Abstract
Purpose. This study was aimed at the in vitro evaluations of folate receptor (FR)-targeted liposomes as carriers for a lipophilic boron agent, K[nido-7-CH3(CH2)15-7,8-C2B9H11], in FR-overexpressing tumor cells for neutron capture therapy.
Methods. Large unilamellar vesicles (∼200 nm in diameter) were prepared with the composition of egg PC/chol/K[nido-7-CH3(CH2)15-7,8-C2B9H11] (2:2:1, mol/mol), with an additional 0.5 mol % of folate-PEG-DSPE or PEG-DSPE added for the FR-targeted or nontargeted liposomal formulations, respectively.
Results. Boron-containing, FR-targeted liposomes readily bound to KB cells, an FR-overexpressing cell line, and were internalized via FR-mediated endocytosis. The boron uptake in cells treated with these liposomes was approximately 10 times greater compared with those treated with control liposomes. In contrast, FR-targeted and nontargeted liposomes showed no difference in boron delivery efficiency in F98 cells, which do not express the FR. The subcellular distribution of the boron compound in KB cells treated with the FR-targeted liposomes was investigated by cellular fractionation experiments, which showed that most of the boron compound was found in either the cytosol/endosomal or cell membrane fractions, indicating efficient internalization of the liposomal boron.
Conclusion. FR-targeted liposomes incorporating the lipophilic boron agent, K[nido-7-CH3(CH2)15-7,8-C2B9H11], into its bilayer were capable of specific receptor binding and receptor-mediated endocytosis in cultured KB cells. Such liposomes warrant further investigations for use in neutron capture therapy.
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REFERENCES
P. Garin-Chesa, I. Campbell, P. Saigo, J. Lewis, L. Old, and W. Rettig. Trophoblast and ovarian cancer antigen LK26. Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein. Am.J.Pathol. 142:557-567 (1993).
S. D. Weitman, R. H. Lark, L. R. Coney, D. W. Fort, V. Frasca, V. R. J. Zurawski, and B. A. Kamen. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res. 52:3396-3401 (1992).
X. Wang, F. Shen, J. H. Freisheim, L. E. Gentry, and M. Ratnam. Differential stereospecificities and affinities of folate receptor isoforms for folate compounds and antifolates. Biochem.Pharmacol. 44:1898-1901 (1992).
C. P. Leamon and P. S. Low. Delivery of macromolecules into living cells: A method that exploits folate receptor endocytosis. Proc.Natl.Acad.Sci.USA 88:5572-5576 (1991).
J. J. Sudimack and R. J. Lee. Targeted drug delivery via the folate receptor. Adv.Drug Deliv.Rev. 41:147-162 (2000).
M. A. Gosselin and R. J. Lee. Folate receptor-targeted liposomes as vectors for therapeutic agents. In M. R. El-Gewely (ed.), Biotechnology Annual Review, Elsevier Science B. V., Amsterdam, 2002, pp. 103-131 (in press).
R. F. Barth, A. H. Soloway, R. G. Fairchild, and R. M. Brugger. Boron neutron capture therapy for cancer. Cancer 70:2995-3007 (1992).
R. F. Barth, A. H. Soloway, and R. G. Fairchild. Boron neutron capture therapy for cancer. Cancer Res. 50:1061-1070 (1990).
S. C. Mehta and D. R. Lu. Targeted drug delivery for boron neutron capture therapy. Pharm.Res. 13:344-351 (1996).
M. Johnsson, N. Bergstrand, and K. Edwards. Optimization of drug loading procedures and characterization of liposomal formulations of two novel agents intended for boron neutron capture therapy (BNCT). J.Liposome Res. 9:53-79 (1999).
K. Shelly, D. A. Feakes, M. F. Hawthorne, P. G. Schmidt, T. A. Krisch, and W. F. Bauer. Model studies directed toward the boron neutron-capture therapy of cancer: Boron delivery to murine tumors with liposomes. Proc.Natl.Acad.Sci.USA 89:9039-9043 (1992).
D. A. Feakes, K. Shelly, C. B. Knobler, and M. F. Hawthorne. Na3[B20H17NH3]: Synthesis and liposomal delivery to murine tumors. Proc.Natl.Acad.Sci.USA 91:3029-3033 (1994).
D. A. Feakes, K. Shelly, and M. F. Hawthorne. Selective boron delivery to murine tumors by lipophilic species incorporated in the membranes of unilamellar liposomes. Proc.Natl.Acad.Sci.USA 92:1367-1370 (1995).
