AAPS PharmSci

, Volume 2, Issue 1, pp 48–58 | Cite as

Targeted prodrug design to optimize drug delivery

  • Hyo-Kyung Han
  • Gordon L. AmidonEmail author


Classical prodrug design often represents a nonspecific chemical approach to mask undesirable drug properties such as limited bioavailability, lack of site specificity, and chemical instability. On the other hand, targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrugs to a specific enzyme or a specific membrane transporter, or both, has potential as a selective drug delivery system in cancer chemotherapy or as an efficient oral drug delivery system. Site-selective targeting with prodrugs can be further enhanced by the simultaneous use of gene delivery to express the requisite enzymes or transporters. This review highlights evolving strategies in targeted prodrug design, including antibody-directed enzyme prodrug therapy, genedirected enzyme prodrug therapy, and peptide transporter-associated prodrug therapy.


Peptide Transporter Amidon Palytoxin Oral Drug Absorption Enzyme Prodrug Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Stella V. Pro-drugs: an overview and definition In: Higuchi T, Stella V, eds Prodrugs As Novel Drug Delivery Systems. ACS Symposium Series. Washington, DC: American Chemical Society, 1975:1–115.CrossRefGoogle Scholar
  2. 2.
    Albert A. Chemical aspects of selective toxicity. Nature. 1958;182:421–423. Harper NJ. Drug latentiation Prog Drug Res. 1962;4:221–294.PubMedCrossRefGoogle Scholar
  3. 3.
    Roche EB. Design of Biopharmaceutical Properties through Prodrugs and Analogs. Washington, DC: American Pharmaceutical Association, 1977.Google Scholar
  4. 4.
    Sinkula AA, Yalkowsky SH. Rationale for design of biologically reversible drug derivatives prodrugs. J Pharm Sci. 1975;64:181–210.PubMedCrossRefGoogle Scholar
  5. 5.
    Stella VJ, Charman WN, Naringrekar VH. Prodrugs. Do they have advantages in clinical practice? Drugs. 1985;29:455–473.PubMedCrossRefGoogle Scholar
  6. 6.
    Banerjee PK, Amidon GL. Design of prodrugs based on enzymes-substrate specificity. In: Bundgaard H, ed. Design of Prodrugs. New York: Elsevier. 1985;93–133.Google Scholar
  7. 7.
    Amidon GL, Leesman GD, Elliott RL. Improving intestinal absorption of water-insoluble compounds a membrane metabolism strategy. J Pharm Sci. 1980;69:1363–1368.PubMedCrossRefGoogle Scholar
  8. 8.
    Fleisher D, Stewart BH, Amidon GL. Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting. Methods Enzymol. 1985;112:360–381.PubMedCrossRefGoogle Scholar
  9. 9.
    Bai JP, Amidon GL. Structural specificity of mucosal-cell transport and metabolism of peptide drugs: implication for oral peptide drug delivery. Pharm Res. 1992;9:969–978.PubMedCrossRefGoogle Scholar
  10. 10.
    Stella VJ, Himmelstein KJ. Prodrugs and site-specific drug delivery. J Med Chem. 1980;23:1275–1282.PubMedCrossRefGoogle Scholar
  11. 11.
    Stella VJ. Himmelstein KJ. Critique of prodrugs and site specific delivery. In: Bundgaard H, ed. Optimization of Drug Delivery Alfred Benzon Symposium 17. Copenhagen, Munksgaard, 1982: 132–155.Google Scholar
  12. 12.
    Friend DR, Chang GW. A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria. J Med Chem. 1984;27:261–266.PubMedCrossRefGoogle Scholar
  13. 13.
    Behme H, Ahrens KH, Hotzel HH. Properties and reactions of N-(alpha-hydroxyalkyl)-thionanides. Arch Pharm (Weinhem) 1974;307:748–755.CrossRefGoogle Scholar
  14. 14.
    Wilk S, Mizoguchi H, Orlowski M. Gamma-glutamyl dopa: a kidney-specific dopamine precursor. J Pharmacol Exp Ther. 1978;206:227–232.PubMedGoogle Scholar
  15. 15.
