Targeting of Bisphosphonate-Functionlized Gold Nanoparticles to Bone
3. Results and discussion
3.6. Pharmacokinetic analysis of the tested gold nanoparticles in blood
A non compartmental model was used in order to estimate the pharmacokinetic parameters of the nanoparticle formulations after intravenous injection. Blood concentration-time profiles for the injected nanoparticles are presented in Figure 10 with the calculated parameters summarized in Table 2. For a successful application of the particles as targeted drug delivery system a low elimination rate constant and a long half life in blood is necessary.
The determined half life in blood for the three samples are in the following order; solution III
> solution II > solution I, between 8.96 to 7.25 hours, which are certainly not statistically significant. The relatively long half lives of the investigated gold nanoparticles are due to the surface PEGylation of the nanoparticles, which significantly increases the half lives of nanoparticles as well known form literature [4,5,29,30]. Furthermore, the long circulation half life of nanoparticles helps the particles in vivo to reach their intended target, because the particles need to circulate in blood for a sufficiently long time to have the chance to interact with their specific target cells or tissues [31,32]. In contrast to the here observed behavior, the half life of the non-PEGylated nanoparticles is commonly very short and they rapidly excreted form the blood. Simon et al. [33] studied the circulation half time and body distribution of amine modified polystyrene nanoparticles. They observed that the half lives of the studied
particles are very short and after 30 minutes 60-70% of the 100 nm particles are already accumulated in the liver, which prohibits further reaching of the target organ.
0 10 20 30 40 50 60
0.00 5.00 10.00 15.00 20.00 25.00 30.00
Time (h)
%ID/g blood
soln 1 Soln 2 soln 3
Figure 10: Blood profiles of the gold nanoparticles in blood after intravenous administration
Table 2: Pharmacokinetic parameter of the injected gold nanoparticles
Kel ( h-1) t1/2 ( h) AUC (ng/g*h) MRT (h)
Solution 1 (control) 0.0955 7.25 1973.19 8.25
Solution 2 (40% BP) 0.0869 7.97 2040.3 9.45
Solution 3 (80% BP) 0.0773 8.96 3356.56 11.2
5. Conclusions
The presented study revealed that the prepared gold nanoparticles can be successfully stabilized and modified to perform their intended tasks for in vivo experiments. The nanoparticles were synthesized with an appropriately small size and their surfaces were modified with mixtures of polymers, which on the one hand made them inert to high ionic strength or protein solutions, but on the other hand also introduced a high specific affinity to the main bone mineral hydroxyapatite. The conducted in vivo investigations strongly indicated that the functionalized gold nanoparticles showed a minimum uptake by the reticuloendothelial system (liver and spleen) and therefore circulated for very long time in blood. On the other hand the particle also showed a strong tendency to extravasate or distribute to other organs after injection into mice, but the largest accumulation was observed in the kidneys. Also in bone a steady accumulation of the bisphosphonate functionalized nanoparticles was observed in comparison to the control nanoparticles, but further studies have to be conducted here in order to investigate especially the long term fate of the particles in bone.
Acknowledgements
The authors want especially to thank the animalerie house of Angers for the skilful technical support with the animals for the biodistribution study [Service Commun d'Animalerie Hospitalo-Universitaire (S.C.A.H.U.), Pavillon Olivier, Rue Haute de Reculée, 49045 Angers Cedex 01 (France)].
6. References
1. Ganeshchandra Sonavane, Keishiro Tomoda, and Kimiko Makino, "Biodistribution of colloidal gold nanoparticles after intravenous administration: Effect of particle size,"
Colloids and Surfaces, B: Biointerfaces 66, 274-280 (2008).
2. Sha Jin and Kaiming Ye, "Nanoparticle-Mediated Drug Delivery and Gene Therapy,"
Biotechnology Progress 23, 32-41 (2007).
3. U. Gaur, S. K. Sahoo, T. K. De, P. C. Ghosh, A. Maitra, and P. K. Ghosh, "Biodistribution of fluoresceinated dextran using novel nanoparticles evading reticuloendothelial system,"
International Journal of Pharmaceutics 202, 1-10 (2000).
4. Frank Alexis, Eric Pridgen, Linda K. Molnar, and Omid C. Farokhzad, "Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles," Molecular Pharmaceutics 5, 505-515 (2008).
