activated Release of Anticancer Drugs to Folate Receptor-Overexpressing Cells. Biomacromolecules 2009, 11 (1), 294-303.
118. Ke, C.-Y.; Mathias, C. J.; Green, M. A., Folate-Receptor-Targeted Radionuclide Imaging Agents. Adv. Drug Del. Rev. 2004, 56 (8), 1143-1160.
119. Hwa Kim, S.; Hoon Jeong, J.; Joe, C. O.; Gwan Park, T., Folate Receptor Mediated Intracellular Protein Delivery using PLL–PEG–FOL Conjugate. J. Controlled Release 2005, 103 (3), 625-634.
120. Sun, C.; Sze, R.; Zhang, M., Folic Acid-PEG Conjugated Superparamagnetic Nanoparticles for Targeted Cellular Uptake and Detection by MRI. Journal of Biomedical Materials Research Part A 2006, 78A (3), 550-557.
121. Gabizon, A.; Shmeeda, H.; Horowitz, A. T.; Zalipsky, S., Tumor Cell Targeting of Liposome-Entrapped Drugs with Phospholipid-Anchored Folic Acid–PEG Conjugates. Adv. Drug Del. Rev. 2004, 56 (8), 1177-1192.
122. Muller, C.; Schibli, R., Folic Acid Conjugates for Nuclear Imaging of Folate Receptor–Positive Cancer. J. Nucl. Med. 2011, 52 (1), 1-4.
123. Ross, T. L.; Honer, M.; Muller, C.; Groehn, V.; Schibli, R.; Ametamey, S. M., A New 18F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors. J. Nucl. Med. 2010, 51 (11), 1756-1762.
124. Sega, E.; Low, P., Tumor Detection Using Folate Receptor-Targeted Imaging Agents. Cancer Metastasis Rev. 2008, 27 (4), 655-664.
125. Ding, N.; Lu, Y.; Lee, R. J.; Yang, C.; Huang, L.; Liu, J.; Xiang, G., Folate Receptor-Targeted Fluorescent Paramagnetic Bimodal Liposomes for Tumor Imaging. Int J Nanomedicine 2011, 6, 2513-2520.
126. Yamada, A.; Taniguchi, Y.; Kawano, K.; Honda, T.; Hattori, Y.; Maitani, Y., Design of Folate-Linked Liposomal Doxorubicin to its Antitumor Effect in Mice. Clin. Cancer. Res. 2008, 14 (24), 8161-8168.
127. Liu, F.; Park, J.-Y.; Zhang, Y.; Conwell, C.; Liu, Y.; Bathula, S. R.; Huang, L., Targeted Cancer Therapy with Novel High Drug-Loading Nanocrystals. J. Pharm. Sci. 2010, 99 (8), 3542-3551.
128. Lu, Y.; Yang, J.; Sega, E., Issues Related to Targeted Delivery of Proteins and Peptides. The AAPS Journal 2006, 8 (3), E466-E478.
129. Corbin, I. R.; Chen, J.; Cao, W.; Li, H.; Lund-Katz, S.; Zheng, G., Enhanced Cancer-Targeted Delivery Using Engineered High-Density Lipoprotein-Based Nanocarriers. Journal of Biomedical Nanotechnology 2007, 3 (4), 367-376.
130. Lu, J. Y.; Lowe, D. A.; Kennedy, M. D.; Low, P. S., Folate-Targeted Enzyme Prodrug Cancer Therapy Utilizing Penicillin-V Amidase and a Doxorubicin Prodrug. J. Drug Targeting 1999, 7 (1), 43-53.
131. Gabizon, A.; Horowitz, A. T.; Goren, D.; Tzemach, D.; Mandelbaum-Shavit, F.; Qazen, M. M.; Zalipsky, S., Targeting Folate Receptor with Folate Linked to Extremities of Poly(ethylene glycol)-Grafted Liposomes:  In Vitro Studies. Bioconjugate Chem. 1999, 10 (2), 289-298.
132. Lu, Y.; Low, P. S., Folate-Mediated Delivery of Macromolecular Anticancer Therapeutic Agents. Adv. Drug Del. Rev. 2002, 54 (5), 675-693.
133. He, X.; Wang, K.; Cheng, Z., In Vivo Near-Infrared Fluorescence Imaging of Cancer with Nanoparticle-Based Probes. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2010, 2 (4), 349-366.