    Mizoguchi H, Orlowski M, Wilk S, Green JP. Gamma-glutamyl DOPA and gamma-glutamyl dopamine: effect on plasma glucose levels. Eur J Pharmacol. 1979;57:239–245.PubMedCrossRefGoogle Scholar
  16. 16.
    Connors TA, Whisson ME. Cure of mice bearing advanced plasma cell tumours with aniline mustard the relationship between glucuronidase activity and tumour sensitivity. Nature 1966;210:866–867.PubMedCrossRefGoogle Scholar
  17. 17.
    Cobb LM, Connors TA, Elson LA, Khan AH, Mitchley BC, Ross WC, et al. 2,4-Dinitro-5-ethyleneiminobenzamide (CB1954): a potent and selective inhibitor of the growth of the Walker carcinoma 256. Biochem Pharmacol 1969;18:1519–1527.PubMedCrossRefGoogle Scholar
  18. 18.
    Connors TA. Prodrugs in cancer chemotherapy. Xenobiotica. 1986;16:975–988.PubMedCrossRefGoogle Scholar
  19. 19.
    Bagshawe KD. Antibody-directed enzyme prodrug therapy (ADEPT). Adv Pharmacol 1993;24:99–121.PubMedCrossRefGoogle Scholar
  20. 20.
    Bagshawe KD. Antibody directed enzymes revive anti-cancer prodrugs concept. Br J Cancer 1987;56:531–532.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Bagshawe KD, Springer CJ, Searle F, Antoniw P, Sharma SK, Melton RG, Sherwood RF. A cytotoxic agent can be generated selectively at cancer sites. Br J Cancer. 1988;58:700–703.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Bagshawe KD. The first Bagshawe lecture Towards generating cytotoxic agents at cancer sites. Br J Cancer. 1989;60:275–281.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Senter PD, Saulnier MG, Schreiber GJ, Hirschberg DL, Brown JP, Hellstrom I, et al. Anti-tumor effects of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate. Proc Natl Acad Sci. U S A. 1988;85:4842–4846.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Connor TA, Knox RJ. Prodrugs in cancer chemotherapy. Stem cells. 1995;13:501–511.CrossRefGoogle Scholar
  25. 25.
    Sharma SK, Bagshawe KD, Melton RG, Sherwood RF. Human immune response to monoclonal antibody-enzyme conjugates in ADEPT pilot clinical trial. Cell Biophys. 1992;2:109–120.CrossRefGoogle Scholar
  26. 26.
    Springer CJ, Poon GK, Sharma SK, Bagshawe KD. Identification of prodrug, active drug, and metabolites in an ADEPT clinical study. Cell Biophys. 1993;22:9–26.PubMedCrossRefGoogle Scholar
  27. 27.
    Harris JD, Gutierrez AA, Hurst HC, Sikora K, Lemoine NR. Gene therapy for cancer using tumour-specific prodrug activation. Gene Ther. 1994;1:170–175.PubMedGoogle Scholar
  28. 28.
    Huber BE, Richards CA, Austin EA. Virus-directed enzyme/prodrug therapy (VDEPT) selectively engineering drug sensitivity into tumors. Ann NY Acad Sci. 1994;716:104–114.PubMedCrossRefGoogle Scholar
  29. 29.
    Culver KW, Van Gilder J, Link CJ, Carlstrom T, Buroker T, Yuh W, et al. Gene therapy for the treatment of malignant brain tumors with in vivo tumor transduction with the herpes simplex thymidine kinase gene/ganciclovir system. Hum Gene Ther. 1994;5:343–379.PubMedCrossRefGoogle Scholar
  30. 30.
    Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH. Blaese RM In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science. 1992;256:1550–1552.PubMedCrossRefGoogle Scholar
  31. 31.
    Mullen CA, Kilstrup M, Blaese RM. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Proc Natl Acad Sci U S A. 1992;89:33–37.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Barba D, Hardin J, Ray J, Gage FH. Thymidine kinase-mediated killing of rat brain tumors. J Neurosurg 1993;79:729–735.PubMedCrossRefGoogle Scholar
  33. 33.
