臺灣博碩士論文加值系統

微脂體包覆是以高濃度包覆藥物藉此降低全身毒性的一種成熟技術。然而，許多抗癌藥物是疏水性的，這導致如何設計防止內部貨物的藥物洩漏的策略，是非常有挑戰性的。我們假設，使用能夠在裝載的親脂性狀態和親水狀態之間進行交換的糖苷開關，可逆地連接到藥物上，並且在親油性狀態和親水狀態之間可調控地切換，用於有效裝載藥物，而增強微脂體保留。含有水溶性羧酸酯基的糖苷開關（葡糖苷酸-G）與疏水性藥物（藥物-GW）連接，並通過在酸性甲醇（藥物-GL）中產生酯衍生物而轉變為親油性狀態。糖苷開關 - 藥物偶聯物的親脂性酯形式通過在鹼性pH下皂化，並且快速返回到親水性羧酸酯基團。將外部為低pH和內部為高pH的微脂體與親脂性糖苷開關的疏水性藥物反應之後，其迅速積聚在微脂體內並在鹼性pH下自發皂化（水解）至親水性羧酸鹽狀態以改善保留。這種方法有助於包覆抗癌藥物9-氨基喜樹鹼（9AC），5,6-二氫-4H-苯並[de]喹啉 - 喜樹鹼（BQC）和4-甲基繖形酮（4MU）。與疏水性藥物9AC和BQC的微脂體製劑相比，微脂體9AC-GW和BQC-GW在7天的生物環境中顯著更穩定。此外，微脂體9AC-GW被癌細胞攝取，疏水性藥物9AC在細胞內再生。在體內，微脂體9AC-GW能夠治愈絕大多數帶有皮下MDA-Mb-468人乳腺癌腫瘤的小鼠，而沒有顯著的體重減輕。總之，這種新的方法提供了一種可靠地保留微脂體內各種各樣的疏水藥物的方式，以幫助減少體內過早的“爆發”釋放，從而為腫瘤治療和其他疾病的工程化微脂體提供新的視角。

Liposomal encapsulation is a proven technology to encapsulate drugs at high concentrations and lower systemic toxicity. Yet, numerous anticancer drugs are hydrophobic which results in the design of challenging strategies to prevent drug leakage of internalized cargo. We hypothesized that conjugating hydrophobic drugs with a glycosidic switch, able to interchange between a lipophilic state for loading and a hydrophilic state for retention, might enhance liposomal retention due to increased membrane impermeability. A glycosidic switch (glucuronide, -G) containing a water solubilizing carboxylate group was conjugated to hydrophobic drugs (drug-GW) and switched to a lipophilic state by generation of an ester derivate in acidic methanol (drug-GL). The lipophilic ester form of the switch-drug conjugate rapidly returned back to the hydrophilic carboxylate group by saponification at basic pH. The resulting liposomes with an external low pH and an internal high pH were incubated with hydrophobic drugs conjugated with the lipophilic switch, which rapidly accumulated inside liposomes and spontaneously saponified (hydrolyzed) to a hydrophilic carboxylate state at basic pH for improved retention. This method helped encapsulate anticancer drugs 9-aminocamptothecin (9AC), 5,6-dihydro-4H-benzo[de]quinoline-camptothecin (BQC) and 4-methylumbelliferone (4MU). Liposomal 9AC-GW and BQC-GW were significantly more stable in biological environments over a period of 7 days, compared to the liposomal formulation of hydrophobic parental drugs 9AC and BQC. Moreover, liposomal 9AC-GW was taken up by cancer cells and parental hydrophobic drug 9AC was regenerated within the cells. In vivo, liposomal 9AC-GW was able to cure the majority of treated mice bearing subcutaneous MDA-Mb-468 human breast cancer tumors without significant body weight loss. In conclusion, this new methodology provides a way to reliably retain a wide variety of hydrophobic drugs inside liposomes to help reduce premature “burst” release in vivo, thereby offering new perspectives in engineering liposomes for cancer therapy and other diseases.

