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EGFR Targeted Theranostic Nanoemulsion for Image-Guided Ovarian Cancer Therapy

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Abstract

Purpose

Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose-limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro-apoptotic agent, C6-ceramide.

Methods

The surface of the nanoemulsion is annotated with an endothelial growth factor receptor (EGFR) binding peptide to improve targeting ability and gadolinium to provide diagnostic capability for image-guided therapy of EGFR overexpressing ovarian cancers. A high shear microfludization process was employed to produce the formulation with particle size below 150 nm.

Results

Pharmacokinetic study showed a prolonged blood platinum and gadolinium levels with nanoemulsions in nu/nu mice. The theranostic nanoemulsions also exhibited less toxicity and enhanced the survival time of mice as compared to an equivalent cisplatin treatment.

Conclusions

Magnetic resonance imaging (MRI) studies indicate the theranostic nanoemulsions were effective contrast agents and could be used to track accumulation in a tumor. The MRI study additionally indicate that significantly more EGFR-targeted theranostic nanoemulsion accumulated in a tumor than non-targeted nanoemulsuion providing the feasibility of using a targeted theranostic agent in conjunction with MRI to image disease loci and quantify the disease progression.

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Abbreviations

DNA:

Deoxyribonucleic acid

EGFR:

Endothelial growth factor receptor

g:

Grams

Gd:

Gadolinium

hrs/h:

Hours

kg:

Kilograms

mg:

Milligrams

min:

Minutes

mm:

Millimeters

mmoles:

Millimoles

msec:

Milliseconds

mV:

Millivolts

ng:

Nanograms

nm:

Nanometers

psi:

Pounds per square inch

Pt:

Platinum

rpm:

Revolutions per minute

w/v :

Weight/volume

μL:

Microliters

References

  1. Siegel R, Naishadham D, Jemal A. CA Cancer J Clin. 2013;63(1):11–30.

    Article  PubMed  Google Scholar 

  2. Jelovac D, Armstrong DK. Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin. 2011;61(3):183–203.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Neijt JP, ten Bokkel Huinink WW, van der Burg ME, van Oosterom AT, Willemse PH, Vermorken JB, et al. Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer. 1991;27(11):1367–72.

    Article  CAS  PubMed  Google Scholar 

  4. Kartalou M, Essigmann JM. Mechanisms of resistance to cisplatin. Mutat Res. 2001;478(1-2):23–43.

    Article  CAS  PubMed  Google Scholar 

  5. Uchino H, Matsumura Y, Negishi T, Koizumi F, Hayashi T, Honda T, et al. Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats. Br J Cancer. 2005;93(6):678–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol Off J Am Soc Clin Oncol. 1991;9(3):389–93.

    CAS  Google Scholar 

  7. Moghimi SM, Hunter AC, Murray JC. Nanomedicine: current status and future prospects. FASEB J Off Publ Fed Am Soc Exp Biol. 2005;19(3):311–30.

    CAS  Google Scholar 

  8. Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov. 2003;2(5):347–60.

    Article  CAS  PubMed  Google Scholar 

  9. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol. 2007;2(12):751–60.

    Article  CAS  PubMed  Google Scholar 

  10. Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. J Control Release Off J Control Release Soc. 2001;73(2-3):137–72.

    Article  CAS  Google Scholar 

  11. Oberoi HS, Nukolova NV, Kabanov AV, Bronich TK. Nanocarriers for delivery of platinum anticancer drugs. Adv Drug Deliv Rev. 2013;65(13-14):1667–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Stathopoulos GP. Liposomal cisplatin: a new cisplatin formulation. Anti-Cancer Drugs. 2010;21(8):732–6.

    Article  CAS  PubMed  Google Scholar 

  13. Zamboni WC, Gervais AC, Egorin MJ, Schellens JH, Zuhowski EG, Pluim D, et al. Systemic and tumor disposition of platinum after administration of cisplatin or STEALTH liposomal-cisplatin formulations (SPI-077 and SPI-077 B103) in a preclinical tumor model of melanoma. Cancer Chemother Pharmacol. 2004;53(4):329–36.

    Article  CAS  PubMed  Google Scholar 

  14. Ganta S, Singh A, Patel NR, Cacaccio J, Rawal YH, Davis BJ, et al. Development of EGFR-targeted nanoemulsion for imaging and novel platinum therapy of ovarian cancer. Pharm Res. 2014;31(9):2490–502.

