Abstract
This review article describes the current status and future perspectives of site-specific drug delivery by means of macromolecular carrier systems. Basic aspects and recent advances of targeted delivery of 1) conventional drugs, 2) protein drugs, and 3) gene medicines including antisense oligonucleotides and plasmid DNA, are reviewed from a pharmacokintic perspective. Successful in vivo application of macromolecular carrier systems requires pharmacokinetic considerations at whole body, organ, cellular and subcellular levels. The integration of simultaneous research progress in the multidisciplinary fields such as biochemistry, cell and molecular biology, pharmacology, and pharmacokinetics will accelerate the emergence of marketed drugs with macromolecular carrier systems.
Similar content being viewed by others
REFERENCES
H. Sezaki and M. Hashida. Macromolecule-drug conjugates in targeted cancer chemotherapy. CRC Crit. Rev. Ther. Drug Carrier Syst. 1:1–38 (1984).
H. Sezaki, Y. Takakura and M. Hashida. Soluble macromolecular carriers for the delivery of antitumor drugs. Adv. Drug Delivery Rev. 3:247–266 (1989).
Y. Takakura and M. Hashida. Macromolecular drug carrier systems in cancer chemotherapy: macromolecular prodrugs. Crit. Rev. Oncol. Hematol. 18:207–231 (1995).
V. H. L. Lee, M. Hashida and Y. Mizushima (eds.), Trends and Future Perspectives in Peptide and Protein Drug Delivery. Harwood Academic Publishers, Chur, Swizerland, 1995.
J. A. Wolff (ed.), Gene Therapeutics: Methods and Applications of Directed Gene Transfer, Birkhauser, Boston, 1994.
S. T. Crooke and B. Lebleu (eds.), Antisense Research and Applications, CRC Press, Boca Raton, 1993.
V.J. Stella and A. S. Kearney. Pharmacokinetics of drug targeting: Specific implications for targeting via prodrugs. In R.L. Juliano (ed.), Targeted Drug Delivery (Handbook of Experimental Pharmacology vol. 100), Springer-Verlag, Berlin Heidelberg, 1991, pp. 71–103.
T. R. Tritton. Cell surface actions of adriamycin. Pharmacol. Ther. 49:293–309 (1991).
F. Fuertges and A. Abuchowski. The clinical efficacy of poly(ethylene glycol)-modified proteins. J. Controlled Release 11:139–148 (1990).
N. V. Katre. The conjugation of proteins with polyethylene glycol and other polymers: Altering properties of proteins to enhance their therapeutic potential. Adv. Drug Delivey Rev. 10:91–114 (1993).
J.-P. Leonetti and L. D. Leserman. Targeted delivery of oligonucleotides. In S. T. Crooke and B. Lebleu (eds.), Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 493–504.
J. C. Perales, T. Ferkol, M. Molas and R. W. Hanson. An evaluation of receptor-mediated gene transfer using synthetic DNA-ligand complexes. Eur. J. Blochem. 226:255–266 (1994).
E. Timlinson. Microsphere delivery systems for drug targeting and controlled release. Int. J. Pharm. Tech. Prod. Mfr. 4:49–57 (1983).
K. J. Widder, A. E. Senyei and D. F. Ranney. Magnetically responsive microspheres and other carriers for the biophysical targeting of antitumor agents. Adv. Pharmacol. Chemother. 16:213–271 (1977).
A. E. Taylor and D. N. Granger. Exchange of macromolecules across the microcirculation. In E. M. Renkin and C. C. Michel (eds.), Handbook of Physiology: The Cardiovascular System IV., American Physiological Society, Bethesda, 1984, pp. 467–520.
W. M. Pardridge (ed.), The Blood-Brain Barrier: Cellular and Molecular Biology, Raven Press, New York, 1993.
E. Wisse and A. M. De Leeuw. Structural elements determining transport and exchange processes in the liver. In S. S. Davis, L. Illum, J. G. McVie and E. Tomlinson (eds.), Microspheres and Drug Therapy: Pharmaceutical, Immunological and Medical Aspects. Elsevier Science Publishers B.V., Amsterdam, 1984, pp. 1–23.