CONTENTS..............i
ACKNOWLEDGEMENTS.............iv
ABSTRACT..................vi
ABBREVIATIONS & DEFINITIONS............ vii
INTRODUCTION..............1
I. BACKGROUND......................... 2
II. MEDICAL USES OF LIPOSOMES.............6
A. CANCER THERAPY.........6
B. LIPOSOMES AS A DRUG DELIVERY SYSTEM.............7
1. Different factors influencing drug delivery..........8
a. Liposomes size.........8
b. Membranes composition..............9
c. Targeting.......10
d. Long circulating liposomes......................11
2. Drug loading: Passive loading...................11
3. Drug loading: Active loading....................12
a. Lipophilic compounds.................12
b. Partition coefficient and pH gradient...............13
c. Chemical gradient................14
d. Advantages and limitations...................14

III. CURRENT ISSUES..............19
A. CASE BY CASE RESEARCH AND DEVELOPMENT.............19
B. DRUG RETENTION.............19
C. SAFETY..............20

GOALS...............21
MATERIALS & METHODS....................31
RESULTS...........41
I. CHARACTERIZATION OF THE PHYSICOCHEMICAL PROPERTIES OF DRUGS CONJUGATED TO SWITCH.................42
1. Goals.................43
2. Results.................43
3. Conclusions..............45
II. COMPARISON OF LOADING AND RETENTION OF SWITCH DRUG CONJUGATES TO PARENTAL DRUGS IN LIPOSOMES.......49
1. Goals.................50
2. Results....................50
3. Conclusions................53
III. CELLULAR REGENERATION OF PARENTAL DRUGS.........61
1. Goals...............62
2. Results..................62
3. Conclusions.............64
IV. ANTICANCER ACTIVITY OF LIPOSOMES LOADED WITH DRUG CONJUGATED TO SWITCH................69
1. Goals.............70
2. Results.............70
3. Conclusions............76

DISCUSSION..............85
REFERENCES.............88
APPENDICES..............98
I. CURRICULUM VITAE.............99
II. PUBLICATIONS....................101
A novel virally inactivated human platelet lysate preparation rich in TGF-beta, EGF and IGF, and depleted of PDGF and VEGF. Burnouf PA, Juan PK, Su CY, Kuo YP, Chou ML, Su CH, Tseng YH, Lin CT, Burnouf T. Biotechnol Appl Biochem. 2010 Aug 6;56(4):151-60............102

Versatile Online SPE-HPLC Method for the Analysis of Irinotecan and its Clinically Relevant Metabolites in Biomaterials. Prijovich ZM, Burnouf PA, Roffler SR. J Sep Sci 37(4) : 360-367.................112

Selective Delivery of PEGylated Compounds to Tumor Cells by Anti-PEG Hybrid Antibodies. Tung HY, Su YC, Chen BM, Burnouf PA, Huang WC, Chuang KH, Yan YT, Cheng TL, Roffler SR. Mol Cancer Ther. 2015 Jun;14(6):1317-26..................120

Engineering Chimeric Receptors To Investigate the Size- and Rigidity-Dependent Interaction of PEGylated Nanoparticles with Cells. Huang WC, Burnouf PA*, Su YC, Chen BM, Chuang KH, Lee CW, Wei PK, Cheng TL, Roffler SR. ACS Nano. 2016 Jan 26;10(1):648-62. (*equal contribution)................130

Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation. Prijovich ZM, Burnouf PA, Chou HC, Huang PT, Chen KC, Cheng TL, Leu YL, Roffler SR. Mol Pharm. 2016 Apr 4;13(4):1242-50..........................................145

Measurement of Pre-Existing IgG and IgM Antibodies against Polyethylene Glycol in Healthy Individuals. Chen BM, Su YC, Chang CJ, Burnouf PA, Chuang KH, Chen CH, Cheng TL, Chen YT, Wu JY, Roffler SR. Anal Chem. 2016 Nov 1;88(21):10661-10666.........................154

Conditional internalization of PEGylated nanomedicines by PEG engagers for triple negative breast cancer therapy. Su YC, Burnouf PA, Chuang KH, Chen BM, Cheng TL, Roffler SR. Nat Commun. 2017.................160

1. Bangham, A. D.; Horne, R. W. Negative Staining of Phospholipids and Their Structural Modification by Surface-Active Agents as Observed in the Electron Microscope. J Mol Biol 1964, 8, 660-668.
2. Sessa, G.; Weissmann, G. Phospholipid Spherules (Liposomes) as a Model for Biological Membranes. J Lipid Res 1968, 9, 310-318.
3. Bangham, A. D.; Standish, M. M.; Miller, N. Cation Permeability of Phospholipid Model Membranes: Effect of Narcotics. Nature 1965, 208, 1295-1297.
4. Bangham, A. D.; Standish, M. M.; Watkins, J. C.; Weissmann, G. The Diffusion of Ions from a Phospholipid Model Membrane System. Protoplasma 1967, 63, 183-187.
5. Papahadjopoulos, D.; Miller, N. Phospholipid Model Membranes. I. Structural Characteristics of Hydrated Liquid Crystals. Biochim Biophys Acta 1967, 135, 624-638.
6. Gregoriadis, G.; Ryman, B. E. Liposomes as Carriers of Enzymes or Drugs: A New Approach to the Treatment of Storage Diseases. Biochem J 1971, 124, 58P.
7. Gregoriadis, G. Drug Entrapment in Liposomes. FEBS Lett 1973, 36, 292-296.
8. Gregoriadis, G. The Carrier Potential of Liposomes in Biology and Medicine (Second of Two Parts). N Engl J Med 1976, 295, 765-770.
9. Gregoriadis, G. The Carrier Potential of Liposomes in Biology and Medicine (First of Two Parts). N Engl J Med 1976, 295, 704-710.
10. Thanki, K.; Gangwal, R. P.; Sangamwar, A. T.; Jain, S. Oral Delivery of Anticancer Drugs: Challenges and Opportunities. J Control Release 2013, 170, 15-40.
11. Dedrick, R. L.; Flessner, M. F. Pharmacokinetic Problems in Peritoneal Drug Administration: Tissue Penetration and Surface Exposure. J Natl Cancer Inst 1997, 89, 480-487.