134. Saul, J. M.; Annapragada, A.; Natarajan, J. V.; Bellamkonda, R. V., Controlled Targeting of Liposomal Doxorubicin via the Folate Receptor In Vitro. J. Controlled Release 2003, 92 (1-2), 49-67.
135. Gruner, B. A.; Weitman, S. D., The Folate Receptor as a Potential Therapeutic Anticancer Target. Invest. New Drugs 1999, 16 (3), 205-219.
136. Moon, W. K.; Lin, Y.; O'Loughlin, T.; Tang, Y.; Kim, D.-E.; Weissleder, R.; Tung, C.-H., Enhanced Tumor Detection Using a Folate Receptor-Targeted Near-Infrared Fluorochrome Conjugate. Bioconjugate Chem. 2003, 14 (3), 539-545.
137. Mathias, C. J.; Wang, S.; Low, P. S.; Waters, D. J.; Green, M. A., Receptor-Mediated Targeting of 67Ga-Deferoxamine-Folate to Folate-Receptor-Positive Human KB Tumor Xenografts. Nucl. Med. Biol. 1999, 26 (1), 23-25.
138. Panwar, P.; Shrivastava, V.; Tandon, V.; Mishra, P.; Chuttani, K.; Sharma, R. K.; Chandra, R.; Mishra, A. K., 99mTc-Tetraethylenepentamine-Folate a New 99mTc Based Folate Derivative for the Detection of Folate Receptor Positive Tumors: Synthesis and Biological Evaluation. Cancer Biology & Therapy 2004, 3 (10), 995-1001.
139. Bharali, D. J.; Lucey, D. W.; Jayakumar, H.; Pudavar, H. E.; Prasad, P. N., Folate-Receptor-Mediated Delivery of InP Quantum Dots for Bioimaging Using Confocal and Two-Photon Microscopy. J. Am. Chem. Soc. 2005, 127 (32), 11364-11371.
140. Basal, E.; Eghbali-Fatourechi, G. Z.; Kalli, K. R.; Hartmann, L. C.; Goodman, K. M.; Goode, E. L.; Kamen, B. A.; Low, P. S.; Knutson, K. L., Functional Folate Receptor Alpha Is Elevated in the Blood of Ovarian Cancer Patients. PLoS ONE 2009, 4 (7), e6292.
141. Konda, S. D.; Wang, S.; Brechbiel, M.; Wiener, E. C., Biodistribution of a 153Gd-Folate Dendrimer, Generation = 4, in Mice With Folate-Receptor Positive and Negative Ovarian Tumor Xenografts. Invest. Radiol. 2002, 37 (4), 199-204.
142. Leamon, C. P.; Reddy, J. A.; Vlahov, I. R.; Vetzel, M.; Parker, N.; Nicoson, J. S.; Xu, L.-C.; Westrick, E., Synthesis and Biological Evaluation of EC72:  A New Folate-Targeted Chemotherapeutic. Bioconjugate Chem. 2005, 16 (4), 803-811.
143. Yoo, H. S.; Park, T. G., Folate-Receptor-Targeted Delivery of Doxorubicin Nano-Aggregates Stabilized by Doxorubicin–PEG–Folate Conjugate. J. Controlled Release 2004, 100 (2), 247-256.
144. Reddy, J.; Westrick, E.; Vlahov, I.; Howard, S.; Santhapuram, H.; Leamon, C., Folate Receptor Specific Anti-Tumor Activity of Folate–Mitomycin Conjugates. Cancer Chemother. Pharmacol. 2006, 58 (2), 229-236.
145. Kennedy, M. D.; Jallad, K. N.; Thompson, D. H.; Ben-Amotz, D.; Low, P. S., Optical Imaging of Metastatic Tumors using a Folate-Targeted Fluorescent Probe. Journal of Biomedical Optics 2003, 8 (4), 636-641.
146. Kranz, D. M.; Patrick, T. A.; Brigle, K. E.; Spinella, M. J.; Roy, E. J., Conjugates of Folate and Anti-T-Cell-Receptor Antibodies Specifically Target Folate-Receptor-Positive Tumor Cells for Lysis. Proceedings of the National Academy of Sciences 1995, 92 (20), 9057-9061.