5. Donald E. Owens and Nicholas A. Peppas, "Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles," International Journal of Pharmaceutics 307, 93-102 (2006).
6. Jamie M. Bergen, Horst A. von Recum, Thomas T. Goodman, Archna P. Massey, and Suzie H. Pun, "Gold nanoparticles as a versatile platform for optimizing physicochemical parameters for targeted drug delivery," Macromolecular Bioscience 6, 506-516 (2006).
7. Marites P. Melancon, Wei Lu, Zhi Yang, Rui Zhang, Zhi Cheng, Andrew M. Elliot, Jason Stafford, Tammy Olson, Jin Z. Zhang, and Chun Li, "In vitro and in vivo targeting of hollow gold nanoshells directed at epidermal growth factor receptor for photothermal ablation therapy," Molecular Cancer Therapeutics 7, 1730-1739 (2008).
8. Huaizhong Pan, Monika Sima, Pavla Kopeckova, Kuangshi Wu, Songqi Gao, Jihua Liu, Dong Wang, Scott C. Miller, and Jindrich Kopecek, "Biodistribution and Pharmacokinetic Studies of Bone-Targeting N-(2-Hydroxypropyl)methacrylamide Copolymer-Alendronate Conjugates," Molecular Pharmaceutics 5, 548-558 (2008).
9. Geeti Bansal, Jennifer E. I. Wright, Cezary Kucharski, and Hasan Uludag, "A dendritic tetra(bisphosphonic acid) for improved targeting of proteins to bone," Angewandte Chemie, International Edition 44, 3710-3714 (2005).
10. Sebastien A. Gittens, Geeti Bansal, Ronald F. Zernicke, and Hasan Uludag, "Designing proteins for bone targeting," Advanced Drug Delivery Reviews 57, 1011-1036 (2005).
11. V. Hengst, C. Oussoren, T. Kissel, and G. Storm, "Bone targeting potential of bisphosphonate-targeted liposomes. Preparation, characterization and hydroxyapatite binding in vitro," Int J Pharm 331, 224-227 (2007).
12. Hasan Uludag and Jennifer Yang, "Targeting Systemically Administered Proteins to Bone by Bisphosphonate Conjugation," Biotechnology Progress 18, 604-611 (2002).
13. X. Wen, Q. P. Wu, Y. Lu, Z. Fan, C. Charnsangavej, S. Wallace, D. Chow, and C. Li,
"Poly(ethylene glycol)-conjugated anti-EGF receptor antibody C225 with radiometal
14. Xiaoxia Wen, Qing Ping Wu, Shi Ke, Sidney Wallace, Chusilp Charnsangavej, Peng Huang, Dong Liang, Diana Chow, and Chun Li, "Improved Radiolabeling of PEGylated Protein: PEGylated Annexin V for Noninvasive Imaging of Tumor Apoptosis," Cancer Biotherapy & Radiopharmaceuticals 18, 819-827 (2003).
15. Emiko Nakamura, Kimiko Makino, Teruo Okano, Tatsuhiro Yamamoto, and Masayuki Yokoyama, "A polymeric micelle MRI contrast agent with changeable relaxivity," Journal of Controlled Release 114, 325-333 (2006).
16. Vanessa Carla Furtado Mosqueira, Philippe Legrand, Jean Louis Morgat, Michel Vert, Evgueni Mysiakine, Ruxandra Gref, Jean Philippe Devissaguet, and Gillian Barratt,
"Biodistribution of long-circulating PEG-grafted nanocapsules in mice: effects of PEG chain length and density," Pharmaceutical Research 18, 1411-1419 (2001).
17. Alf Lamprecht, Jean Louis Saumet, Jerome Roux, and Jean Pierre Benoit, "Lipid nanocarriers as drug delivery system for ibuprofen in pain treatment," International Journal of Pharmaceutics 278, 407-414 (2004).
18. Priyabrata Mukherjee, Resham Bhattacharya, Nancy Bone, Yean K. Lee, Chitta Ranjan Patra, Shanfeng Wang, Lichun Lu, Charla Secreto, Pataki C. Banerjee, Michael J.
Yaszemski, Neil E. Kay, and Debabrata Mukhopadhyay, "Potential therapeutic application of gold nanoparticles in B-chronic lymphocytic leukemia (BCLL): enhancing apoptosis," Journal of Nanobiotechnology 5, No (2007).