    Deonarain MP, Spooner RA, Epenetos AA. Genetic delivery of enzymes for cancer therapy. Gene Ther 1995;2:235–244.PubMedGoogle Scholar
  34. 34.
    Connors TA. The choice of prodrugs for gene directed enzyme prodrug therapy of cancer. Gene Ther 1995;2:702–709.PubMedGoogle Scholar
  35. 35.
    Anlezark GM, Melton RG, Sherwood RF, Coles B, Friedlos F, Knox RJ. The bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954)-I Purification and properties of a nitroreductase enzyme from Eschenchia coli—a potential enzyme for antibody-directed enzyme prodrug therapy (ADEPT) Biochem Pharmacol. 1992;44:2289–2295.PubMedCrossRefGoogle Scholar
  36. 36.
    Haisma HJ, Boven E, van Muijen M, de Jong J, van der Vijgh WJ, Pinedo HM. A monoclonal antibody-β-glucuronidase conjugate as activator of the prodrug epirubicin-glucuronide for specific treatment of cancer. Br J Cancer. 1992;66:474–478.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Eccles SA, Court WJ, Box GA, Dean CJ, Melton RG, Springer CJ. Regression of established breast carcinoma xenografts with antibody-directed enzyme prodrug therapy against c-erb B2p185. Cancer Res. 1994;54:5171–5177PubMedGoogle Scholar
  38. 38.
    Tsuji A, Tamai I. Carrier-mediated intestinal transport of drugs. Pharm Res. 1996;13:963–77.PubMedCrossRefGoogle Scholar
  39. 39.
    Mizuma T, Ohta K, Hayashi M, Awazu S. Intestinal active absorption of sugar-conjugated compounds by glucose transport system implication of improvement of poorly absorbable drugs. Biochem Pharmacol 1992;43:2037–2039.PubMedCrossRefGoogle Scholar
  40. 40.
    Mizuma T, Ohta K, Hayashi M, Awazu S. Comparative study of active absorption by the intestine and disposition of anomers of sugar-conjugated compounds. Biochem Pharmacol. 1993;45:1520–1523.PubMedCrossRefGoogle Scholar
  41. 41.
    Hokari M, Wu HQ, Schwarcz R, Smith QR. Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. Neuroreport. 1996;8:15–18.PubMedCrossRefGoogle Scholar
  42. 42.
    Hu M, Subramanian P, Mosberg HI, Amidon GL. Use of the peptide carrier system to improve the intestinal absorption of L-alpha-methyldopa: carrier kinetics, intestinal permeabilities, and in vitro hydrolysis of dipeptidyl derivatives of L-alpha-methyldopa. Pharm Res. 1989;6:66–70.PubMedCrossRefGoogle Scholar
  43. 43.
    Swaan PW, Tukker JJ. Carrier-mediated transport mechanism of foscarnet (trisodium phosphonoformate hexahydrate) in rat intestinal tissue. J Pharmacol Exp Ther. 1995;272:242–247.PubMedGoogle Scholar
  44. 44.
    Grappel SF, Giovenella AJ, Nisbet LJ. Activity of a peptidyl prodrug, alafosfalin, against anaerobic bacteria. Antimicrob Agents Chemother. 1985;27:961–963.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Oh D-M, Han H-k, Amidon GL. Drug transport and targeting Intestinal transport. In Amidon GL, Sadee W, eds. Membrane Transporters as Drug Targets. New York: Plenum Press, 1999;59–88.Google Scholar
  46. 46.
    Ganapathy V, Brandsch M, Leibach FH. Intestinal transport of amino acids and peptides. In Johnson LR, ed. Physiology of the Gastrointestinal Tract. New York, Raven Press, 1994:1773–1794.Google Scholar
  47. 47.
    Ganapathy V, Leibach FH. Peptide transporters. Curr Opin Nephrol Hypertens. 1996;5:395–400.PubMedCrossRefGoogle Scholar
  48. 48.
    Liang R, Fei YJ, Prasad PD, Ramamoorthy S, Han H, Yang-Feng L, et al. Human intestinal H+/peptide cotransporter: cloning. functional expression and chromosomal localization. J Biol Chem. 1995;270:6456–6463.PubMedCrossRefGoogle Scholar
  49. 49.