147. Cho, B. K.; Roy, E. J.; Patrick, T. A.; Kranz, D. M., Single-Chain Fv/Folate Conjugates Mediate Efficient Lysis of Folate-Receptor-Positive Tumor Cells. Bioconjugate Chem. 1997, 8 (3), 338-346.
148. Rosenholm, J. M.; Meinander, A.; Peuhu, E.; Niemi, R.; Eriksson, J. E.; Sahlgren, C.; Linden, M., Targeting of Porous Hybrid Silica Nanoparticles to Cancer Cells. ACS Nano 2008, 3 (1), 197-206.
149. Chan, S. Y.; Empig, C. J.; Welte, F. J.; Speck, R. F.; Schmaljohn, A.; Kreisberg, J. F.; Goldsmith, M. A., Folate Receptor-± Is a Cofactor for Cellular Entry by Marburg and Ebola Viruses. Cell 2001, 106 (1), 117-126.
150. Mohapatra, S.; Mallick, S. K.; Maiti, T. K.; Ghosh, S. K.; Pramanik, P., Synthesis of Highly Stable Folic Acid Conjugated Magnetite Nanoparticles for Targeting Cancer Cells. Nanotechnology 2007, 18 (38), 385102.
151. Qi, H.; Ratnam, M., Synergistic Induction of Folate Receptor β by All-Trans Retinoic Acid and Histone Deacetylase Inhibitors in Acute Myelogenous Leukemia Cells: Mechanism and Utility in Enhancing Selective Growth Inhibition by Antifolates. Cancer Res. 2006, 66 (11), 5875-5882.
152. Atkinson, S. F.; Bettinger, T.; Seymour, L. W.; Behr, J.-P.; Ward, C. M., Conjugation of Folate via Gelonin Carbohydrate Residues Retains Ribosomal-inactivating Properties of the Toxin and Permits Targeting to Folate Receptor Positive Cells. J. Biol. Chem. 2001, 276 (30), 27930-27935.
153. Slowing, I.; Trewyn, B. G.; Lin, V. S. Y., Effect of Surface Functionalization of MCM-41-Type Mesoporous Silica Nanoparticles on the Endocytosis by Human Cancer Cells. J. Am. Chem. Soc. 2006, 128 (46), 14792-14793.
154. Rosenholm, J.; Sahlgren, C.; Linden, M., Cancer-Cell Targeting and Cell-Specific Delivery by Mesoporous Silica Nanoparticles. J. Mater. Chem. 2010, 20 (14), 2707-2713.
155. Wang, L.-S.; Wu, L.-C.; Lu, S.-Y.; Chang, L.-L.; Teng, I. T.; Yang, C.-M.; Ho, J.-a. A., Biofunctionalized Phospholipid-Capped Mesoporous Silica Nanoshuttles for Targeted Drug Delivery: Improved Water Suspensibility and Decreased Nonspecific Protein Binding. ACS Nano 2010, 4 (8), 4371-4379.
156. Kamaly, N.; Kalber, T.; Thanou, M.; Bell, J. D.; Miller, A. D., Folate Receptor Targeted Bimodal Liposomes for Tumor Magnetic Resonance Imaging. Bioconjugate Chem. 2009, 20 (4), 648-655.
157. Mantovani, L. T.; Miotti, S.; Menard, S.; Canevari, S.; Raspagliesi, F.; Bottini, C.; Bottero, F.; Colnaghi, M. I., Folate Binding Protein Distribution in Normal Tissues and Biological Fluids from Ovarian Carcinoma Patients as Detected by the Monoclonal Antibodies MOv18 and MOv19. Eur. J. Cancer 1994, 30 (3), 363-369.
158. Gupta, Y.; Jain, A.; Jain, P.; Jain, S. K., Design and Development of Folate Appended Liposomes for Enhanced Delivery of 5-FU to Tumor Cells. J. Drug Targeting 2007, 15 (3), 231-240.
159. Kurosaki, T.; Morishita, T.; Kodama, Y.; Sato, K.; Nakagawa, H.; Higuchi, N.; Nakamura, T.; Hamamoto, T.; Sasaki, H.; Kitahara, T., Nanoparticles Electrostatically Coated with Folic Acid for Effective Gene Therapy. Mol. Pharm. 2011, 8 (3), 913-919.
