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Pharmaceutical Research

, Volume 27, Issue 12, pp 2776–2780 | Cite as

Quantitative Aspects of Intracellularly-Targeted Drug Delivery

  • David StepenskyEmail author
Commentary

INTRODUCTION

Many pharmacological agents act intracellularly, need to be endocytosed, and reach the site of action in specific organelle to exert their action. The cell’s interior is highly compartmentalized, and complexity of the cellular endocytosis and trafficking pathways (1,2) leads to suboptimal magnitude and duration of pharmacological effects at the organelle of interest, as well as to non-specific effects due to exposure of additional organelles to the drug. Thus, attaining efficient and selective pharmacological effects for intracellularly acting drugs requires development of specialized drug delivery systems (DDS) that should be targeted to specific organelle and deliver the drug in a controlled fashion (3,4).

For this purpose, particle or vesicle (liposome)-based DDS can be used, and intracellular targeting can be achieved by decorating the drug or the DDS with organelle-specific targeting moieties. This approach relies on recognition of these moieties by the endogenous...

KEY WORDS

anti-cancer vaccines intracellular trafficking organelle-specific drug delivery targeted drug delivery systems targeting efficiency and kinetics 

REFERENCES

  1. 1.
    Burgdorf S, Kautz A, Bohnert V, Knolle PA, Kurts C. Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science. 2007;316:612–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Miaczynska M, Stenmark H. Mechanisms and functions of endocytosis. J Cell Biol. 2008;180:7–11.CrossRefPubMedGoogle Scholar
  3. 3.
    Torchilin VP. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu Rev Biomed Eng. 2006.Google Scholar
  4. 4.
    Breunig M, Bauer S, Goepferich A. Polymers and nanoparticles: intelligent tools for intracellular targeting? Eur J Pharm Biopharm. 2008;68:112–28.CrossRefPubMedGoogle Scholar
  5. 5.
    Prokop A, Davidson JM. Nanovehicular intracellular delivery systems. J Pharm Sci. 2008;97:3518–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Akita H, Ito R, Khalil IA, Futaki S, Harashima H. Quantitative three-dimensional analysis of the intracellular trafficking of plasmid DNA transfected by a nonviral gene delivery system using confocal laser scanning microscopy. Mol Ther. 2004;9:443–51.CrossRefPubMedGoogle Scholar
  7. 7.
    Seib FP, Jones AT, Duncan R. Establishment of subcellular fractionation techniques to monitor the intracellular fate of polymer therapeutics I. Differential centrifugation fractionation B16F10 cells and use to study the intracellular fate of HPMA copolymer—doxorubicin. J Drug Target. 2006;14:375–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Cartiera MS, Johnson KM, Rajendran V, Caplan MJ, Saltzman WM. The uptake and intracellular fate of PLGA nanoparticles in epithelial cells. Biomaterials. 2009;30:2790–8.CrossRefPubMedGoogle Scholar
  9. 9.
    El-Sayed A, Futaki S, Harashima H. Delivery of macromolecules using arginine-rich cell-penetrating peptides: ways to overcome endosomal entrapment. AAPS J. 2009;11:13–22.CrossRefPubMedGoogle Scholar
  10. 10.
    Tachibana R, Harashima H, Shono M, Azumano M, Niwa M, Futaki S, et al. Intracellular regulation of macromolecules using pH-sensitive liposomes and nuclear localization signal: qualitative and quantitative evaluation of intracellular trafficking. Biochem Biophys Res Commun. 1998;251:538–44.CrossRefPubMedGoogle Scholar
  11. 11.
    Panyam J, Zhou WZ, Prabha S, Sahoo SK, Labhasetwar V. Rapid endo-lysosomal escape of poly(DL-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. FASEB J. 2002;16:1217–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Shen H, Ackerman AL, Cody V, Giodini A, Hinson ER, Cresswell P, et al. Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles. Immunology. 2006;117:78–88.CrossRefPubMedGoogle Scholar
  13. 13.