    Saito H, Okuda M, Terada T, Sasaki S, Inui K. Cloning and characterization of a rat H+/peptide cotransporter mediating absorption of beta-lactam antibiotics in the intestine and kidney. J Pharmacol Exp Ther. 1995;275:1631–1637.PubMedGoogle Scholar
  50. 50.
    Liu W, Ramamoorthy S, Fei YJ, Ganapathy NE, Hediger MA, Ganapathy V, et al. Molecular cloning of PEPT2, a new member of the H+/peptide cotransporter family from human kidney. Biochim Biophys Acta 1995;1235:461–466.PubMedCrossRefGoogle Scholar
  51. 51.
    Saito H, Terada T, Okuda M, Sasaki S, Inui K. Molecular cloning and tissue distribution of rat peptide transporter PEPT2. Biochim Biophys Acta. 1996;1280:173–177.PubMedCrossRefGoogle Scholar
  52. 52.
    Bai JPF, Stewart BH, Amidon GL. Gastrointestinal transport of peptide and protein drugs and prodrugs. In: Welling PG, Balant LP, eds. Handbook of Experimental Pharmacology Heidelberg: Springer-Verlag, 1994;110:189–206.Google Scholar
  53. 53.
    Leibach FH, Ganapathy V. Peptide transporters in the intestine and the kidney. Annu Rev Nutr 1996;16:99–119.PubMedCrossRefGoogle Scholar
  54. 54.
    Bai P-F, Subramanian P, Mosberg HI, Amidon GL. Structural requirements for the intestinal mucosal-cell peptide transporter the need for N-terminal alpha-amino group. Pharm Res. 1991;8:593–599.PubMedCrossRefGoogle Scholar
  55. 55.
    Samanen J, Wilson G, Smith PL, Lee CP, Bondinell W, Ku T, et al. Chemical approaches to improve the oral bioavailability of peptidergic molecules. J Pharm Pharmacol. 1996; 48: 119–135.PubMedCrossRefGoogle Scholar
  56. 56.
    Hidalgo IJ, Bhatnagar P, Lee CP, Miller J, Cucullino G, Smith PL. Structural requirements for interaction with the oligopeptide transporter in Caco-2 cells. Pharm Res. 1995; 12: 317–319.PubMedCrossRefGoogle Scholar
  57. 57.
    Tsuji A, Tamai I, Nakanishi M, Terasaki T, Hamano S. Intestinal brush-border transport of the oral cephalosporin antibiotic, cefdimir, mediated by dipeptide and monocarboxylic acid transport systems in rabbits. J Pharm Pharmacol. 1993; 45: 996–998.PubMedCrossRefGoogle Scholar
  58. 58.
    Tsuji A, Terasaki T, Tamai I, Hirooka H. H+gradient-dependent and carrier-mediated transport of cefixime, a new cephalosporin antibiotic, across brush-border membrane vesicles from rat small intestine. J Pharmacol Exp Ther. 1987; 241: 594–601.PubMedGoogle Scholar
  59. 59.
    Friedman DI, Amidon GL. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats: enalapril and fosinopril. Pharm Res. 1989; 6: 1043–1047.PubMedCrossRefGoogle Scholar
  60. 60.
    Yee S, Amidon GL. Intestinal absorption mechanism of three angiotensin-converting enzyme inhibitors: quinapril, benazepril and CGS 16617. Pharm Sci. 1990; 7: S-155.Google Scholar
  61. 61.
    Kramer W, Girbig F, Gutjaha U, Kleemann H-W, Leipe I, Urbach H, et al. Interaction of renin inhibitors with the intestinal uptake system for oligopeptides and beta-lactam antibiotics. Biochim Biophys Acta. 1990; 1027: 25–30.PubMedCrossRefGoogle Scholar
  62. 62.
    Humphrey MJ, Ringrose PS. Peptides and related drugs: a review of their absorption, metabolism, and excretion. Drug Metab Rev. 1986; 17: 283–310.PubMedCrossRefGoogle Scholar
  63. 63.