160. Shmeeda, H.; Mak, L.; Tzemach, D.; Astrahan, P.; Tarshish, M.; Gabizon, A., Intracellular Uptake and Intracavitary Targeting of Folate-Conjugated Liposomes in a Mouse Lymphoma Model with Up-Regulated Folate Receptors. Mol. Cancer Ther. 2006, 5 (4), 818-824.
161. Viola-Villegas, N.; Vortherms, A.; Doyle, R. P., Targeting Gallium to Cancer Cells through the Folate Receptor. Drug Target Insights 2008, 3 (DTI-3-Doyle-et-al), 13.
162. Campbell, I. G.; Jones, T. A.; Foulkes, W. D.; Trowsdale, J., Folate-binding Protein Is a Marker for Ovarian Cancer. Cancer Res. 1991, 51 (19), 5329-5338.
163. Meier, R.; Henning, T. D.; Boddington, S.; Tavri, S.; Arora, S.; Piontek, G.; Rudelius, M.; Corot, C.; Daldrup-Link, H. E., Breast Cancers: MR Imaging of Folate-Receptor Expression with the Folate-Specific Nanoparticle P1133 1. Radiology 2010, 255 (2), 527-535.
164. Franklin, W. A.; Waintrub, M.; Edwards, D.; Christensen, K.; Prendegrast, P.; Woods, J.; Bunn, P. A.; Kolhouse, S. F., New Anti-Lung-Cancer Antibody Cluster 12 Reacts with Human Folate Receptors Present on Adenocarcinoma. Int. J. Cancer 1994, 57 (S8), 89-95.
165. Chung, K. N.; Saikawa, Y.; Paik, T. H.; Dixon, K. H.; Mulligan, T.; Cowan, K. H.; Elwood, P. C., Stable Transfectants of Human MCF-7 Breast Cancer Cells with Increased Levels of the Human Folate Receptor Exhibit an Increased Sensitivity to Antifolates. The Journal of Clinical Investigation 1993, 91 (4), 1289-1294.
166. Pan, J.; Feng, S.-S., Targeting and Imaging Cancer Cells by Folate-Decorated, Quantum Dots (QDs)- Loaded Nanoparticles of Biodegradable Polymers. Biomaterials 2009, 30 (6), 1176-1183.
167. Jhaveri, M. S.; Rait, A. S.; Chung, K.-N.; Trepel, J. B.; Chang, E. H., Antisense Oligonucleotides Targeted to the Human α Folate Receptor Inhibit Breast Cancer Cell Growth and Sensitize the Cells to Doxorubicin Treatment. Mol. Cancer Ther. 2004, 3 (12), 1505-1512.
168. Lu, J.; Liong, M.; Li, Z.; Zink, J. I.; Tamanoi, F., Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small 2010, 6 (16), 1794-1805.
169. Konda, S. D.; Aref, M.; Brechbiel, M.; Wiener, E. C., Development of a Tumor-Targeting MR Contrast Agent Using the High-Affinity Folate Receptor: Work in Progress. Invest. Radiol. 2000, 35 (1), 50.
170. Liong, M.; Lu, J.; Kovochich, M.; Xia, T.; Ruehm, S. G.; Nel, A. E.; Tamanoi, F.; Zink, J. I., Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery. ACS Nano 2008, 2 (5), 889-896.
171. Hubner, R. A.; Houlston, R. S., Folate and Colorectal Cancer Prevention. Br. J. Cancer 2008, 100 (2), 233-239.
172. Nel, A. E.; Madler, L.; Velegol, D.; Xia, T.; Hoek, E. M. V.; Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M., Understanding Biophysicochemical Interactions at the Nano-Bio Interface. Nat Mater 2009, 8 (7), 543-557.
173. Lin, Y.-S.; Tsai, C.-P.; Huang, H.-Y.; Kuo, C.-T.; Hung, Y.; Huang, D.-M.; Chen, Y.-C.; Mou, C.-Y., Well-Ordered Mesoporous Silica Nanoparticles as Cell Markers. Chem. Mater. 2005, 17 (18), 4570-4573.
174. Huh, S.; Wiench, J. W.; Yoo, J.-C.; Pruski, M.; Lin, V. S. Y., Organic Functionalization and Morphology Control of Mesoporous Silicas via a Co-Condensation Synthesis Method. Chem. Mater. 2003, 15 (22), 4247-4256.