12. Erdlenbruch, B.; Pekrun, A.; Schiffmann, H.; Witt, O.; Lakomek, M. Topical Topic: Accidental Cisplatin Overdose in a Child: Reversal of Acute Renal Failure with Sodium Thiosulfate. Med Pediatr Oncol 2002, 38, 349-352.
13. Tsang, R. Y.; Al-Fayea, T.; Au, H. J. Cisplatin Overdose: Toxicities and Management. Drug Saf 2009, 32, 1109-1122.
14. Wong, H. L.; Bendayan, R.; Rauth, A. M.; Li, Y.; Wu, X. Y. Chemotherapy with Anticancer Drugs Encapsulated in Solid Lipid Nanoparticles. Adv Drug Deliv Rev 2007, 59, 491-504.
15. Gabizon, A. Liposomes as a Drug Delivery System in Cancer Chemotherapy. Horiz Biochem Biophys 1989, 9, 185-211.
16. Gabizon, A.; Chisin, R.; Amselem, S.; Druckmann, S.; Cohen, R.; Goren, D.; Fromer, I.; Peretz, T.; Sulkes, A.; Barenholz, Y. Pharmacokinetic and Imaging Studies in Patients Receiving a Formulation of Liposome-Associated Adriamycin. Br J Cancer 1991, 64, 1125-1132.
17. Gabizon, A.; Catane, R.; Uziely, B.; Kaufman, B.; Safra, T.; Cohen, R.; Martin, F.; Huang, A.; Barenholz, Y. Prolonged Circulation Time and Enhanced Accumulation in Malignant Exudates of Doxorubicin Encapsulated in Polyethylene-Glycol Coated Liposomes. Cancer Res 1994, 54, 987-992.
18. Gabizon, A.; Chemla, M.; Tzemach, D.; Horowitz, A. T.; Goren, D. Liposome Longevity and Stability in Circulation: Effects on the in Vivo Delivery to Tumors and Therapeutic Efficacy of Encapsulated Anthracyclines. J Drug Target 1996, 3, 391-398.
19. Gately, D. P.; Howell, S. B. Cellular Accumulation of the Anticancer Agent Cisplatin: A Review. Br J Cancer 1993, 67, 1171-1176.
20. Poste, G.; Bucana, C.; Raz, A.; Bugelski, P.; Kirsh, R.; Fidler, I. J. Analysis of the Fate of Systemically Administered Liposomes and Implications for Their Use in Drug Delivery. Cancer Res 1982, 42, 1412-1422.
21. Machy, P.; Leserman, L. D. Small Liposomes Are Better Than Large Liposomes for Specific Drug Delivery in Vitro. Biochim Biophys Acta 1983, 730, 313-320.
22. Kao, Y. J.; Juliano, R. L. Interactions of Liposomes with the Reticuloendothelial System - Effects of Reticuloendothelial Blockade on the Clearance of Large Unilamellar Vesicles. Biochimica Et Biophysica Acta 1981, 677, 453-461.
23. Allen, T. M.; Chonn, A. Large Unilamellar Liposomes with Low Uptake into the Reticuloendothelial System. Febs Letters 1987, 223, 42-46.
24. Hsu, M. J.; Juliano, R. L. Interactions of Liposomes with the Reticuloendothelial System .2. Nonspecific and Receptor-Mediated Uptake of Liposomes by Mouse Peritoneal-Macrophages. Biochimica Et Biophysica Acta 1982, 720, 411-419.
25. Moghimi, S. M.; Patel, H. M. Serum-Mediated Recognition of Liposomes by Phagocytic Cells of the Reticuloendothelial System - the Concept of Tissue Specificity. Advanced Drug Delivery Reviews 1998, 32, 45-60.
26. Klibanov, A. L.; Maruyama, K.; Torchilin, V. P.; Huang, L. Amphipathic Polyethyleneglycols Effectively Prolong the Circulation Time of Liposomes. Febs Letters 1990, 268, 235-237.
27. Dawidczyk, C. M.; Kim, C.; Park, J. H.; Russell, L. M.; Lee, K. H.; Pomper, M. G.; Searson, P. C. State-of-the-Art in Design Rules for Drug Delivery Platforms: Lessons Learned from Fda-Approved Nanomedicines. Journal of Controlled Release 2014, 187, 133-144.
28. Chang, H. I.; Yeh, M. K. Clinical Development of Liposome-Based Drugs: Formulation, Characterization, and Therapeutic Efficacy. International Journal of Nanomedicine 2012, 7, 49-60.
29. Barenholz, Y. Doxil (R) - the First Fda-Approved Nano-Drug: Lessons Learned. Journal of Controlled Release 2012, 160, 117-134.
30. Lian, T.; Ho, R. J. Y. Trends and Developments in Liposome Drug Delivery Systems. Journal of Pharmaceutical Sciences 2001, 90, 667-680.
31. Torchilin, V. P. Recent Advances with Liposomes as Pharmaceutical Carriers. Nature Reviews Drug Discovery 2005, 4, 145-160.