    Tamai I, Ling HY, Timbul SM, Nishikido J, Tsuji A. Stereospecific absorption and degradation of cephalexin. J Pharm Pharmacol. 1988; 40: 320–324.PubMedCrossRefGoogle Scholar
  64. 64.
    Lister N, Sykes AP, Bailey PD, Boyd CA, Bronk JR. Dipeptide transport and hydrolysis in isolated loops of rat small intestine: effects of stereospecificity. J Physiol (Lond). 1995; 484: 173–182.CrossRefGoogle Scholar
  65. 65.
    Ganapathy V, Leibach FH. Peptide transport in rabbit kidney: Studies with L-carnosine. Biochim Biophys Acta. 1982; 691: 362–366.PubMedCrossRefGoogle Scholar
  66. 66.
    Boyd CA, Ward MR. A micro-electrode study of oligopeptide absorption by the small intestinal epithelium of Necturus maculosus. J Physiol. 1982; 324: 411–428.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Daniel H, Adibi SA. Functional separation of dipeptide transport and hydrolysis in kidney brush border membrane vesicles. FASEB. 1994; 8: 753–759.Google Scholar
  68. 68.
    Enjoh M, Hashimoto K, Arai S, Shimizu M. Inhibitory effect of arphamenine A on intestinal dipeptide transport. Biosci Biotech Biochem. 1996; 60: 1893–1895.CrossRefGoogle Scholar
  69. 69.
    Temple CS, Stewart AK, Meredith D, Lister NA, Morgan KM, Collier ID, et al. Peptide mimics as substrates for the intestinal peptide transporter. J Biol Chem. 1998; 273: 20–22.PubMedCrossRefGoogle Scholar
  70. 70.
    Han H-K, de Vrueh RLA, Rhie JK, Covitz K-MY, Smith PL, Lee C-P, et al. 5′-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res. 1998; 15: 1154–1159.PubMedCrossRefGoogle Scholar
  71. 71.
    Han H-k, Oh D-M, Amidon GL. Cellular uptake mechanism of amino acid ester prodrugs in Caco-2/hPEPT1 cells overexpressing a human peptide transporter. Pharm Res. 1998; 15: 1382–1386.PubMedCrossRefGoogle Scholar
  72. 72.
    Bai JP, Hu M, Subramanian P, Mosberg HI, Amidon GL. Utilization of peptide carrier system to improve intestinal absorption: targeting prolidase as a prodrug-converting enzyme. J Pharm Sci. 1992; 81: 113–116.PubMedCrossRefGoogle Scholar
  73. 73.
    Hu M, Borchardt RT. Mechanism of L-a-methyldopa transport through a monolayer of polarized human intestinal epithelial cells (Caco-2). Pharm Res. 1990; 7: 1313–1319.PubMedCrossRefGoogle Scholar
  74. 74.
    Bai JPF. PGlu-L-dopa-pro: a tripeptide prodrug targeting the intestinal peptide transporter for absorption and tissue enzymes for conversion. Pharm Res. 1995; 12: 1101–1104.PubMedCrossRefGoogle Scholar
  75. 75.
    Ganapathy ME, Huang W, Wang H, Ganapathy V, Leibach FH. Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun. 1998; 246: 470–475.PubMedCrossRefGoogle Scholar
  76. 76.
    Balimane PV, Tamai I, Guo A, Nakanishi T, Kitada H, Leibach FH, et al. Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem Biophy Res Commun. 1998; 250: 246–251.CrossRefGoogle Scholar
  77. 77.
    Sinko PJ, Balimane PV. Carrier-mediated intestinal absorption of valacyclovir, the L-valyl ester prodrug of acyclovir: 1. Interactions with peptides, organic anions and organic cations in rats. Biopharm Drug Dispos. 1998; 19: 209–217.PubMedCrossRefGoogle Scholar
  78. 78.
    de Vrueh RL, Smith PL, Lee CP. Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2. J Pharmacol Exp Ther. 1998; 286: 1166–1170.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2002

Authors and Affiliations

  1. 1.Parke-Davis Pharmaceutical Research, Division of Warner-LambertDepartment of Pharmacokinetics, Dynamics and MetabolismAnn ArborUSA
  2. 2.College of PharmacyThe University of MichiganAnn Arbor

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