175. Trewyn, B. G.; Whitman, C. M.; Lin, V. S. Y., Morphological Control of Room-Temperature Ionic Liquid Templated Mesoporous Silica Nanoparticles for Controlled Release of Antibacterial Agents. Nano Lett. 2004, 4 (11), 2139-2143.
176. Suzuki, K.; Ikari, K.; Imai, H., Synthesis of Silica Nanoparticles Having a Well-Ordered Mesostructure Using a Double Surfactant System. J. Am. Chem. Soc. 2003, 126 (2), 462-463.
177. Jackie Y, Y., Design and Synthesis of Nanostructured Catalysts. Chem. Eng. Sci. 2006, 61 (5), 1540-1548.
178. Ying, J. Y.; Mehnert, C. P.; Wong, M. S., Synthesis and Applications of Supramolecular-Templated Mesoporous Materials. Angew. Chem. Int. Ed. 1999, 38 (1-2), 56-77.
179. Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C.; Beck, J. S., Ordered Mesoporous Molecular Sieves Synthesized by a Liquid-Crystal Template Mechanism. Nature 1992, 359 (6397), 710-712.
180. Rejman, J.; Oberle, V.; Zuhorn, I. S.; Hoekstra, D., Size-Dependent Internalization of Particles via the Pathways of Clathrin- and Caveolae-Mediated Endocytosis. . Biochem. J. 2004, 377, 159-169.
181. Chithrani, B. D.; Ghazani, A. A.; Chan, W. C. W., Determining the Size and Shape Dependence of Gold Nanoparticle Uptake into Mammalian Cells. Nano Lett. 2006, 6 (4), 662-668.
182. Jiang, W.; KimBetty, Y. S.; Rutka, J. T.; ChanWarren, C. W., Nanoparticle-Mediated Cellular Response is Size-Dependent. Nat Nano 2008, 3 (3), 145-150.
183. Slowing, I. I.; Trewyn, B. G.; Giri, S.; Lin, V. S. Y., Mesoporous Silica Nanoparticles for Drug Delivery and Biosensing Applications. Adv. Funct. Mater. 2007, 17 (8), 1225-1236.
184. Beck, J. S.; Vartuli, J. C.; Roth, W. J.; Leonowicz, M. E.; Kresge, C. T.; Schmitt, K. D.; Chu, C. T. W.; Olson, D. H.; Sheppard, E. W., A New Family of Mesoporous Molecular Sieves Prepared with Liquid Crystal Templates. J. Am. Chem. Soc. 1992, 114 (27), 10834-10843.
185. Lai, C.-Y.; Trewyn, B. G.; Jeftinija, D. M.; Jeftinija, K.; Xu, S.; Jeftinija, S.; Lin, V. S. Y., A Mesoporous Silica Nanosphere-Based Carrier System with Chemically Removable CdS Nanoparticle Caps for Stimuli-Responsive Controlled Release of Neurotransmitters and Drug Molecules. J. Am. Chem. Soc. 2003, 125 (15), 4451-4459.
186. Radu, D. R.; Lai, C.-Y.; Huang, J.; Shu, X.; Lin, V. S. Y., Fine-Tuning the Degree of Organic Functionalization of Mesoporous Silica Nanosphere Materials via an Interfacially Designed Co-Condensation Method. Chem. Commun. 2005, (10), 1264-1266.
187. Radu, D. R.; Lai, C.-Y.; Jeftinija, K.; Rowe, E. W.; Jeftinija, S.; Lin, V. S. Y., A Polyamidoamine Dendrimer-Capped Mesoporous Silica Nanosphere-Based Gene Transfection Reagent. J. Am. Chem. Soc. 2004, 126 (41), 13216-13217.
188. He, Q.; Zhang, Z.; Gao, F.; Li, Y.; Shi, J., In Vivo Biodistribution and Urinary Excretion of Mesoporous Silica Nanoparticles: Effects of Particle Size and PEGylation. Small 2011, 7 (2), 271-280.
189. Huang, X.; Li, L.; Liu, T.; Hao, N.; Liu, H.; Chen, D.; Tang, F., The Shape Effect of Mesoporous Silica Nanoparticles on Biodistribution, Clearance, and Biocompatibility in Vivo. ACS Nano 2011, 5 (7), 5390-5399.
