3H Dendrimer Nanoparticle Organ/Tumor Distribution
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Purpose. To determine the in vivo biodistribution for differently charged poly(amidoamine) (PAMAM) dendrimers in B16 melanoma and DU145 human prostate cancer mouse tumor model systems.
Methods. Neutral (NSD) and positive surface charged (PSD) generation 5 (d =5 nm) PAMAM dendrimers were synthesized by using 3H-labeled acetic anhydride and tested in vivo. Dendrimer derivatives were injected intravenously, and their biodistribution was determined via liquid scintillation counting of tritium in tissue and excretory samples. Mice were also monitored for acute toxicity.
Results. Both PSD and NSD localized to major organs and tumor. Dendrimers cleared rapidly from blood, with deposition peaking at 1 h for most organs and stabilizing from 24 h to 7 days postinjection. Maximal excretion occurred via urine within 24 h postinjection. Neither dendrimer showed acute toxicity.
Conclusions. Changes in the net surface charge of polycationic PAMAMs modify their biodistribution. PSD deposition into tissues is higher than NSD, although the biodistribution trend is similar. Highest levels were found in lungs, liver, and kidney, followed by those in tumor, heart, pancreas, and spleen, while lowest levels were found in brain. These nanoparticles could have future utility as systemic biomedical delivery devices.
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- 1.L. Balogh, A. Bielinska, J. D. Eichman, R. Valluzzi, I. Lee, J. R. Baker, T. S. Lawrence, and M. K. Khan. Dendrimer nanocomposites in medicine. Chimica Oggi/Chemistry Today 20:35-40 (2002).Google Scholar
- 2.R. Esfand and D. A. Tomalia. Poly(amidoamine) (PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications. Drug Discov. Today 6:427-436 (2001).Google Scholar
- 3.J. F. G. A. Jansen, E. M. M. de Brabander-van den Berg, and E. W. Meijer. Encapsulation of guest molecules into a dendritic box. Science 266:1226-1229 (1994).Google Scholar
- 4.J. D. Eichman, A. U. Bielinska, J. F. Kukowska-Latallo, and J. R. Baker. The use of PAMAM dendrimers in the efficient transfer of genetic material into cells. Pharmaceutical Science and Technology Today 3:232-245 (2000).Google Scholar
- 5.J. F. Kukowska-Latallo, A. U. Bielinska, J. Johnson, R. Spindler, D. A. Tomalia, and J. R. Baker Jr. Efficient transfer of genetic material into mammalian cells using Starburst polyamidoamine dendrimers. Proc. Natl. Acad. Sci. U. S. A. 93:4897-4902 (1996).Google Scholar
- 6.A. Bielinska, J. F. Kukowska-Latallo, J. Johnson, D. A. Tomalia, and J. R. Baker Jr. Regulation of in vitro gene expression using antisense oligonucleotides or antisense expression plasmids transfected using starburst PAMAM dendrimers. Nucleic Acids Res. 24:2176-2182 (1996).Google Scholar
- 7.R. Delong, K. Stephenson, T. Loftus, M. Fisher, S. Alahari, A. Nolting, and R. L. Juliano. Characterization of complexes of oligonucleotides with polyamidoamine starburst dendrimers and effects on intracellular delivery. J. Pharm. Sci. 86:762-764 (1997).Google Scholar
- 8.H. Yoo, P. Sazani, and R. L. Juliano. PAMAM dendrimers as delivery agents for antisense oligonucleotides. Pharm. Res. 16:1799-1804 (1999).Google Scholar
- 9.N. Malik, E. G. Evagorou, and R. Duncan. Dendrimer-platinate: a novel approach to cancer chemotherapy. Anticancer Drugs 10:767-776 (1999).Google Scholar
- 10.B. Raduchel, H. Schmitt-Willich, J. Platzek, W. Ebert, T. Frenzel, B. Misselwitz, and H. J. Weinmann. Synthesis and characterization of novel dendrimer-based gadolinium complexes as MRI contrast agents for the vascular system. Proc. Amer. Chem. Soc. Polym. Mater. Sci. Eng. 79:516-517 (1998).Google Scholar
- 11.H. Kobayashi, N. Sato, S. Kawamoto, T. Saga, A. Hiraga, T. L. Haque, T. Ishimori, J. Konishi, K. Togashi, and M. W. Brechbiel. Comparison of the macromolecular MR contrast agents with ethylenediamine-core versus ammonia-core generation-6 polyamidoamine dendrimer. Bioconjug. Chem. 12:100-107 (2001).Google Scholar