H. Maeda and Y. Matsumura. Tumoritropic and lymphotropic principles of macromolecular drugs. Crit. Rev. Ther. Drug Carrier Syst. 6:193–210. (1989).
Y. Takakura, M. Hashida and H. Sezaki. Lymphatic transport after parenteral drug administartion. In W.N. Charman and V.J. Stella (eds.), Lymphatic Transport of Drugs, CRC Press, Boca Taton, 1992, pp. 255–277.
K. Nishida, K. Mihara, T. Takino, S. Nakane, Y. Takakura, M. Hashida and H, Sezaki. Hepatic disposition characteristics of electrically charged macromolecules in rat in vivo and in the perfused liver. Pharm. Res. 8:437–444 (1991).
Y. Takakura, T. Fujita, H. Furitsu, M. Nishikawa, H. Sezaki and M. Hashida. Pharmacokinetics of succinylated proteins and dextran sulfate in mice: implications for hepatic targeting of protein drugs by direct succinylation via scavenger receptors. Int. J. Pharmaceut. 105:19–29 (1994).
K. Kawabata, Y. Takakura and M. Hashida. The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake. Pharm. Res. 12:825–830 (1995).
Y. Takakura, A. Takagi, M. Hashida and H. Sezaki. Disposition and tumor localization of mitomycin C-dextran conjugates in mice. Pharm. Res. 4:293–300 (1987).
Y. Takakura, T. Fujita, M. Hashida and H. Sezaki. Disposition characteristics of macromolecules in tumor-bearing mice. Pharm. Res. 7:339–346 (1990).
T. Miyao, Y. Takakura, T. Akiyama, F. Yoneda, H. Sezaki and M. Hashida. Stability and pharmacokinetic characteristics of oligonucleotides modified at terminal linkages in mice. Antisense Res. Develop. 5:115–121 (1995).
A. Takagi, H. Masuda, Y. Takakura and M. Hashida. Disposition characteristics of recombinant human interleukin-11 after a bolus intravenous administration in mice J. Pharmacol. Exp. Ther. 275:537–543 (1995).
Y. Takakura, K. Mihara and M. Hashida. Control of the disposition profiles of proteins in the kidney via chemical modification. J. Controlled Release 28:111–119 (1994).
P. D. Senter, P. M. Wallace, H. P. Svensson, V. M. Vrudhuna, D. E. Kerr, I. Hellstorm and K. E. Hellstorm. Generation of cytotoxic agents by targeted enzymes. Bioconjugate Chem. 4:3–9 (1993).
A. Trouet, D. D.-D. Campeneere and C. De Duve. Chemotherapy through lysosomes with a DNA-daunorubicin complex. Nature 239:110–112 (1972).
L. W. Seymour. Passive tumor targeting of soluble macromolecules and drug conjugates. Crit. Rev. Ther. Drug Carrier Syst. 9:135–187 (1992).
F. Yuan, M. Dellian, D. Fukumura, M. Leunig, D. A. Berk, V. P. Torchilin and R. K. Jain. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 55:3752–3756 (1995).
A. Noguchi, T. Takahashi, T. Yamaguchi, K. Kitamura, Y. Takakura, M. Hashida and H. Sezaki. Tumor localization and in vivo antitumor activity of the immunoconjugate composed of antihuman colon cancer monoclonal antibody and mitomycin C-dextran conjugate. Jpn. J. Cancer Res. 82:219–226 (1990).
C. Sung, R. J. Youle and R. L. Dedrick. Pharmacokinetic analysis of immunotoxin uptake in solid tumors: role of plasma kinetics, capillary permeability, and binding. Cancer Res. 50:7382–7392 (1990).
T. Fujita, M. Nishikawa, C. Tamaki, Y. Takakura, M. Hashida and H. Sezaki. Targeted delivery of human superoxide dismutase by chemical modification with mono-and polysaccharide derivatives. J. Pharmacol. Exp. Ther. 263:971–978 (1992).
U. Bickel, T. Yoshikawa and W. M. Pardridge. Delivery of peptides and proteins through the blood-brain barrier. Adv. Drug Delivery Rev. 10:205–245 (1993).
