Evaluating Nanomedicines: Obstacles and Advancements

  • Magdalena Swierczewska
  • Rachael M. Crist
  • Scott E. McNeilEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1682)


Continued advancements in nanotechnology are expanding the boundaries of medical research, most notably as drug delivery agents for treatment against cancer. Drug delivery with nanotechnology can offer greater control over the biodistribution of therapeutic agents to improve the therapeutic index. In the last 20 years, a number of nanomedicines have transitioned into the clinic. As nanomedicines evolve, techniques to properly evaluate their safety and efficacy must also evolve. Characterization methods for nano-based materials must be adapted to the demands of nanomedicine developers and regulators. This second edition book provides updated characterization protocols designed to address the clinical potential of nanomedicines during their preclinical development. In this chapter, the characterization challenges of nanoparticles intended for drug delivery will be discussed, along with examples of advancements and improvements in nanomedicine characterization.

Key words

Nanoparticles Nanomedicine Therapy Efficacy Toxicity Active targeting Passive targeting 



This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.


  1. 1.
    Weissig V, Pettinger TK, Murdock N (2014) Nanopharmaceuticals (part 1): products on the market. Int J Nanomedicine 9:4357–4373. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Anselmo AC, Mitragotri S (2016) Nanoparticles in the clinic. Bioeng Transl Med 1(1):10–29. Google Scholar
  3. 3.
    Havel HA (2016) Where are the nanodrugs? An industry perspective on development of drug products containing nanomaterials. AAPS J 18(6):1351–1353. CrossRefPubMedGoogle Scholar
  4. 4.
    Boswell GW, Buell D, Bekersky I (1998) AmBisome (Liposomal Amphotericin B): a comparative review. J Clin Pharmacol 38(7):583–592. CrossRefPubMedGoogle Scholar
  5. 5.
    Shi J, Kantoff PW, Wooster R, Farokhzad OC (2017) Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17(1):20–37. CrossRefPubMedGoogle Scholar
  6. 6.
    Barenholz Y (2012) Doxil®—the first FDA-approved nano-drug: lessons learned. J Control Release 160(2):117–134. CrossRefPubMedGoogle Scholar
  7. 7.
    Grossman JH, Crist RM, Clogston JD (2017) Early development challenges for drug products containing nanomaterials. AAPS J 19(1):92–102. CrossRefPubMedGoogle Scholar
  8. 8.
    Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12 Part 1):6387–6392PubMedGoogle Scholar
  9. 9.
    Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65(1–2):271–284. CrossRefPubMedGoogle Scholar
  10. 10.
    Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A, Barenholz Y (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54(4):987–992PubMedGoogle Scholar
  11. 11.
    (2016) Celator Pharmaceuticals® presented phase 3 trial results in patients with high-risk acute myeloid leukemia demonstrating VYXEOS™ (CPX-351) significantly improved overall survival. Ewing, NJ.
  12. 12.
    Prabhakar U, Maeda H, Jain RK, Sevick-Muraca EM, Zamboni W, Farokhzad OC, Barry ST, Gabizon A, Grodzinski P, Blakey DC (2013) Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res 73(8):2412–2417. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Adiseshaiah PP, Crist RM, Hook SS, McNeil SE (2016) Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat Rev Clin Oncol 13(12):750–765. CrossRefPubMedGoogle Scholar
  14. 14.
    Chauhan VP, Jain RK (2013) Strategies for advancing cancer nanomedicine. Nat Mater 12(11):958–962. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hrkach J, Von Hoff D, Mukkaram Ali M, Andrianova E, Auer J, Campbell T, De Witt D, Figa M, Figueiredo M, Horhota A, Low S, McDonnell K, Peeke E, Retnarajan B, Sabnis A, Schnipper E, Song JJ, Song YH, Summa J, Tompsett D, Troiano G, Van Geen HT, Wright J, LoRusso P, Kantoff PW, Bander NH, Sweeney C, Farokhzad OC, Langer R, Zale S (2012) Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl. Med 4(128):128ra139. CrossRefGoogle Scholar
  16. 16.
    Kamoun WS, Luus L, Pien C, Kornaga T, Oyama S, Huang ZR, Tipparaju S, Kirpotin DB, Marks JD, Koshkaryev A, Geddie M, Xu L, Lugovosky A, Drummond DC (2016) Abstract 871: nanoliposomal targeting of ephrin receptor A2 (EphA2): preclinical in vitro and in vivo rationale. Cancer Res 76(14 Supplement):871–871. CrossRefGoogle Scholar
  17. 17.
    Kirpotin DB, Tipparaju S, Huang ZR, Kamoun WS, Pien C, Kornaga T, Oyama S, Olivier K, Marks JD, Koshkaryev A, Schihl SS, Fetterly G, Schoeberl B, Noble C, Hayes M, Drummond DC (2016) Abstract 3912: MM-310, a novel EphA2-targeted docetaxel nanoliposome. Cancer Res 76(14 Supplement):3912–3912. CrossRefGoogle Scholar
  18. 18.