32. Ando, N.; Iizuka, T.; Ide, H.; Ishida, K.; Shinoda, M.; Nishimaki, T.; Takiyama, W.; Watanabe, H.; Isono, K.; Aoyama, N., et al. Surgery Plus Chemotherapy Compared with Surgery Alone for Localized Squamous Cell Carcinoma of the Thoracic Esophagus: A Japan Clinical Oncology Group Study - Jcog9204. Journal of Clinical Oncology 2003, 21, 4592-4596.
33. Nordlinger, B.; Sorbye, H.; Glimelius, B.; Poston, G. J.; Schlag, P. M.; Rougier, P.; Bechstein, W. O.; Primrose, J. N.; Euan, T. W.; Finch-Jones, M., et al. Perioperative Chemotherapy with Folfox4 and Surgery Versus Surgery Alone for Resectable Liver Metastases from Colorectal Cancer (Eortc Intergroup Trial 40983): A Randomised Controlled Trial. Lancet 2008, 371, 1007-1016.
34. Roth, J. A.; Atkinson, E. N.; Fossella, F.; Komaki, R.; Ryan, M. B.; Putnam, J. B.; Lee, J. S.; Dhingra, H.; De Caro, L.; Chasen, M., et al. Long-Term Follow-up of Patients Enrolled in a Randomized Trial Comparing Perioperative Chemotherapy and Surgery with Surgery Alone in Resectable Stage Iiia Non-Small-Cell Lung Cancer. Lung Cancer 1998, 21, 1-6.
35. Gaucher, G.; Dufresne, M. H.; Sant, V. P.; Kang, N.; Maysinger, D.; Leroux, J. C. Block Copolymer Micelles: Preparation, Characterization and Application in Drug Delivery. Journal of Controlled Release 2005, 109, 169-188.
36. Gill, P. S.; Wernz, J.; Scadden, D. T.; Cohen, P.; Mukwaya, G. M.; vonRoenn, J. H.; Jacobs, M.; Kempin, S.; Silverberg, I.; Gonzales, G., et al. Randomized Phase Iii Trial of Liposomal Daunorubicin Versus Doxorubicin, Bleomycin, and Vincristine in Aids-Related Kaposi's Sarcoma. Journal of Clinical Oncology 1996, 14, 2353-2364.
37. Sarris, A. H.; Hagemeister, F.; Romaguera, J.; Rodriguez, M. A.; McLaughlin, P.; Tsimberidou, A. M.; Medeiros, L. J.; Samuels, B.; Pate, O.; Oholendt, M., et al. Liposomal Vincristine in Relapsed Non-Hodgkin's Lymphomas: Early Results of an Ongoing Phase Ii Trial. Annals of Oncology 2000, 11, 69-72.
38. Ko, A. H.; Tempero, M. A.; Shan, Y. S.; Su, W. C.; Lin, Y. L.; Dito, E.; Ong, A.; Wang, Y. W.; Yeh, C. G.; Chen, L. T. A Multinational Phase 2 Study of Nanoliposomal Irinotecan Sucrosofate (Pep02, Mm-398) for Patients with Gemcitabine-Refractory Metastatic Pancreatic Cancer. British Journal of Cancer 2013, 109, 920-925.
39. Jahn, F.; Jordan, K.; Behlendorf, T.; Globig, C.; Schmoll, H. J.; Muller-Tidow, C.; Jordan, B. Safety and Efficacy of Liposomal Cytarabine in the Treatment of Neoplastic Meningitis. Oncology 2015, 89, 137-142.
40. Moen, M. D.; Lyseng-Williamson, K. A.; Scott, L. J. Liposomal Amphotericin B a Review of Its Use as Empirical Therapy in Febrile Neutropenia and in the Treatment of Invasive Fungal Infections. Drugs 2009, 69, 361-392.
41. Just, M.; Berger, R.; Drechsler, H.; Brantschen, S.; Gluck, R. A Single Vaccination with an Inactivated Hepatitis-a Liposome Vaccine Induces Protective Antibodies after Only 2 Weeks. Vaccine 1992, 10, 737-739.
42. Babai, I.; Barenholz, Y.; Zakay-Rones, Z.; Greenbaum, E.; Samira, S.; Hayon, I.; Rochman, M.; Kedar, E. A Novel Liposomal Influenza Vaccine (Influsome-Vac) Containing Hemagglutinin-Neuraminidase and Il-2 or Gm-Csf Induces Protective Anti-Neuraminidase Antibodies Cross-Reacting with a Wide Spectrum of Influenza a Viral Strains. Vaccine 2001, 20, 505-515.
43. Morris, G. J.; Mcgrath, S. S. The Response of Multilamellar Liposomes to Freezing and Thawing. Cryobiology 1980, 17, 613-614.
44. Szoka, F.; Olson, F.; Heath, T.; Vail, W.; Mayhew, E.; Papahadjopoulos, D. Preparation of Unilamellar Liposomes of Intermediate Size (0.1-0.2-Mumm) by a Combination of Reverse Phase Evaporation and Extrusion through Polycarbonate Membranes. Biochimica Et Biophysica Acta 1980, 601, 559-571.
45. Olson, F.; Hunt, C. A.; Szoka, F. C.; Vail, W. J.; Papahadjopoulos, D. Preparation of Liposomes of Defined Size Distribution by Extrusion through Polycarbonate Membranes. Biochimica Et Biophysica Acta 1979, 557, 9-23.