190. Souris, J. S.; Lee, C.-H.; Cheng, S.-H.; Chen, C.-T.; Yang, C.-S.; Ho, J.-a. A.; Mou, C.-Y.; Lo, L.-W., Surface Charge-Mediated Rapid Hepatobiliary Excretion of Mesoporous Silica Nanoparticles. Biomaterials 2010, 31 (21), 5564-5574.
191. Huang, D.; Wujek, J.; Kidd, G.; He, T. T.; Cardona, A.; Sasse, M. E.; Stein, E. J.; Kish, J.; Tani, M.; Charo, I. F.; Proudfoot, A. E.; Rollins, B. J.; Handel, T.; Ransohoff, R. M., Chronic Expression of Monocyte Chemoattractant Protein-1 in the Central Nervous System Causes Delayed Encephalopathy and Impaired Microglial Function in Mice. The FASEB Journal 2005, 19 (7), 761-772.
192. Vallet-Regi, M.; Ramila, A.; del Real, R. P.; Perez-Pariente, J., A New Property of MCM-41:  Drug Delivery System. Chem. Mater. 2000, 13 (2), 308-311.
193. Munoz, B.; Ramila, A.; Perez-Pariente, J.; Diaz, I.; Vallet-Regi, M., MCM-41 Organic Modification as Drug Delivery Rate Regulator. Chem. Mater. 2002, 15 (2), 500-503.
194. Andersson, J.; Rosenholm, J.; Areva, S.; Linden, M., Influences of Material Characteristics on Ibuprofen Drug Loading and Release Profiles from Ordered Micro- and Mesoporous Silica Matrices. Chem. Mater. 2004, 16 (21), 4160-4167.
195. Charnay, C.; Begu, S.; Tourne-Peteilh, C.; Nicole, L.; Lerner, D. A.; Devoisselle, J. M., Inclusion of Ibuprofen in Mesoporous Templated Silica: Drug Loading and Release Property. Eur. J. Pharm. Biopharm. 2004, 57 (3), 533-540.
196. Horcajada, P.; Ramila, A.; Pariente, P.; Regi, V., Influence of Pore Size of MCM-41 Matrices on Drug Delivery Rate. Microporous Mesoporous Mater. 2004, 68 (1-3), 105-109.
197. Zeng, W.; Qian, X.-F.; Zhang, Y.-B.; Yin, J.; Zhu, Z.-K., Organic Modified Mesoporous MCM-41 through Solvothermal Process as Drug Delivery System. Mater. Res. Bull. 2005, 40 (5), 766-772.
198. Slowing, I. I.; Trewyn, B. G.; Lin, V. S. Y., Mesoporous Silica Nanoparticles for Intracellular Delivery of Membrane-Impermeable Proteins. J. Am. Chem. Soc. 2007, 129 (28), 8845-8849.
199. Zhao, Y.; Trewyn, B. G.; Slowing, I. I.; Lin, V. S. Y., Mesoporous Silica Nanoparticle-Based Double Drug Delivery System for Glucose-Responsive Controlled Release of Insulin and Cyclic AMP. J. Am. Chem. Soc. 2009, 131 (24), 8398-8400.
200. Mal, N. K.; Fujiwara, M.; Tanaka, Y., Photocontrolled Reversible Release of Guest Molecules from Coumarin-Modified Mesoporous Silica. Nature 2003, 421 (6921), 350-353.
201. Mal, N. K.; Fujiwara, M.; Tanaka, Y.; Taguchi, T.; Matsukata, M., Photo-Switched Storage and Release of Guest Molecules in the Pore Void of Coumarin-Modified MCM-41. Chem. Mater. 2003, 15 (17), 3385-3394.
202. Lin, Y.-S.; Hung, Y.; Su, J.-K.; Lee, R.; Chang, C.; Lin, M.-L.; Mou, C.-Y., Gadolinium(III)-Incorporated Nanosized Mesoporous Silica as Potential Magnetic Resonance Imaging Contrast Agents. The Journal of Physical Chemistry B 2004, 108 (40), 15608-15611.
203. Raab, O., Uber die Wirkung Fluoreszierender Stoffe auf Infusorien. (Action of Fluorescent Materials on Infusorial Substances.). Zeitung Biol. 1900, 39, 524-526.
204. Prime, J., Les Accidents Toxiques par l'eosinate de Sodium. Jouve and Boyer, Paris. 1900.
205. von Tappeiner, H.; Jesionek, A., Therapeutische Versuche mit Fluoreszierenden Stoffen. Muench Med. Wochenschr. 1903, 47, 2042-2044.