- 12.L. P. Balogh, S. S. Nigavekar, A. C. Cook, L. Minc, and M. K. Khan. Development of dendrimer-gold radioactive nanocomposites to treat cancer microvasculature. PharmaChem 2:94-99 (2003).Google Scholar
- 13.A. Bielinska, J. D. Eichman, I. Lee, J. R. Baker, and L. Balogh. Imaging Au0-PAMAM gold-dendrimer nanocomposites in cells. J. Nanoparticle Res. 4:395-403 (2002).Google Scholar
- 14.A. Quintana, E. Raczka, L. Piehler, I. Lee, A. Myc, I. Majoros, A. K. Patri, T. Thomas, J. Mule, and J. R. Baker Jr. Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm. Res. 19:1310-1316 (2002).Google Scholar
- 15.S. Shukla, G. Wu, M. Chatterjee, W. Yang, M. Sekido, L. A. Diop, and R. Muller. S. J. J., R. J. Lee, R. F. Barth, and W. Tjarks. Synthesis and biological evaluation of folate receptor-targeted boronated PAMAM dendrimers as potential agents for neutron capture therapy. Bioconjug. Chem. 14:158-167 (2003).Google Scholar
- 16.J. C. Roberts, M. K. Bhalgat, and R. T. Zera. Preliminary biological evaluation of polyamidoamine (PAMAM) Starburst dendrimers. J. Biomed. Mater. Res. 30:53-65 (1996).Google Scholar
- 17.J. Peterson, V. Allikmaa, J. Subbi, T. Pehk, and M. Lopp. Structural deviations in poly(amidoamine) dendrimers: a MALDI-TOF MS analysis. European Polymer J. 39:33-42 (2003).Google Scholar
- 18.D. A. Tomalia, A. M. Naylor, and W. A. Goddard III. Starburst dendrimers: molecular-level control of size, shape, surface chemistry, topology, and flexibility from atoms to macroscopic matter. Angewandte Chemie International Edition English 29:138-175 (1990).Google Scholar
- 19.I. J. Majoros, B. Keszler, S. Wochler, T. Bull, and J. R. Baker Jr. Acetylation of poly(amidoamine) dendrimers. Macromolecules 36:5526-5529 (2003).Google Scholar
- 20.M. S. O'Reilly, L. Holmgren, Y. Shing, C. Chen, R. A. Rosenthal, M. Moses, W. S. Lane, Y. Cao, E. H. Sage, and J. Folkman. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315-328 (1994).Google Scholar
- 21.D. S. Wilbur, P. M. Pathare, D. K. Hamlin, K. R. Buhler, and R. L. Vessella. Biotin reagents for antibody pretargeting. 3. Synthesis, radioiodination, and evaluation of biotinylated starburst dendrimers. Bioconjug. Chem. 9:813-825 (1998).Google Scholar
- 22.C. Zhang, S. O'Brien, and L. Balogh. Comparison and Stability of CdSe Nanocrystals Covered with Amphiphilic Poly(Amidoamine) Dendrimers. J. Phys. Chem. B. 106:10316-10321 (2002).Google Scholar
- 23.J. Folkman. Tumor Angiogenesis. In J. F. Holland, R. C. Bast Jr., D. L. Morton, E. Frie III, D. W. Kufe, and R. R. Weichselbaum (eds.), Cancer Medicine, 4th edition, Williams and Wilkens, Baltimore, 1996, pp. 181-204.Google Scholar
- 24.J. Folkman. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1:27-31 (1995).Google Scholar
- 25.H. Hashizume, P. BalukZ, S. Morikawa, J. W. McLean, G. Thurston, S. Roberge, R. K. Jain, and D. M. McDonald. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156:1363-1380 (2000).Google Scholar
- 26.L. F. Brown, M. Detmar, K. Claffey, J. A. Nagy, D. Feng, A. M. Dvorak, and H. F. Dvorak. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. EXS 79:233-269 (1997).Google Scholar
- 27.T. W. Grunt, A. Lametschwandtner, and K. Karrer. The characteristic structural features of the blood vessels of the Lewis lung carcinoma (a light microscopic and scanning electron microscopic study). Scan. Electron Microsc. (Pt 2)2:575-89. (1986).Google Scholar
- 28.P. A. Stewart, K. Hayakawa, C. L. Farrell, and R. F. Del Maestro. Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood-brain barrier defect. J. Neurosurg. 67:697-705 (1987).Google Scholar
- 29.J. M. Brown and A. J. Giaccia. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 58:1408-1416 (1998).Google Scholar
- 30.M. El-Sayed, M. F. Kiani, M. D. Naimark, A. H. Hikal, and H. Ghandehari. Extravasation of poly(amidoamine) (PAMAM) dendrimers across microvascular network endothelium. Pharm. Res. 18:23-28 (2001).Google Scholar