46. Fang, J.; Nakamura, H.; Maeda, H. The Epr Effect: Unique Features of Tumor Blood Vessels for Drug Delivery, Factors Involved, and Limitations and Augmentation of the Effect. Advanced Drug Delivery Reviews 2011, 63, 136-151.
47. Papahadjopoulos, D.; Allen, T. M.; Gabizon, A.; Mayhew, E.; Matthay, K.; Huang, S. K.; Lee, K. D.; Woodle, M. C.; Lasic, D. D.; Redemann, C., et al. Sterically Stabilized Liposomes - Improvements in Pharmacokinetics and Antitumor Therapeutic Efficacy. Proceedings of the National Academy of Sciences of the United States of America 1991, 88, 11460-11464.
48. Nagayasu, A.; Uchiyama, K.; Kiwada, H. The Size of Liposomes: A Factor Which Affects Their Targeting Efficiency to Tumors and Therapeutic Activity of Liposomal Antitumor Drugs. Advanced Drug Delivery Reviews 1999, 40, 75-87.
49. Juliano, R. L.; Stamp, D. The Effect of Particle Size and Charge on the Clearance Rates of Liposomes and Liposome Encapsulated Drugs. Biochem Biophys Res Commun 1975, 63, 651-658.
50. Litzinger, D. C.; Buiting, A. M. J.; Vanrooijen, N.; Huang, L. Effect of Liposome Size on the Circulation Time and Intraorgan Distribution of Amphipathic Poly(Ethylene Glycol)-Containing Liposomes. Biochimica Et Biophysica Acta-Biomembranes 1994, 1190, 99-107.
51. Ishida, O.; Maruyama, K.; Sasaki, K.; Iwatsuru, M. Size-Dependent Extravasation and Interstitial Localization of Polyethyleneglycol Liposomes in Solid Tumor-Bearing Mice. International Journal of Pharmaceutics 1999, 190, 49-56.
52. Liu, D. X.; Mori, A.; Huang, L. Role of Liposome Size and Res Blockade in Controlling Biodistribution and Tumor Uptake of Gm1-Containing Liposomes. Biochimica Et Biophysica Acta 1992, 1104, 95-101.
53. Haley, B.; Frenkel, E. Nanoparticles for Drug Delivery in Cancer Treatment. Urol Oncol 2008, 26, 57-64.
54. Danhier, F.; Feron, O.; Preat, V. To Exploit the Tumor Microenvironment: Passive and Active Tumor Targeting of Nanocarriers for Anti-Cancer Drug Delivery. J Control Release 2010, 148, 135-146.
55. Sawant, R. R.; Torchilin, V. P. Challenges in Development of Targeted Liposomal Therapeutics. AAPS J 2012, 14, 303-315.
56. Degier, J.; Mandersloot, J. G.; Vandeene.Ll. Lipid Composition and Permeability of Liposomes. Biochimica Et Biophysica Acta 1968, 150, 666-+.
57. Allen, T. M.; Austin, G. A.; Chonn, A.; Lin, L.; Lee, K. C. Uptake of Liposomes by Cultured Mouse Bone-Marrow Macrophages - Influence of Liposome Composition and Size. Biochimica Et Biophysica Acta 1991, 1061, 56-64.
58. Gabizon, A.; Price, D. C.; Huberty, J.; Bresalier, R. S.; Papahadjopoulos, D. Effect of Liposome Composition and Other Factors on the Targeting of Liposomes to Experimental-Tumors - Biodistribution and Imaging Studies. Cancer Research 1990, 50, 6371-6378.
59. Papahadjopoulos, D.; Jacobson, K.; Nir, S.; Isac, T. Phase-Transitions in Phospholipid Vesicles - Fluorescence Polarization and Permeability Measurements Concerning Effect of Temperature and Cholesterol. Biochimica Et Biophysica Acta 1973, 311, 330-348.
60. Blok, M. C.; Van Deenen, L. L.; De Gier, J. The Effect of Cholesterol Incorporation on the Temperature Dependence of Water Permeation through Liposomal Membranes Prepared from Phosphatidylcholines. Biochim Biophys Acta 1977, 464, 509-518.
61. Ogihara-Umeda, I.; Kojima, S. Cholesterol Enhances the Delivery of Liposome-Encapsulated Gallium-67 to Tumors. Eur J Nucl Med 1989, 15, 612-617.
62. Kirby, C.; Gregoriadis, G. The Effect of the Cholesterol Content of Small Unilamellar Liposomes on the Fate of Their Lipid Components Invivo. Life Sciences 1980, 27, 2223-2230.
63. Senior, J.; Gregoriadis, G. Stability of Small Unilamellar Liposomes in Serum and Clearance from the Circulation - the Effect of the Phospholipid and Cholesterol Components. Life Sciences 1982, 30, 2123-2136.
64. Owens, D. E.; Peppas, N. A. Opsonization, Biodistribution, and Pharmacokinetics of Polymeric Nanoparticles. International Journal of Pharmaceutics 2006, 307, 93-102.