  15. Ganta S, Talekar M, Singh A, Coleman TP, Amiji MM. Nanoemulsions in translational research-opportunities and challenges in targeted cancer therapy. AAPS PharmSciTech. 2014;15(3):694–708.

  16. Sarker DK. Engineering of nanoemulsions for drug delivery. Curr Drug Deliv. 2005;2(4):297–310.

    Article  CAS  PubMed  Google Scholar 

  17. Ganta S, Paxton JW, Baguley BC, Garg S. Pharmacokinetics and pharmacodynamics of chlorambucil delivered in parenteral emulsion. Int J Pharm. 2008;360(1–2):115–21.

    Article  CAS  PubMed  Google Scholar 

  18. Ganta S, Deshpande D, Korde A, Amiji M. A review of multifunctional nanoemulsion systems to overcome oral and CNS drug delivery barriers. Mol Membr Biol. 2010;27(7):260–73.

    Article  CAS  PubMed  Google Scholar 

  19. Ganta S, Sharma P, Paxton JW, Baguley BC, Garg S. Pharmacokinetics and pharmacodynamics of chlorambucil delivered in long-circulating nanoemulsion. J Drug Target. 2010;18(2):125–33.

    Article  CAS  PubMed  Google Scholar 

  20. Ganta S, Singh A, Rawal Y, Cacaccio J, Patel NR, Kulkarni P, et al. Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer. Drug Deliv. 2014:1–13. doi:10.3109/10717544.2014.923068

  21. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release Off J Control Release Soc. 2000;65(1-2):271–84.

    Article  CAS  Google Scholar 

  22. Ganta S, Amiji M. Coadministration of Paclitaxel and curcumin in nanoemulsion formulations to overcome multidrug resistance in tumor cells. Mol Pharm. 2009;6(3):928–39.

    Article  CAS  PubMed  Google Scholar 

  23. Talekar M, Ganta S, Singh A, Amiji M, Kendall J, Denny WA, et al. Phosphatidylinositol 3-kinase inhibitor (PIK75) containing surface functionalized nanoemulsion for enhanced drug delivery, cytotoxicity and pro-apoptotic activity in ovarian cancer cells. Pharm Res. 2012;29(10):2874–86.

    Article  CAS  PubMed  Google Scholar 

  24. Ganta S, Devalapally H, Amiji M. Curcumin enhances oral bioavailability and anti-tumor therapeutic efficacy of paclitaxel upon administration in nanoemulsion formulation. J Pharm Sci. 2010;99(11):4630–41.

    Article  CAS  PubMed  Google Scholar 

  25. Maeda M, Sasaki T, inventors; Sumitomo Pharmaceuticals Company Ltd, assignee. Liposoluble platinum (II) complex and preparation thereof patent 6,613,799 B1. 2003.

  26. Nagaraja TN, Croxen RL, Panda S, Knight RA, Keenan KA, Brown SL, et al. Application of arsenazo III in the preparation and characterization of an albumin-linked, gadolinium-based macromolecular magnetic resonance contrast agent. J Neurosci Methods. 2006;157(2):238–45.

    Article  CAS  PubMed  Google Scholar 

  27. Zamboni WC, Gervais AC, Egorin MJ, Schellens JH, Hamburger DR, Delauter BJ, et al. Inter- and intratumoral disposition of platinum in solid tumors after administration of cisplatin. Clin Cancer Res. 2002;8(9):2992–9.

    CAS  PubMed  Google Scholar 

  28. Jamieson ER, Jacobson MP, Barnes CM, Chow CS, Lippard SJ. Structural and kinetic studies of a cisplatin-modified DNA icosamer binding to HMG1 domain B. J Biol Chem. 1999;274(18):12346–54.

    Article  CAS  PubMed  Google Scholar 

  29. Wong E, Giandomenico CM. Current status of platinum-based antitumor drugs. Chem Rev. 1999;99(9):2451–66.

    Article  CAS  PubMed  Google Scholar 

  30. Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov. 2005;4(4):307–20.

    Article  CAS  PubMed  Google Scholar 

  31. Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc Natl Acad Sci U S A. 2008;105(45):17356–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Dhar S, Kolishetti N, Lippard SJ, Farokhzad OC. Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo. Proc Natl Acad Sci U S A. 2011;108(5):1850–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Paraskar AS, Soni S, Chin KT, Chaudhuri P, Muto KW, Berkowitz J, et al. Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy. Proc Natl Acad Sci U S A. 2010;107(28):12435–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Stathopoulos GP, Boulikas T. Lipoplatin formulation review article. J Drug Delivery. 2012;2012:581363.