206. Huang, Z., A Review of Progress in Clinical Photodynamic Therapy. Technol Cancer Res Treat. 2005, 4 (3), 283-293.
207. Celli, J. P.; Spring, B. Q.; Rizvi, I.; Evans, C. L.; Samkoe, K. S.; Verma, S.; Pogue, B. W.; Hasan, T., Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and Optimization. Chem. Rev. 2010, 110 (5), 2795-2838.
208. Sternberg, E. D.; Dolphin, D., Porphyrin-Based Photosensitizers for use in Photodynamic Therapy. Tetrahedron 1998, 54, 4151-4202.
209. Tanielian, C.; Mechin, R., Reaction and Quenching of Singlet Molecular Oxygen with Esters of Polyunsaturated Fatty Acids. Photochem. Photobiol. 1994, 59 (3), 263-268.
210. Michaeli, A.; Feitelson, J., Reactivity of Singlet Oxygen toward Amino Acids and Peptides. Photochem. Photobiol. 1994, 59 (3), 284-289.
211. Lovell, J. F.; Liu, T. W. B.; Chen, J.; Zheng, G., Activatable Photosensitizers for Imaging and Therapy. Chem. Rev. 2010, 110 (5), 2839-2857.
212. Zeisser-Labouebe, M.; Mattiuzzo, M.; Lange, N.; Gurny, R.; Delie, F., Quenching-Induced Deactivation of Photosensitizer by Nanoencapsulation to Improve Phototherapy of Cancer. J. Drug Targeting 2009, 17 (8), 619-626.
213. Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K., Photodynamic Therapy for Cancer. Nat Rev Cancer 2003, 3 (5), 380-387.
214. Elena, R., Role of Delivery Vehicles for Photosensitizers in the Photodynamic Therapy of Tumours. J. Photochem. Photobiol. B: Biol. 1997, 37 (3), 189-195.
215. Tu, H.-L.; Lin, Y.-S.; Lin, H.-Y.; Hung, Y.; Lo, L.-W.; Chen, Y.-F.; Mou, C.-Y., In Vitro Studies of Functionalized Mesoporous Silica Nanoparticles for Photodynamic Therapy. Adv. Mater. 2009, 21 (2), 172-177.
216. Li, B.; Moriyama, E. H.; Li, F.; Jarvi, M. T.; Allen, C.; Wilson, B. C., Diblock Copolymer Micelles Deliver Hydrophobic Protoporphyrin IX for Photodynamic Therapy. Photochem. Photobiol. 2007, 83 (6), 1505-1512.
217. Kojima, C.; Toi, Y.; Harada, A.; Kono, K., Preparation of Poly(ethylene glycol)-Attached Dendrimers Encapsulating Photosensitizers for Application to Photodynamic Therapy. Bioconjugate Chem. 2007, 18 (3), 663-670.
218. Ho, J.-a. A.; Hung, C.-H.; Wu, L.-C.; Liao, M.-Y., Folic Acid-Anchored PEGgylated Phospholipid Bioconjugate and Its Application in a Liposomal Immunodiagnostic Assay for Folic Acid. Anal. Chem. 2009, 81 (14), 5671-5677.
219. Cosserat-Gerardin, I.; Bezdetnaya, L.; Notter, D.; Vigneron, C.; Guillemin, F., Biosynthesis and Photodynamic Efficacy of Protoporphyrin IX (PpIX) Generated by 5-Aminolevulinic Acid (ALA) or its Hexylester (hALA) in Rat Bladder Carcinoma Cells. J. Photochem. Photobiol. B: Biol. 2000, 59 (1-3), 72-79.
220. Mosinger, J.; Mosinger, B., Photodynamic Sensitizers Assay: Rapid and Sensitive Iodometric Measurement. Cell. Mol. Life Sci. 1995, 51 (2), 106-109.
221. Thomas, A. H.; Suarez, G.; Cabrerizo, F. M.; Martino, R.; Capparelli, A. L., Study of the Photolysis of Folic Acid and 6-Formylpterin in Acid Aqueous Solutions. J. Photochem. Photobiol. A: Chem. 2000, 135 (2), 147-154.