65. Moghimi, S. M.; Szebeni, J. Stealth Liposomes and Long Circulating Nanoparticles: Critical Issues in Pharmacokinetics, Opsonization and Protein-Binding Properties. Progress in Lipid Research 2003, 42, 463-478.
66. Li, S. D.; Huang, L. Stealth Nanoparticles: High Density but Sheddable Peg Is a Key for Tumor Targeting. Journal of Controlled Release 2010, 145, 178-181.
67. Xie, J.; Xu, C.; Kohler, N.; Hou, Y.; Sun, S. Controlled Pegylation of Monodisperse Fe3o4 Nanoparticles for Reduced Non-Specific Uptake by Macrophage Cells. Advanced Materials 2007, 19, 3163-+.
68. Ni, F.; Jiang, L.; Yang, R. X.; Chen, Z. P.; Qi, X.; Wang, J. W. Effects of Peg Length and Iron Oxide Nanoparticles Size on Reduced Protein Adsorption and Non-Specific Uptake by Macrophage Cells. Journal of Nanoscience and Nanotechnology 2012, 12, 2094-2100.
69. Levchenko, T. S.; Rammohan, R.; Lukyanov, A. N.; Whiteman, K. R.; Torchilin, V. P. Liposome Clearance in Mice: The Effect of a Separate and Combined Presence of Surface Charge and Polymer Coating. International Journal of Pharmaceutics 2002, 240, 95-102.
70. Senior, J.; Delgado, C.; Fisher, D.; Tilcock, C.; Gregoriadis, G. Influence of Surface Hydrophilicity of Liposomes on Their Interaction with Plasma-Protein and Clearance from the Circulation - Studies with Poly(Ethylene Glycol)-Coated Vesicles. Biochimica Et Biophysica Acta 1991, 1062, 77-82.
71. Malone, R. W.; Felgner, P. L.; Verma, I. M. Cationic Liposome-Mediated Rna Transfection. Proceedings of the National Academy of Sciences of the United States of America 1989, 86, 6077-6081.
72. Aleku, M.; Schulz, P.; Keil, O.; Santel, A.; Schaeper, U.; Dieckhoff, B.; Janke, O.; Endruschat, J.; Durieux, B.; Roder, N., et al. Atu027, a Liposomal Small Interfering Rna Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression. Cancer Research 2008, 68, 9788-9798.
73. Gershon, H.; Ghirlando, R.; Guttman, S. B.; Minsky, A. Mode of Formation and Structural Features of DNA Cationic Liposome Complexes Used for Transfection. Biochemistry 1993, 32, 7143-7151.
74. Kowalska, E. Unilamellar Liposomes as DNA-Molecules Carriers in the Presence of Polyethylene-Glycol. Studia Biophysica 1987, 122, 93-98.
75. Nicolau, C.; Cudd, A. Liposomes as Carriers of DNA. Critical Reviews in Therapeutic Drug Carrier Systems 1989, 6, 239-271.
76. Bertling, W. M.; Gareis, M.; Paspaleeva, V.; Zimmer, A.; Kreuter, J.; Nurnberg, E.; Harrer, P. Use of Liposomes, Viral Capsids, and Nanoparticles as DNA Carriers. Biotechnology and Applied Biochemistry 1991, 13, 390-405.
77. Magee, W. E.; Goff, C. W.; Schoknecht, J.; Smith, M. D.; Cherian, K. The Interaction of Cationic Liposomes Containing Entrapped Horseradish Peroxidase with Cells in Culture. J Cell Biol 1974, 63, 492-504.
78. Miller, C. R.; Bondurant, B.; McLean, S. D.; McGovern, K. A.; O'Brien, D. F. Liposome-Cell Interactions in Vitro: Effect of Liposome Surface Charge on the Binding and Endocytosis of Conventional and Sterically Stabilized Liposomes. Biochemistry 1998, 37, 12875-12883.
79. Gaede, H. C.; Gawrisch, K. Lateral Diffusion Rates of Lipid, Water, and a Hydrophobic Drug in a Multilamellar Liposome. Biophys J 2003, 85, 1734-1740.
80. Khokhar, A. R.; Al-Baker, S.; Perez-Soler, R. Toxicity and Anti-Tumor Activity of Hydrophobic Diammine and Diaminocyclohexane Platinum Complexes Entrapped in Multilamellar Vesicles. Anticancer Drug Des 1988, 3, 177-184.
81. Belenduik, G. W.; Rudnic, E. M.; McCarty, J. A. Multilamellar Drug Delivery Systems. Google Patents: 1995.
82. Anton, N.; Saulnier, P.; Gaillard, C.; Porcher, E.; Vrignaud, S.; Benoit, J. P. Aqueous-Core Lipid Nanocapsules for Encapsulating Fragile Hydrophilic and/or Lipophilic Molecules. Langmuir 2009, 25, 11413-11419.
83. Xu, X. M.; Khan, M. A.; Burgess, D. J. Predicting Hydrophilic Drug Encapsulation inside Unilamellar Liposomes. International Journal of Pharmaceutics 2012, 423, 410-418.
84. Cavallo, T.; Sade, R.; Folkman, J.; Cotran, R. S. Tumor Angiogenesis - Rapid Induction of Endothelial Mitoses Demonstrated by Autoradiography. Journal of Cell Biology 1972, 54, 408-&.
