Formulation and Optimization of Mitochondria-Targeted Polymeric Nanoparticles

Part of the Methods in Molecular Biology book series (MIMB, volume 1265)

Abstract

Targeted delivery of therapeutics to the mitochondria of cells without alteration of drug properties can be a vital technique in the treatment of a variety of mitochondrial-dysfunction-related diseases. Herein, we describe a detailed protocol for synthesis and characterization of a functionalized polymer to build mitochondria-targeted nanoparticles (NPs). The block polymer was decorated with a lipophilic triphenylphosphonium (TPP) cation for mitochondrial trafficking of payload-loaded polymeric NPs. TPP-based lipophilic cations have the ability to cross the mitochondrial membrane. A mitochondria-targeted block copolymer poly(dl-lactide-co-glycolide)-b-polyethylene glycol-TPP and a nontargeted poly(dl-lactide-co-glycolide)-b-polyethylene glycol polymer were synthesized and their NPs were prepared. A nanoprecipitation method combined with polymer blending technology was adopted in order to get suitable size and charged NPs for efficient mitochondrial trafficking.

Key words

Biodegradable polymeric nanoparticles Poly(dl-lactide-co-glycolide) Mitochondria Triphenylphosphonium cation Nanoprecipitation Polymer blending 

References

  1. 1.
    Murphy MP, Smith RA (2000) Drug delivery to mitochondria: the key to mitochondrial medicine. Adv Drug Deliv Rev 41:235–250CrossRefPubMedGoogle Scholar
  2. 2.
    Debatin KM, Poncet D, Kroemer G (2002) Chemotherapy: targeting the mitochondrial cell death pathway. Oncogene 21:8786–8803CrossRefPubMedGoogle Scholar
  3. 3.
    Toogood PL (2008) Mitochondrial drugs. Curr Opin Chem Biol 12:457–463CrossRefPubMedGoogle Scholar
  4. 4.
    Rajendran L, Knolker HJ, Simons K (2010) Subcellular targeting strategies for drug design and delivery. Nat Rev Drug Discov 9:29–42CrossRefPubMedGoogle Scholar
  5. 5.
    Chaturvedi RK, Flint Beal M (2013) Mitochondrial diseases of the brain. Free Rad Biol Med 63:1–29CrossRefPubMedGoogle Scholar
  6. 6.
    Duchen MR (2004) Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med 25:365–451CrossRefPubMedGoogle Scholar
  7. 7.
    Fulda S, Galluzzi L, Kroemer G (2010) Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 9:447–464CrossRefPubMedGoogle Scholar
  8. 8.
    Galluzzi L, Morselli E, Kepp O, Vitale I, Rigoni A, Vacchelli E et al (2010) Mitochondrial gateways to cancer. Mol Aspects Med 31:1–20CrossRefPubMedGoogle Scholar
  9. 9.
    Neuzil J, Dong L-F, Ramanathapuram L, Hahn T, Chladova M, Wang X-F et al (2007) Vitamin E analogues as a novel group of mitocans: anti-cancer agents that act by targeting mitochondria. Mol Aspects Med 28:607–645CrossRefPubMedGoogle Scholar
  10. 10.
    Smith RAJ, Porteous CM, Gane AM, Murphy MP (2003) Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci U S A 100:5407–5412CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Neuzil J, Wang X-F, Dong L-F, Low P, Ralph SJ (2006) Molecular mechanism of “mitocan”-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins. FEBS Lett 580:5125–5129CrossRefPubMedGoogle Scholar
  12. 12.
    Hoye AT, Davoren JE, Wipf P, Fink MP, Kagan VE (2008) Targeting mitochondria. Acc Chem Res 41:87–97CrossRefPubMedGoogle Scholar
  13. 13.
    Boddapati SV, D’Souza GGM, Erdogan S, Torchilin VP, Weissig V (2008) Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett 8:2559–2563CrossRefPubMedGoogle Scholar
  14. 14.
    Murphy MP (2008) Targeting lipophilic cations to mitochondria. Biochim Biophys Acta 1777:1028–1031CrossRefPubMedGoogle Scholar
  15. 15.
    Murphy MP, Smith RA (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 47:629–656CrossRefPubMedGoogle Scholar
  16. 16.
    Hrkach J, Von Hoff D, Ali MM, Andrianova E, Auer J, Campbell T et al (2012) Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med 4:128ra139CrossRefGoogle Scholar
  17. 17.
    Marrache S, Pathak RK, Darley KL, Choi JH, Zaver D, Kolishetti N et al (2013) Nanocarriers for tracking and treating diseases. Curr Med Chem 20:3500–3514CrossRefPubMedGoogle Scholar
  18. 18.
    Marrache S, Dhar S (2012) Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics. Proc Natl Acad Sci U S A 109:16288–16293CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Marrache S, Tundup S, Harn DA, Dhar S (2013) Ex vivo programming of dendritic cells by mitochondria-targeted nanoparticles to produce interferon-gamma for cancer immunotherapy. ACS Nano 7:7392–7402CrossRefPubMedGoogle Scholar
  20. 20.
    Adler J, Parmryd I (2010) Quantifying colocalization by correlation: the Pearson correlation coefficient is superior to the Mander’s overlap coefficient. Cytometry A 77:733–742CrossRefPubMedGoogle Scholar
  21. 21.
    Dunn KW, Kamocka MM, McDonald JH (2011) A practical guide to evaluating colocalization in biological microscopy. Am J Physiol Cell Physiol 300:C723–C742CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sean Marrache
    • 1
  • Rakesh K. Pathak
    • 1
  • Shanta Dhar
    • 1
    • 2
  1. 1.NanoTherapeutics Research Laboratory, Department of ChemistryUniversity of GeorgiaAthensUSA
  2. 2.Department of ChemistryUniversity of GeorgiaAthensUSA

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