    Article  CAS  Google Scholar 

  35. Harrington KJ, Lewanski CR, Northcote AD, Whittaker J, Wellbank H, Vile RG, et al. Phase I-II study of pegylated liposomal cisplatin (SPI-077) in patients with inoperable head and neck cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2001;12(4):493–6.

    Article  CAS  Google Scholar 

  36. Cronin MT, Dearden JC, Duffy JC, Edwards R, Manga N, Worth AP, et al. The importance of hydrophobicity and electrophilicity descriptors in mechanistically-based QSARs for toxicological endpoints. SAR QSAR Environ Res. 2002;13(1):167–76.

    Article  CAS  PubMed  Google Scholar 

  37. Shen DW, Pouliot LM, Hall MD, Gottesman MM. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev. 2012;64(3):706–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Milane L, Duan Z, Amiji M. Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells. Mol Pharm. 2011;8(1):185–203.

    Article  CAS  PubMed  Google Scholar 

  39. Song S, Liu D, Peng J, Sun Y, Li Z, Gu JR, et al. Peptide ligand-mediated liposome distribution and targeting to EGFR expressing tumor in vivo. Int J Pharm. 2008;363(1-2):155–61.

    Article  CAS  PubMed  Google Scholar 

  40. Li Z, Zhao R, Wu X, Sun Y, Yao M, Li J, et al. Identification and characterization of a novel peptide ligand of epidermal growth factor receptor for targeted delivery of therapeutics. FASEB J Off Publ Fed Am Soc Exp Biol. 2005;19(14):1978–85.

    CAS  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by the NIH grants (R43 CA144591 and U54 CA151881). The Authors would like to thank Susan Riley Keyes, Allison Morse, Samantha Orosz, Laurie Cote, Phil Heisler and Keri Forbringer for their insightful discussion of the findings and assistance with development of this manuscript.

Author information

Authors and Affiliations

  1. Nemucore Medical Innovations, Inc., Worcester, Massachusetts, 01608, USA

    Srinivas Ganta, Aleksandr Piroyan, Rupa R. Sawant, Niravkumar R. Patel, Barbara Davis & Timothy P. Coleman

  2. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, 02115, USA

    Amit Singh, Praveen Kulkarni & Mansoor M. Amiji

  3. Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts, 02115, USA

    Praveen Kulkarni & Craig Ferris

  4. Center for Translational Cancer Nanomedicine, Northeastern University, Boston, Massachusetts, 02115, USA

    Srinivas Ganta, Praveen Kulkarni, Aleksandr Piroyan, Rupa R. Sawant, Niravkumar R. Patel, Barbara Davis, Craig Ferris, Mansoor M. Amiji & Timothy P. Coleman

  5. University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA

    Sara O’Neal & William Zamboni

  6. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA

    Amanda W. Keeler, Sara O’Neal & William Zamboni

  7. Translational Oncology and Nanoparticle Drug Development Initiative (TOND2I) Lab, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Sara O’Neal & William Zamboni

  8. Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Sara O’Neal & William Zamboni

  9. Center of Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    William Zamboni

  10. Blue Ocean Biomanufacturing, Inc., Worcester, Massachusetts, 01608, USA

    Timothy P. Coleman

  11. Foundation for the Advancement of Personalized Medicine Manufacturing, Phoenix, Arizona, 85013, USA

    Timothy P. Coleman

Authors
  1. Srinivas Ganta
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  2. Amit Singh
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  3. Praveen Kulkarni
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  4. Amanda W. Keeler
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  5. Aleksandr Piroyan
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  6. Rupa R. Sawant
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  7. Niravkumar R. Patel
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  8. Barbara Davis
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  9. Craig Ferris
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  10. Sara O’Neal
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  11. William Zamboni
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  12. Mansoor M. Amiji
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  13. Timothy P. Coleman
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Corresponding author

Correspondence to Timothy P. Coleman.

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Ganta, S., Singh, A., Kulkarni, P. et al. EGFR Targeted Theranostic Nanoemulsion for Image-Guided Ovarian Cancer Therapy. Pharm Res 32, 2753–2763 (2015). https://doi.org/10.1007/s11095-015-1660-z

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  • DOI: https://doi.org/10.1007/s11095-015-1660-z

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