85. Brannon-Peppas, L.; Blanchette, J. O. Nanoparticle and Targeted Systems for Cancer Therapy. Adv Drug Deliv Rev 2004, 56, 1649-1659.
86. Kirpotin, D. B.; Drummond, D. C.; Shao, Y.; Shalaby, M. R.; Hong, K.; Nielsen, U. B.; Marks, J. D.; Benz, C. C.; Park, J. W. Antibody Targeting of Long-Circulating Lipidic Nanoparticles Does Not Increase Tumor Localization but Does Increase Internalization in Animal Models. Cancer research 2006, 66, 6732-6740.
87. Forssen, E.; Willis, M. Ligand-Targeted Liposomes. Advanced Drug Delivery Reviews 1998, 29, 249-271.
88. Schiffelers, R. M.; Molema, G.; ten Hagen, T. L.; Janssen, A. P.; Schraa, A. J.; Kok, R. J.; Koning, G. A.; Storm, G. Ligand-Targeted Liposomes Directed against Pathological Vasculature. J Liposome Res 2002, 12, 129-135.
89. Immordino, M. L.; Dosio, F.; Cattel, L. Stealth Liposomes: Review of the Basic Science, Rationale, and Clinical Applications, Existing and Potential. Int J Nanomedicine 2006, 1, 297-315.
90. Price, M. E.; Cornelius, R. M.; Brash, J. L. Protein Adsorption to Polyethylene Glycol Modified Liposomes from Fibrinogen Solution and from Plasma. Biochim Biophys Acta 2001, 1512, 191-205.
91. Nichols, J. W.; Deamer, D. W. Catecholamine Uptake and Concentration by Liposomes Maintaining Ph Gradients. Biochimica et Biophysica Acta (BBA)-Biomembranes 1976, 455, 269-271.
92. Avdeef, A.; Box, K.; Comer, J.; Hibbert, C.; Tam, K. Ph-Metric Logp 10. Determination of Liposomal Membrane-Water Partition Coefficients of Lonizable Drugs. Pharmaceutical research 1998, 15, 209-215.
93. Barenolz, Y.; Haran, G. Method of Amphiphatic Drug Loading in Liposomes by Ph Gradient. Google Patents: 1993.
94. Clerc, S.; Barenholz, Y. Loading of Amphipathic Weak Acids into Liposomes in Response to Transmembrane Calcium Acetate Gradients. Biochimica et Biophysica Acta (BBA)-Biomembranes 1995, 1240, 257-265.
95. Shelley, J. C.; Cholleti, A.; Frye, L. L.; Greenwood, J. R.; Timlin, M. R.; Uchimaya, M. Epik: A Software Program for Pka Prediction and Protonation State Generation for Drug-Like Molecules. Journal of computer-aided molecular design 2007, 21, 681-691.
96. Mayer, L.; Bally, M.; Cullis, P. Uptake of Adriamycin into Large Unilamellar Vesicles in Response to a Ph Gradient. Biochimica Et Biophysica Acta (BBA)-Biomembranes 1986, 857, 123-126.
97. Taggar, A. S.; Alnajim, J.; Anantha, M.; Thomas, A.; Webb, M.; Ramsay, E.; Bally, M. B. Copper-Topotecan Complexation Mediates Drug Accumulation into Liposomes. Journal of Controlled Release 2006, 114, 78-88.
98. Chiu, G. N. C.; Abraham, S. A.; Ickenstein, L. M.; Ng, R.; Karlsson, G.; Edwards, K.; Wasan, E. K.; Bally, M. B. Encapsulation of Doxorubicin into Thermosensitive Liposomes Via Complexation with the Transition Metal Manganese. Journal of Controlled Release 2005, 104, 271-288.
99. Khan, D. R.; Rezler, E. M.; Lauer-Fields, J.; Fields, G. B. Effects of Drug Hydrophobicity on Liposomal Stability. Chemical Biology & Drug Design 2008, 71, 3-7.
100. Leu, Y. L.; Roffler, S. R.; Chern, J. W. Design and Synthesis of Water-Soluble Glucuronide Derivatives of Camptothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (Adept). J Med Chem 1999, 42, 3623-3628.
101. Prijovich, Z. M.; Leu, Y. L.; Roffler, S. R. Stability of the New Prodrug 9-Aminocamptothecin Glucuronide (9acg) in the Presence of Human Serum Albumin. Biochem Pharmacol 2003, 66, 1181-1187.
102. Stella, V. J.; Nti-Addae, K. W. Prodrug Strategies to Overcome Poor Water Solubility. Advanced Drug Delivery Reviews 2007, 59, 677-694.
103. Mulder, G. J. Glucuronidation and Its Role in Regulation of Biological-Activity of Drugs. Annual Review of Pharmacology and Toxicology 1992, 32, 25-49.
104. Muller, C. E. Prodrug Approaches for Enhancing the Bioavailability of Drugs with Low Solubility. Chemistry & Biodiversity 2009, 6, 2071-2083.
