Sustained Analgesia Achieved Through Esterase-Activated Morphine Prodrugs Complexed with PAMAM Dendrimer

ABSTRACT

Purpose

Design and evaluate the in vitro and in vivo efficacy of two extended release morphine formulations developed for IV administration by complexing esterase activated morphine prodrugs to surface-modified, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimer.

Methods

Prodrugs were synthesized, complexed with PAMAM dendrimer, characterized via ultra performance liquid chromatography (UPLC), nuclear magnatic resonance (NMR), and tested in vitro using rat plasma vs. saline control and in an in vivo rat and guinea pig pain model (modified Randall and Selitto test).

Results

We demonstrated that complexation with dendrimer allowed the solubilization of the prodrugs for in vivo applications without the need for salt, and that the structural design of the morphine prodrugs allowed the controlled release of morphine which extended the action of morphine-induced analgesia in an animal pain model from 2 h (control) to 6 h (Morphine Prodrug A).

Conclusion

The concept of complexing/solubilizing appropriately designed esterase-sensitive prodrugs with dendrimer to enhance the sustained release of these drugs may be a useful pharmacokinetic strategy for a range of therapeutics.

This is a preview of subscription content, access via your institution.

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

REFERENCES

  1. 1.

    The persistent problem with pain. Lancet. 2001;357:1217.

  2. 2.

    Melzack R, Coderre TJ, Katz J, Vaccarino AL. Central neuroplasticity and pathological pain. Ann N Y Acad Sci. 2001;933:157–74.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Soberg HL, Bautz-Holter E, Roise O, Finset A. Mental health and posttraumatic stress symptoms 2 years after severe multiple trauma: self-reported disability and psychosocial functioning. Arch Phys Med Rehabil. 2010;91:481–8.

    PubMed  Article  Google Scholar 

  4. 4.

    Bloodworth D. Opioids in the treatment of chronic pain: legal framework and therapeutic indications and limitations. Phys Med Rehabil Clin N Am. 2006;17:355–79.

    PubMed  Article  Google Scholar 

  5. 5.

    Quintana A, Raczka E, Piehler L, Lee I, Myc A, Majoros I, et al. Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm Res. 2002;19:1310–6.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Kukowska-Latallo JF, Candido KA, Cao Z, Nigavekar SS, Majoros IJ, Thomas TP, et al. Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer. Cancer Res. 2005;65:5317–24.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Hong S, Leroueil PR, Majoros IJ, Orr BG, Baker Jr JR, Holl MM. The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform. Chem Biol. 2007;14:107–15.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Islam MT, Majoros IJ, Baker Jr JR. HPLC analysis of PAMAM dendrimer based multifunctional devices. J Chromatogr B Anal Technol Biomed Life Sci. 2005;822:21–6.

    Article  CAS  Google Scholar 

  9. 9.

    Shukla R, Thomas TP, Peters JL, Desai AM, Kukowska-Latallo J, Patri AK, et al. HER2 specific tumor targeting with dendrimer conjugated anti-HER2 mAb. Bioconjug Chem. 2006;17:1109–15.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Choi Y, Thomas T, Kotlyar A, Islam MT, Baker Jr JR. Synthesis and functional evaluation of DNA-assembled polyamidoamine dendrimer clusters for cancer cell-specific targeting. Chem Biol. 2005;12:35–43.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Mecke A, Majoros IJ, Patri AK, Baker Jr JR, Holl MM, Orr BG. Lipid bilayer disruption by polycationic polymers: the roles of size and chemical functional group. Langmuir. 2005;21:10348–54.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Beatty KE, Liu JC, Xie F, Dieterich DC, Schuman EM, Wang Q, et al. Fluorescence visualization of newly synthesized proteins in mammalian cells. Angew Chem Int Ed Engl. 2006;45:7364–7.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Morgan MT, Carnahan MA, Immoos CE, Ribeiro AA, Finkelstein S, Lee SJ, et al. Dendritic molecular capsules for hydrophobic compounds. J Am Chem Soc. 2003;125:15485–9.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Morgan MT, Nakanishi Y, Kroll DJ, Griset AP, Carnahan MA, Wathier M, et al. Dendrimer-encapsulated camptothecins: increased solubility, cellular uptake, and cellular retention affords enhanced anticancer activity in vitro. Cancer Res. 2006;66:11913–21.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Jansen JF, de Brabander-van den Berg EM, Meijer EW. Encapsulation of guest molecules into a dendritic box. Science. 1994;266:1226–9.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Kolhe P, Misra E, Kannan RM, Kannan S, Lieh-Lai M. Drug complexation, in vitro release and cellular entry of dendrimer and hyperbranched polymers. Int J Pharm. 2003;259:143–60.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Dhanikula RS, Argaw A, Bouchard JF, Hildgen P. Methotrexate loaded polyether-copolyester dendrimer for the treatment of gliomas: enhanced efficacy and intratumoral transport capability. Mol Pharm. 2008;5:105–16.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Huang B, Desai A, Zong H, Tang S, Leroueil P, Baker Jr JR. Copper-free click conjugation of methotrexate to a PAMAM dendrimer platform. Tetrahedron Lett. 2011;52:1411–14.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Huang B, Kukowska-Latallo JF, Tang S, Zong H, Johnson KB, Desai A, Gordon CL, Leroueil PR, Baker Jr JR. ‘The facile synthesis of multifunctional PAMAM dendrimer conjugates through copper-free click chemistry’. Bioorg Med Chem Lett. 2012;22:3152–56.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Groth LJ, Steffansen A, Christrup B. Bioactivation of morphine-3-propionate, a prodrug of morphine, in tissues from different species. Int J Pharm. 1997;154:149–55.