K. Mihara, Y. Oka, K. Sawai, Y. Takakura and M. Hashida. Improvement of therapeutic effect of human recombinant superoxide dismutase on ischemic acute renal failure in the rat via cationization and conjugation with polyethylene glycol. J. Drug Targeting 2:317–321 (1994).
E. J. F. Franssen, F. Moolenaar, D. d. Zeeuwand D. K. F. Meijer. Drug targeting to the kidney with low-molecular-weight proteins. Adv. Drug Delivery Rev. 14:67–88 (1994).
B. L. Ferraiolo, R. J. Wills and M. A. Mohler. Biotechnology products. In P. G. Welling and L. P. Balant (eds.), Pharmacokinetics of Drugs (Handbook of Experimental Pharmacology vol. 110), Springer-Verlag, Berlin Heidelberg, 1991, pp. 355–370.
Y. Sugiyama and M. Hanano. Receptor-meditaed transport of peptide hormones and its importance in the over all hormone disposition in the body. Pharm. Res. 6:192–202 (1989).
M. Inoue, I. Ebashi, N. Watanabe and Y. Morino. Synthesis of a superoxide dismutase derivative that circulates bound to albumin and accumulates in tissues whose pH is decreased. Biochemistry 28:6619–6624 (1989).
L. Fiume, C. Busi, G. Stefano and A. Mattioli. Targeting of antiviral drugs to the liver using glycoprotein carriers. Adv. Drug Delivery Rev. 14:51–65 (1994).
M. Nishikawa, A. Kamijo, T. Fujita, Y. Takakura, H. Sezaki and M. Hashida. Synthesis and pharmacokinetics of a new liver-specific carrier, glycosylated carboxymethyl-dextran, and its application to drug targeting. Pharm. Res. 10:1253–1261 (1993).
M. Hashida, H. Hirabayashi, M. Nishikawa and Y. Takakura. Targeted delivery of drugs and proteins to the liver via receptor-mediated endocytosis. J. Controlled Release, submitted.
L. W. Seymour, K. Ulbrich, S. R. Wedge, I. C. Hume, J. Strohalm and R. Duncan. N-(2-hydroxypropyl)methacrylamide copolymers targeted to the hepatocytes galactose-receptor: pharmacokinetics in DBA2 mice. Br. J. Cancer 63:859–866 (1991).
T. Fujita, H. Furitsu, M. Nishikawa, Y. Takakura, H. Sezaki, and M. Hashida. Therapeutic effects of superoxide dismutase derivatives modified with mono-and polysaccharides on hepatic injury induced by ischemia/reperfusion. Biochem. Biophys. Res. Commun. 189:191–196 (1992).
J. Frese, Jr., C. H. Wu and G. Y. Wu. Targeting of genes to the liver with glycoprotein carriers. Adv. Drug Delivery Rev. 14:137–152 (1994).
J. C. Perales, T. Ferkol, H. Beegen and O. D. Ratnoff. Gene transfer in vivo: sustained expression and regulation of genes introduced into the liver by receptor-targeted uptake. Proc. Natl. Acad. Sci. USA 91:4086–4090. (1994).
J. Chen, R. J. Stickles, and K. A. Daichendt. Galactosylated histone-mediated gene transfer and expression. Human Gene Therapy 5:429–435. (1994).
M. Monsigny, A.-C. Roche, P. Midoux and R. Mayer. Glycoconjugates as carriers for specific delivery of therapeutic drugs and genes. Adv. Drug Delivery Rev. 14:1–24 (1994).
Y. Takakura, S. Masuda, H. Tokuda, M. Nishikawa, and M. Hashida. Targeted delivery of superoxide dismutase to macrophages via mannose receptor-mediated mechanism. Biochem. Pharmacol. 47:853–858 (1994).
A. Mukhopadhyay, B. Mukhopadhyay, and S. K. Basu. Enhancement of tumoricidal activity of daunomycin by receptor-mediated delivery: In vivo studies. Biochem. Pharmacol. 46:919–924 (1993).