105. Yates, T. J.; Lopez, L. E.; Lokeshwar, S. D.; Ortiz, N.; Kallifatidis, G.; Jordan, A.; Hoye, K.; Altman, N.; Lokeshwar, V. B. Dietary Supplement 4-Methylumbelliferone: An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer. J Natl Cancer Inst 2015, 107.
106. Prijovic, Z. M.; Leu, Y. L.; Roffler, S. R. Bqc-G, a Tumor-Selective Anti-Cancer Prodrug. Google Patents: 2013.
107. Prijovich, Z. M.; Burnouf, P. A.; Roffler, S. R. Versatile Online Spe-Hplc Method for the Analysis of Irinotecan and Its Clinically Relevant Metabolites in Biomaterials. J Sep Sci 2014, 37, 360-367.
108. Shigehiro, T.; Kasai, T.; Murakami, M.; Sekhar, S. C.; Tominaga, Y.; Okada, M.; Kudoh, T.; Mizutani, A.; Murakami, H.; Salomon, D. S., et al. Efficient Drug Delivery of Paclitaxel Glycoside: A Novel Solubility Gradient Encapsulation into Liposomes Coupled with Immunoliposomes Preparation. PLoS One 2014, 9, e107976.
109. Anderson, J. A.; Lamichhane, S.; Remund, T.; Kelly, P.; Mani, G. Preparation, Characterization, in Vitro Drug Release, and Cellular Interactions of Tailored Paclitaxel Releasing Polyethylene Oxide Films for Drug-Coated Balloons. Acta Biomater 2016, 29, 333-351.
110. Stapleton, S.; Milosevic, M.; Allen, C.; Zheng, J.; Dunne, M.; Yeung, I.; Jaffray, D. A. A Mathematical Model of the Enhanced Permeability and Retention Effect for Liposome Transport in Solid Tumors. PLoS One 2013, 8, e81157.
111. Wong, A. D.; Ye, M.; Ulmschneider, M. B.; Searson, P. C. Quantitative Analysis of the Enhanced Permeation and Retention (Epr) Effect. PLoS One 2015, 10, e0123461.
112. Fahr, A.; van Hoogevest, P.; May, S.; Bergstrand, N.; ML, S. L. Transfer of Lipophilic Drugs between Liposomal Membranes and Biological Interfaces: Consequences for Drug Delivery. Eur J Pharm Sci 2005, 26, 251-265.
113. Koudelka, S.; Turanek, J. Liposomal Paclitaxel Formulations. J Control Release 2012, 163, 322-334.
114. Boggara, M. B.; Mihailescu, M.; Krishnamoorti, R. Structural Association of Nonsteroidal Anti-Inflammatory Drugs with Lipid Membranes. J Am Chem Soc 2012, 134, 19669-19676.
115. Barry, J.; Fritz, M.; Brender, J. R.; Smith, P. E.; Lee, D. K.; Ramamoorthy, A. Determining the Effects of Lipophilic Drugs on Membrane Structure by Solid-State Nmr Spectroscopy: The Case of the Antioxidant Curcumin. J Am Chem Soc 2009, 131, 4490-4498.
116. Kao, C. H.; Wang, J. Y.; Chuang, K. H.; Chuang, C. H.; Cheng, T. C.; Hsieh, Y. C.; Tseng, Y. L.; Chen, B. M.; Roffler, S. R.; Cheng, T. L. One-Step Mixing with Humanized Anti-Mpeg Bispecific Antibody Enhances Tumor Accumulation and Therapeutic Efficacy of Mpegylated Nanoparticles. Biomaterials 2014, 35, 9930-9940.
117. Kuan, S. F.; Byrd, J. C.; Basbaum, C. B.; Kim, Y. S. Characterization of Quantitative Mucin Variants from a Human Colon Cancer Cell Line. Cancer Res 1987, 47, 5715-5724.
118. Kawano, K.; Onose, E.; Hattori, Y.; Maitani, Y. Higher Liposomal Membrane Fluidity Enhances the in Vitro Antitumor Activity of Folate-Targeted Liposomal Mitoxantrone. Mol Pharm 2009, 6, 98-104.
119. Vogel, K.; Wang, S.; Lee, R. J.; Chmielewski, J.; Low, P. S. Peptide-Mediated Release of Folate-Targeted Liposome Contents from Endosomal Compartments. J Am Chem Soc 1996, 118, 1581-1586.
120. Koshkaryev, A.; Thekkedath, R.; Pagano, C.; Meerovich, I.; Torchilin, V. P. Targeting of Lysosomes by Liposomes Modified with Octadecyl-Rhodamine B. J Drug Target 2011, 19, 606-614.
121. Thekkedath, R.; Koshkaryev, A.; Torchilin, V. P. Lysosome-Targeted Octadecyl-Rhodamine B-Liposomes Enhance Lysosomal Accumulation of Glucocerebrosidase in Gaucher's Cells in Vitro. Nanomedicine (Lond) 2013, 8, 1055-1065.
122. Sievers, E. L.; Senter, P. D. Antibody-Drug Conjugates in Cancer Therapy. Annu Rev Med 2013, 64, 15-29.
123. Wu, A. M.; Senter, P. D. Arming Antibodies: Prospects and Challenges for Immunoconjugates. Nat Biotechnol 2005, 23, 1137-1146.