    Article  CAS  Google Scholar 

  21. 21.

    Mignat C, Heber D, Schlicht H, Ziegler A. Synthesis, opioid receptor affinity, and enzymatic hydrolysis of sterically hindered morphine 3-esters. J Pharm Sci. 1996;85:690–4.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Christrup LLC, Friis CB, Jorgensen GJ. Improvement of buccal delivery of morphine using the prodrug approach. Int J Pharm. 1997;154:157–65.

    Article  CAS  Google Scholar 

  23. 23.

    Drustrup JF, Christrup A, Bundgaard L. Utilization of prodrugs to enhance the transdermal absorption of morphine. Int J Pharm. 1991;71:105–16.

    Article  CAS  Google Scholar 

  24. 24.

    Patri AK, Kukowska-Latallo JF, Baker Jr JR. Targeted drug delivery with dendrimers: comparison of release kinetics of covalently conjugated drug and non-covalend drug inclusion complex. Adv Drug Deliv Rev. 2005;57:2203–14.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Shi X, Banyai I, Rodriguez K, Islam MT, Lesniak W, Balogh P, et al. Electrophoretic mobility and molecular distribution studies of poly(amidoamine) dendrimer of defined charges. Electrophoresis. 2006;27:1758–67.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Majoros IJ, Woehler B, Bull S, Baker Jr JR. Acetylation of poly(amidoamine) dendrimer. Macromolecules. 2003;36:5526–9.

    Article  CAS  Google Scholar 

  27. 27.

    Shi XB, Islam I, Lesniak MT, Davis W, Baker Jr JR, Balogh L. Generational, skeletal and substitutional diversities in generation one poly(amidoamine) dendrimer. Polymer. 2005;46:3022–34.

    Article  CAS  Google Scholar 

  28. 28.

    Shi XL, Islam W, MuÑiz MT, Balogh MC, Baker Jr JR. Comprehensive characterization of surface–functionalized poly(amidoamine) dendrimer with acetamide, hydroxyl, and carboxyl groups. Colloids Surf. 2006;272:139–50.

    Article  CAS  Google Scholar 

  29. 29.

    Shi X, Thomas TP, Myc LA, Kotlyar A, Baker Jr JR. Synthesis, characterization, and intracellular uptake of carboxyl-terminated poly(amidoamine) dendrimer-stabilized iron oxide nanoparticles. Phys Chem Chem Phys. 2007;9:5712–20.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Shi X, Patri AK, Lesniak W, Islam MT, Zhang C, Baker Jr JR, et al. Analysis of poly(amidoamine)-succinamic acid dendrimer by slab-gel electrophoresis and capillary zone electrophoresis. Electrophoresis. 2005;26:2960–7.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Hughes RA, Toth I, Ward P, Ireland SJ, Gibbons WA. Lipidic peptides. III: lipidic amino acid and oligomer conjugates of morphine. J Pharm Sci. 1991;80:1103–5.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Randall LO, Selitto JJ. A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Ther. 1957;111:409–19.

    PubMed  CAS  Google Scholar 

  33. 33.

    Tokiwa Y, Suzuki T. Hydrolysis of copolyesters containing aromatic and aliphatic ester blocks by lipase. J Appl Polym Sci. 1981;126(2):441–8.

    Article  Google Scholar 

  34. 34.

    Thomas TP, Huang B, Desai A, Zong H, Cheng XM, Kotlyar A, et al. Plasma-mediated release of morphine from synthesized prodrugs. Bioorg Med Chem Lett. 2010;20:6250–3.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments and Disclosures

This project has been funded in whole or in part with Federal funds from the Defense Advanced Research Projects Agency—DOD, under award W911NF-07-1-0437.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Brent B. Ward.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ward, B.B., Huang, B., Desai, A. et al. Sustained Analgesia Achieved Through Esterase-Activated Morphine Prodrugs Complexed with PAMAM Dendrimer. Pharm Res 30, 247–256 (2013). https://doi.org/10.1007/s11095-012-0869-3

Download citation

KEY WORDS

  • dendrimer
  • in vivo
  • morphine
  • pain control
  • sustained release