    Reits E, Griekspoor A, Neijssen J, Groothuis T, Jalink K, van Veelen P, et al. Peptide diffusion, protection, and degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity. 2003;18:97–108.CrossRefPubMedGoogle Scholar
  14. 14.
    Hayashi A, Wakita H, Yoshikawa T, Nakanishi T, Tsutsumi Y, Mayumi T, et al. A strategy for efficient cross-presentation of CTL-epitope peptides leading to enhanced induction of in vivo tumor immunity. J Control Release. 2007;117:11–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Matsuo K, Yoshikawa T, Oda A, Akagi T, Akashi M, Mukai Y, et al. Efficient generation of antigen-specific cellular immunity by vaccination with poly(gamma-glutamic acid) nanoparticles entrapping endoplasmic reticulum-targeted peptides. Biochem Biophys Res Commun. 2007;362:1069–72.CrossRefPubMedGoogle Scholar
  16. 16.
    Hoshino A, Fujioka K, Oku T, Nakamura S, Suga M, Yamaguchi Y, et al. Quantum dots targeted to the assigned organelle in living cells. Microbiol Immunol. 2004;48:985–94.PubMedGoogle Scholar
  17. 17.
    Misra R, Sahoo SK. Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy. Eur J Pharm Sci. 2010;39:152–63.CrossRefPubMedGoogle Scholar
  18. 18.
    Audran R, Peter K, Dannull J, Men Y, Scandella E, Groettrup M, et al. Encapsulation of peptides in biodegradable microspheres prolongs their MHC class-I presentation by dendritic cells and macrophages in vitro. Vaccine. 2003;21:1250–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Waeckerle-Men Y, Allmen EU, Gander B, Scandella E, Schlosser E, Schmidtke G, et al. Encapsulation of proteins and peptides into biodegradable poly(D, L-lactide-co-glycolide) microspheres prolongs and enhances antigen presentation by human dendritic cells. Vaccine. 2006;24:1847–57.CrossRefPubMedGoogle Scholar
  20. 20.
    Hamdy S, Molavi O, Ma Z, Haddadi A, Alshamsan A, Gobti Z, et al. Co-delivery of cancer-associated antigen and Toll-like receptor 4 ligand in PLGA nanoparticles induces potent CD8+ T cell-mediated anti-tumor immunity. Vaccine. 2008;26:5046–57.CrossRefPubMedGoogle Scholar
  21. 21.
    Krippendorff BF, Kuester K, Kloft C, Huisinga W. Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis. J Pharmacokinet Pharmacodyn. 2009;36:239–60.CrossRefPubMedGoogle Scholar
  22. 22.
    Trapp S, Rosania GR, Horobin RW, Kornhuber J. Quantitative modeling of selective lysosomal targeting for drug design. Eur Biophys J. 2008;37:1317–28.CrossRefPubMedGoogle Scholar
  23. 23.
    Moriguchi R, Kogure K, Iwasa A, Akita H, Harashima H. Non-linear pharmacodynamics in a non-viral gene delivery system: positive non-linear relationship between dose and transfection efficiency. J Control Release. 2006;110:605–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Parra-Guillen ZP, Gonzalez-Aseguinolaza G, Berraondo P, Troconiz IF. Gene therapy: a pharmacokinetic/pharmacodynamic modelling overview. Pharm Res, in press. 2010.Google Scholar
  25. 25.
    Wagstaff KM, Jans DA. Nuclear drug delivery to target tumour cells. Eur J Pharmacol. 2009;625:174–80.CrossRefPubMedGoogle Scholar
  26. 26.
    de la Fuente JM, Berry CC. Tat peptide as an efficient molecule to translocate gold nanoparticles into the cell nucleus. Bioconjug Chem. 2005;16:1176–80.CrossRefPubMedGoogle Scholar
  27. 27.
    Kang B, Mackey MA, El-Sayed MA. Nuclear targeting of gold nanoparticles in cancer cells induces DNA damage, causing cytokinesis arrest and apoptosis. J Am Chem Soc. 2010;132:1517–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Boddapati SV, D’Souza GG, Erdogan S, Torchilin VP, Weissig V. Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett. 2008;8:2559–63.CrossRefPubMedGoogle Scholar
  29. 29.
    Yamada Y, Akita H, Kamiya H, Kogure K, Yamamoto T, Shinohara Y, et al. MITO-Porter: a liposome-based carrier system for delivery of macromolecules into mitochondria via membrane fusion. Biochim Biophys Acta. 2008;1778:423–32.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Pharmacology and School of PharmacyBen-Gurion University of the NegevBeer-ShevaIsrael

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