E. Wagner, D. Curiel and M. Cotten. Delivery of drugs, proteins and genes into cells using transferrin as a ligand for receptor-mediated endocytosis. Adv. Drug Delivery Rev. 14:113–135 (1994).
G. Citro, C. Szczylik, P. Ginpbbi, G. Zupi and B. Calabretta. Inhibition of leukaemia cell proliferation by folic acid-polylysine-mediated introduction of c-myb antisense oligodeoxynucleotides into HL-60 cells. Br. J. Cancer 69:463–467 (1994).
J. J. Turek, C. P. Leamon and P. S. Low. Endocytosis of folate-protein conjugates: ultrastructural localization in KB cells. J. Cell Sci. 106:423–430 (1993).
G. Y. Wu, P. Zhan, L. L. Sze, A. R. Rosenberg and C. H. Wu. Incorporation of adenovirus into a ligand-based DNA carrier system results in retention of original receptor specificity and enhances targeted gene expression. J. Biol. Chem. 269:11542–11546 (1994).
M. Nishikawa, H. Hirabayashi, Y. Takakura and M. Hashida. Design for cell-specific targeting of proteins utilizing sugar-recognition mechanism: effect of molecular weight of proteins on targeting efficiency. Pharm. Res. 12:209–214 (1995).
M. Nishikawa, C. Miyazaki, F. Yamashita, Y. Takakura and M. Hashida. Galactosylated proteins are recognized by the liver according to the surface density of galactose moieties. Am. J. Physiol. 268:G849–G856 (1995).
Y. C. Lee, C. P. Stowell and M. K. Krantz. 2-imino-2-methoxyethyl 1-thioglycosides: New reagents for attaching sugars to proteins. Biochemistry 15:3956–3963 (1976).
R. W. Jansen, G. Molema, T. L. Ching, R. Oosting, G. Harms, F. Moolenaar, M. J. Hardonk and D. K. F. Meijer. Hepatic endocytosis of various types of mannose-terminated albumins: What is important, sugar recognition, net charge of the combination of these features. J. Biol. Chem. 266:3343–3348 (1991).
F. J. Burrowsand P. E. Thorpe. Vascular targeting—a new approach to the therapy of solid tumors. Pharmacol. Ther. 64:155–174 (1994).
A. L. Epstein, L. A. Khawli, J. L. Hornickand and C. R. Taylor. Identification of a monoclonal antibody, TV-1, directed against the basement membrane of tumor vessels, and its use to enhance the delivery of macromolecules to tumors after conjugation with interleukin 2. Cancer Res. 55:2673–2680 (1995).
W. M. Pardridge. Vector-mediated peptide drug delivery to the brain. Adv. Drug Delivey Rev. 15:109–146 (1995).
T. Ferkol, C. S. Kaetzel and P. B. Davis. Gene transfer into respiratory epithelial cells by targeting the polymeric immunoglobulin receptor. J. Clin. Invest. 92:2394–2400 (1993).
J. Chen, S. Gamou, A. Takayanagi and N. Shimizu. A novel gene delivery system using EGF receptor-mediated endocytosis. FEBS Lett. 338:167–169 (1994).
M. Buschle, M. Cotten, H. Kirlappos, K. Mechtler, G. Schaffner, W. Zauner, M. L. Birnstiel and E. Wagner. Receptor-mediated gene trasfer into human T lymphocytes via binding of DNA/CD3 antibody particles to the CD3 T cell receptor complex. Human Gene Therapy 6:753–761 (1995).
T. Takahashi, T. Yamaguchi, K. Kitamura, A. Noguchi, M. Honda and E. Otsuji. Follow-up study of patients treated with monoclonal antibody-drug conjugate: Report of 77 cases with colorectal cancer. Jpn. J. Cancer Res. 84:976–981 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Takakura, Y., Hashida, M. Macromolecular Carrier Systems for Targeted Drug Delivery: Pharmacokinetic Considerations on Biodistribution. Pharm Res 13, 820–831 (1996). https://doi.org/10.1023/A:1016084508097
Issue Date:
DOI: https://doi.org/10.1023/A:1016084508097