19. Sung Wook Choi and Jung Hyun Kim, "Design of surface-modified poly(d,l-lactide-co-glycolide) nanoparticles for targeted drug delivery to bone," Journal of Controlled Release 122, 24-30 (2007).
20. Xiaoxiao He, Hailong Nie, Kemin Wang, Weihong Tan, Xu Wu, and Pengfei Zhang, "In Vivo Study of Biodistribution and Urinary Excretion of Surface-Modified Silica Nanoparticles," Analytical Chemistry (Washington, DC, United States) 80, 9597-9603 (2008).
21. Goldie Kaul and Mansoor Amiji, "Biodistribution and tumor-targeting potential of poly(ethylene glycol)-modified gelatin nanoparticles," Materials Research Society Symposium Proceedings 845, 229-235 (2005).
22. Sushma Kommareddy and Mansoor Amiji, "Biodistribution and pharmacokinetic analysis of long-circulating thiolated gelatin nanoparticles following systemic administration in breast cancer-bearing mice," Journal of Pharmaceutical Sciences 96, 397-407 (2006).
23. Takuro Niidome, Masato Yamagata, Yuri Okamoto, Yasuyuki Akiyama, Hironobu Takahashi, Takahito Kawano, Yoshiki Katayama, and Yasuro Niidome, "PEG-modified gold nanorods with a stealth character for in vivo applications," Journal of Controlled Release 114, 343-347 (2006).
24. Zhuang Liu, Corrine Davis, Weibo Cai, Lina He, Xiaoyuan Chen, and Hongjie Dai,
"Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy," Proc Natl Acad Sci U S A 105, 1410-1415 (2008).
25. Teng Kuang Yeh, Ze Lu, M. Guillaume Wientjes, and Jessie L. S. Au, "Formulating Paclitaxel in Nanoparticles Alters Its Disposition," Pharmaceutical Research 22, 867-874 (2005).
26. Derek W. Bartlett, Helen Su, Isabel J. Hildebrandt, Wolfgang A. Weber, and Mark E.
Davis, "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 of the United States of America 104, 15549-15554 (2007).
27. Hak Soo Choi, Wenhao Liu, Preeti Misra, Eiichi Tanaka, John P. Zimmer, Binil Itty Ipe, Moungi G. Bawendi, and John V. Frangioni, "Renal clearance of quantum dots," Nature Biotechnology 25, 1165-1170 (2007).
28. Dong Wang, Monika Sima, R. Lee Mosley, Jasmine P. Davda, Nicole Tietze, Scott C.
Miller, Peter R. Gwilt, Pavla Kopeckova, and Jindrich Kopecek, "Pharmacokinetic and Biodistribution Studies of a Bone-Targeting Drug Delivery System Based on N-(2-Hydroxypropyl)methacrylamide Copolymers," Molecular Pharmaceutics 3, 717-725 (2006).
29. J. S. Tan, D. E. Butterfield, C. L. Voycheck, K. D. Caldwell, and J. T. Li, "Surface modification of nanoparticles by PEO/PPO block copolymers to minimize interactions with blood components and prolong blood circulation in rats," Biomaterials 14, 823-833 (1993).
30. Weibo Cai, Ting Gao, Hao Hong, and Jiangtao Sun, "Application of gold nanoparticles in cancer nanotechnology," Nanotechnology, Science and Applications 1, 17-31 (2008).
31. Catherine C. Berry and Adam S. G. Curtis, "Functionalisation of magnetic nanoparticles for applications in biomedicine," Journal of Physics D: Applied Physics 36, R198-R206 (2003).
32. Matti M. van Schooneveld, Esad Vucic, Rolf Koole, Yu Zhou, Joanne Stocks, David P.
Cormode, Cheuk Y. Tang, Ronald E. Gordon, Klaas Nicolay, Andries Meijerink, Zahi A.
Fayad, and Willem J. M. Mulder, "Improved Biocompatibility and Pharmacokinetics of Silica Nanoparticles by Means of a Lipid Coating: A Multimodality Investigation," Nano Letters 8, 2517-2525 (2008).
33. Budhi H. Simon, Howard Y. Ando, and and Pardeep Gupta, "Circulation Time and Body Distribution of 14C-Labeled Amino-Modified Polystyrene Nanoparticles in Mice,"
Journal of Pharmaceutical Sciences 84, 1249-1253 (1995).