222. Thomas, A.; Einschlag, F. G.; Feliz, M. R.; Capparelli, A. L., First Steps in the Photochemistry of Folate in Alkaline Medium. J. Photochem. Photobiol. A: Chem. 1998, 116 (3), 187-190.
223. Suarez, G.; Cabrerizo, F. M.; Lorente, C.; Thomas, A. H.; Capparelli, A. L., Study of the Photolysis of 6-Carboxypterin in Acid and Alkaline Aqueous Solutions. J. Photochem. Photobiol. A: Chem. 2000, 132 (1-2), 53-57.
224. Lowry, O. H.; Bessey, O. A.; Crawford, E. J., Photolytic and Enzymatic Transformations of Pteroylglutamic Acid. J. Biol. Chem. 1949, 180 (1), 389-398.
225. Gorman, A. A.; Rodgers, M. A., Current Perspectives of Singlet Oxygen Detection in Biological Environments. J. Photochem. Photobiol. B. 1992, 14 (3), 159-76.
226. Halliwell, B.; Gutteridge, J., Free Radicals in Biology and Medicine. Oxford University Press: 2007.
227. Frimer, A. A., Singlet Oxygen Volume I, Physical-Chemical Aspects. CRC Press, Boca Raton 1985, 4-7.
228. Reddi, E.; Jori, G., Steady-State and Time-Resolved Spectroscopic Studies of Photodynamic Sensitizers: Porphyrins and Phthalocyanines. Res. Chem. Intermed. 1988, 10 (3), 241-268.
229. Reddi, E.; Jori, G.; Rodgers, M. A. J.; Spikes, J. D., Flash Photolysis Studies of Hemato-and Copro-Porphyrins in Homogeneous and Microheterogeneous Aqueous Dispersions. Photochem. Photobiol. 1983, 38 (6), 639-645.
230. Howard, J. A.; Mendenhall, G. D., Autoxidation and Photooxidation of 1,3-Diphenylisobenzofuran: A Kinetic and Product Study. Can. J. Chem. 1975, 53 (14), 2199-2201.
231. Choi, Y.; McCarthy, J. R.; Weissleder, R.; Tung, C.-H., Conjugation of a Photosensitizer to an Oligoarginine-Based Cell-Penetrating Peptide Increases the Efficacy of Photodynamic Therapy. ChemMedChem 2006, 1 (4), 458-463.
232. Rossi, L. M.; Silva, P. R.; Vono, L. L. R.; Fernandes, A. U.; Tada, D. B.; Baptista, M. c. S., Protoporphyrin IX Nanoparticle Carrier: Preparation, Optical Properties, and Singlet Oxygen Generation. Langmuir 2008, 24 (21), 12534-12538.
233. Rodgers, M. A. J.; Snowden, P. T., Lifetime of Oxygen (O2(1.DELTA.g)) in Liquid Water as Determined by Time-Resolved Infrared Luminescence Measurements. J. Am. Chem. Soc. 1982, 104 (20), 5541-5543.
234. Lambert, C. R.; Reddi, E.; Spikes, J. D.; Rodgers, M. A. J.; Jori, G., The Effects of Porphyrin Structure and Aggregation State on Photosensitized Processes in Aqueous and Micellar Media. Photochem. Photobiol. 1986, 44 (5), 595-601.
235. Flors, C.; Fryer, M. J.; Waring, J.; Reeder, B.; Bechtold, U.; Mullineaux, P. M.; Nonell, S.; Wilson, M. T.; Baker, N. R., Imaging the Production of Singlet Oxygen In Vivo using a New Fluorescent Sensor, Singlet Oxygen Sensor GreenR. J. Exp. Bot. 2006, 57 (8), 1725-1734.
236. Gollmer, A.; Arnbjerg, J.; Blaikie, F. H.; Pedersen, B. W.; Breitenbach, T.; Daasbjerg, K.; Glasius, M.; Ogilby, P. R., Singlet Oxygen Sensor GreenR: Photochemical Behavior in Solution and in a Mammalian Cell. Photochem. Photobiol. 2011, 87 (3), 671-679.
237. Lovell, J. F.; Chen, J.; Jarvi, M. T.; Cao, W.-G.; Allen, A. D.; Liu, Y.; Tidwell, T. T.; Wilson, B. C.; Zheng, G., FRET Quenching of Photosensitizer Singlet Oxygen Generation. The Journal of Physical Chemistry B 2009, 113 (10), 3203-3211.