N. Bergstrand, E. Bohl, J. Carlsson, K. Edwards, H. Ghaneolhosseini, L. Gedda, M. Johnsson, M. Silvander, and S. Sjöberg. Stabilized liposomes with double targeting for use in BNCT. In M. Davidson, A. K. Hughes, T. B. Marder, and K. Wade (eds.), Contemporary Boron Chemistry, Royal Society of Chemistry, Cambridge, 2000, pp. 131-134.
M. F. Hawthorne and K. Shelly. Liposomes as drug delivery vehicles for boron agents. J.Neurooncol. 33:53-58 (1997).
Y. Setiawan, D. E. Moore, and B. J. Allen. Selective uptake of boronated low-density lipoprotein in melanoma xenografts achieved by diet supplementation. Br.J.Cancer 74:1705-1708 (1996).
B. H. Laster, S. B. Kahl, E. A. Popenoe, D. W. Pate, and R. G. Fairchild. Biologic efficacy of boronated low-density lipoprotein for boron neutron capture therapy as measured in cell culture. Cancer Res. 51:4588-4593 (1991).
H. Yanagie, T. Tomita, H. Kobayashi, Y. Fujii, Y. Nonaka, Y. Seagusa, K. Hasumi, M. Eriguchi, T. Kobayashi, and K. Ono. Inhibition of human pancreatic cancer growth in nude mice by boron neutron capture therapy. Br.J.Cancer 75:660-665 (1997).
L. Liu, R. F. Barth, D. M. Adams, A. H. Soloway, and R. A. Reisfeld. Critical evaluation of bispecific antibodies as targeting agents for boron neutron capture therapy of brain tumors. Anticancer Res. 16:2581-2587 (1996).
R. F. Barth, D. M. Adams, A. H. Soloway, F. Alam, and M. V. Darby. Boronated starburst dendrimer-monoclonal antibody immunoconjugates: Evaluation as a potential delivery system for neutron capture therapy. Bioconjug.Chem. 5:58-66 (1994).
H. Yanagie, Y. Fujii, M. Sekiguchi, H. Nariuchi, T. Kobayashi, and K. Kanda. A targeting model of boron neutron-capture therapy to hepatoma cells in vivo with a boronated anti-(alpha-fetoprotein) monoclonal antibody. J.Cancer Res.Clin.Oncol 120:636-640 (1994).
P. Olsson, L. Gedda, H. Goike, L. Liu, V. P. Collins, J. Ponten, and J. Carlsson. Uptake of a boronated epidermal growth factordextran conjugate in CHO xenografts with and without human EGF-receptor expression. Anticancer Drug Des. 13:279-289 (1998).
W. Yang, R. F. Barth, D. M. Adams, and A. H. Soloway. Intratumoral delivery of boronated epidermal growth factor for neutron capture therapy of brain tumors. Cancer Res. 57:4333-4339 (1997).
L. Gedda, P. Olsson, J. Ponten, and J. Carlsson. Development and in vitro studies of epidermal growth factor-dextran conjugates for boron neutron capture therapy. Bioconjug.Chem. 7: 584-591 (1996).
D. W. Deamer and P. S. Uster. Liposome preparation: Methods and mechanisms. In M. J. Ostro (ed.), Liposomes, Dekker, New York, 1983, pp. 27-51.
R. J. Lee and P. S. Low. Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. Biochim.Biophys.Acta 1233:134-144 (1995).
W. Guo, T. Lee, J. J. Sudimack, and R. J. Lee. Receptor-specific delivery of liposomes via folate-PEG-chol. J.Liposome Res. 10: 179-195 (2000).
R. F. Barth, D. M. Adams, A. H. Soloway, E. B. Mechetner, F. Alam, and A. K. Anisuzzaman. Determination of boron in tissues and cells using direct-current plasma atomic emission spectroscopy. Anal.Chem. 63:890-893 (1991).
R. P. Sharma and I. R. Edwards. cis-Platinum: Subcellular distribution and binding to cytosolic ligands. Biochem.Pharmacol. 32: 2565-2669 (1983).
D. Gabel, S. Foster, and R. G. Fairchild. The Monte Carlo simulation of the biologic effect of the 10B(n, α)7Li reaction in cells and tissue and its implication for boron neutron capture therapy. Radiat.Res. 111:14-25 (1987).
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Sudimack, J.J., Adams, D., Rotaru, J. et al. Folate Receptor-Mediated Liposomal Delivery of a Lipophilic Boron Agent to Tumor Cells in Vitro for Neutron Capture Therapy. Pharm Res 19, 1502–1508 (2002). https://doi.org/10.1023/A:1020408716807
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DOI: https://doi.org/10.1023/A:1020408716807