    Davis ME, Zuckerman JE, Choi CHJ, Seligson D, Tolcher A, Alabi CA, Yen Y, Heidel JD, Ribas A (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464(7291):1067–1070. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Smith DM, Simon JK, Baker JR Jr (2013) Applications of nanotechnology for immunology. Nat Rev Immunol 13(8):592–605. CrossRefPubMedGoogle Scholar
  20. 20.
    Swartz MA, Hirosue S, Hubbell JA (2012) Engineering approaches to immunotherapy. Sci Transl Med 4(148):148rv9. CrossRefPubMedGoogle Scholar
  21. 21.
    Bao G, Mitragotri S, Tong S (2013) Multifunctional nanoparticles for drug delivery and molecular imaging. Annu Rev Biomed Eng 15(1):253–282. CrossRefPubMedGoogle Scholar
  22. 22.
    Mura S, Nicolas J, Couvreur P (2013) Stimuli-responsive nanocarriers for drug delivery. Nat Mater 12(11):991–1003. CrossRefPubMedGoogle Scholar
  23. 23.
    van Elk M, Murphy BP, Eufrásio-da-Silva T, O’Reilly DP, Vermonden T, Hennink WE, Duffy GP, Ruiz-Hernández E (2016) Nanomedicines for advanced cancer treatments: transitioning towards responsive systems. Int J Pharm 515(1–2):132–164. CrossRefPubMedGoogle Scholar
  24. 24.
    Bressler NM, Bressler SB (2000) Photodynamic therapy with verteporfin (visudyne): impact on ophthalmology and visual sciences. Invest Ophthalmol Vis Sci 41(3):624–628PubMedGoogle Scholar
  25. 25.
    Landon CD, Park JY, Needham D, Dewhirst MW (2011) Nanoscale drug delivery and hyperthermia: the materials design and preclinical and clinical testing of low temperature-sensitive liposomes used in combination with mild hyperthermia in the treatment of local cancer. Open Nanomed J 3:38–64. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Crist RM, Grossman JH, Patri AK, Stern ST, Dobrovolskaia MA, Adiseshaiah PP, Clogston JD, McNeil SE (2013) Common pitfalls in nanotechnology: lessons learned from NCI’s nanotechnology characterization laboratory. Integr Biol (Camb) 5(1):66–73. CrossRefGoogle Scholar
  27. 27.
    Dobrovolskaia MA, Neun BW, Clogston JD, Grossman JH, McNeil SE (2014) Choice of method for endotoxin detection depends on nanoformulation. Nanomedicine (Lond) 9(12):1847–1856. CrossRefGoogle Scholar
  28. 28.
    Dobrovolskaia MA, Patri AK, Potter TM, Rodriguez JC, Hall JB, McNeil SE (2012) Dendrimer-induced leukocyte procoagulant activity depends on particle size and surface charge. Nanomedicine (Lond) 7(2):245–256. CrossRefGoogle Scholar
  29. 29.
    McNeil SE (ed) (2011) Characterization of nanoparticles intended for drug delivery, Methods in molecular biology, vol 697. Humana Press, New York. Google Scholar
  30. 30.
    Smith DA, Schmid EF (2006) Drug withdrawals and the lessons within. Curr Opin Drug Discov Devel 9(1):38–46PubMedGoogle Scholar
  31. 31.
    Wysowski DK, Nourjah P (2004) Analyzing prescription drugs as causes of death on death certificates. Public Health Rep 119(6):520. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Dobrovolskaia MA, McNeil SE (2007) Immunological properties of engineered nanomaterials. Nat Nanotechnol 2(8):469–478CrossRefPubMedGoogle Scholar
  33. 33.
    Wilke RA, Lin DW, Roden DM, Watkins PB, Flockhart D, Zineh I, Giacomini KM, Krauss RM (2007) Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6(11):904–916. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wysowski DK, Swartz L (2005) Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions. Arch Intern Med 165(12):1363–1369. CrossRefPubMedGoogle Scholar
  35. 35.
    Dobrovolskaia MA, McNeil SE (2013) Understanding the correlation between in vitro and in vivo immunotoxicity tests for nanomedicines. J Control Release 172(2):456–466. CrossRefPubMedGoogle Scholar
  36. 36.
    Dobrovolskaia MA (2015) Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: challenges, considerations and strategy. J Control Release 220(Pt B):571–583. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Szebeni J, Muggia F, Gabizon A, Barenholz Y (2011) Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev 63(12):1020–1030. CrossRefPubMedGoogle Scholar
  38. 38.
    Skoczen S, McNeil SE, Stern ST (2015) Stable isotope method to measure drug release from nanomedicines. J Control Release 220:169–174CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Adiseshaiah PP, Hall JB, McNeil SE (2010) Nanomaterial standards for efficacy and toxicity assessment. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2(1):99–112. CrossRefPubMedGoogle Scholar
  40. 40.
    Batrakova EV, Kim MS (2015) Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release 219:396–405. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Magdalena Swierczewska
    • 1
  • Rachael M. Crist
    • 1
  • Scott E. McNeil
    • 2
    Email author
  1. 1.Cancer Research Technology Program, Nanotechnology Characterization LaboratoryLeidos Biomedical Research, Inc., Frederick National Laboratory for Cancer ResearchFrederickUSA
  2. 2.Nanotechnology Characterization LaboratoryLeidos Biomedical Research, Inc., Frederick National Laboratory for Cancer ResearchFrederickUSA

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