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Early Development Challenges for Drug Products Containing Nanomaterials

  • Research Article
  • Theme: Nanotechnology in Complex Drug Products: Learning from the Past, Preparing for the Future
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Abstract

The vast majority of drug product candidates in early development fail to progress to clinics. This is true for products containing nanomaterials just as for other types of pharmaceuticals. Early development pathways should therefore place high priority on experiments that help candidates fail faster and less expensively. Nanomedicines fail for many reasons, but some are more avoidable than others. Some of the points of failure are not considerations in the development of small molecules or biopharmaceuticals, and so may be unexpected, even to those with previous experience bringing drug products to the clinic. This article reviews experiments that have proven useful in providing “go/no-go” decision-making data for nanomedicines in early preclinical development. Of course, the specifics depend on the particulars of the drug product and the nanomaterial type, and not every product shares the same development pathway or the same potential points of failure. Here, we focus on challenges that differ from those in the development of traditional small molecule therapeutics, and on experiments that reveal deficiencies that can only be corrected by essentially starting over—altering the nanomedicine to an extent that all previous characterization and proof-of-concept testing must be repeated. Conducting these experiments early in the development process can save significant resources and time and allow developers to focus on derisked candidates with a greater likelihood of ultimate success.

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References

  1. Min Y, Caster JM, Eblan MJ, Wang AZ. Clinical translation of nanomedicine. Chem Rev. 2015;115(19):11147–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Noorlander CW, Kooi MW, Oomen AG, Park MV, Vandebriel RJ, Geertsma RE. Horizon scan of nanomedicinal products. Nanomedicine (Lond). 2015;10(10):1599–608.

    Article  CAS  Google Scholar 

  3. Luo D, Carter KA, Lovell JF. Nanomedical engineering: shaping future nanomedicines. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015;7(2):169–88.

    Article  CAS  PubMed  Google Scholar 

  4. Tyner KM, Zou P, Yang X, Zhang H, Cruz CN, Lee SL. Product quality for nanomaterials: current U.S. experience and perspective. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015;7(5):640–54.

    Article  PubMed  Google Scholar 

  5. Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release. 2011;153(3):198–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Stern ST, Hall JB, Yu LL, Wood LJ, Paciotti GF, Tamarkin L, et al. Translational considerations for cancer nanomedicine. J Controlled Release. 2010;146(2):164–74.

    Article  CAS  Google Scholar 

  7. Crist RM, Grossman JH, Patri AK, Stern ST, Dobrovolskaia MA, Adiseshaiah PP, et al. Common pitfalls in nanotechnology: lessons learned from NCI’s Nanotechnology Characterization Laboratory. Integr Biol (Camb). 2013;5(1):66–73.

    Article  CAS  Google Scholar 

  8. Dicko A, Kwak S, Frazier AA, Mayer LD, Liboiron BD. Biophysical characterization of a liposomal formulation of cytarabine and daunorubicin. Int J Pharm. 2010;391(1–2):248–59.

    Article  CAS  PubMed  Google Scholar 

  9. Wei X, Cohen R, Barenholz Y. Insights into composition/structure/function relationships of Doxil gained from “high-sensitivity” differential scanning calorimetry. Eur J Pharm Biopharm. 2016.

  10. Huang X, Peng X, Wang Y, Wang Y, Shin DM, El-Sayed MA, et al. A reexamination of active and passive tumor targeting by using rod-shaped gold nanocrystals and covalently conjugated peptide ligands. ACS Nano. 2010;4(10):5887–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kunjachan S, Pola R, Gremse F, Theek B, Ehling J, Moeckel D, et al. Passive versus active tumor targeting using RGD- and NGR-modified polymeric nanomedicines. Nano Lett. 2014;14(2):972–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Duncan R, Gaspar R. Nanomedicine(s) under the microscope. Mol Pharm. 2011;8(6):2101–41.

    Article  CAS  PubMed  Google Scholar 

  13. Sykes EA, Chen J, Zheng G, Chan WC. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano. 2014;8(6):5696–706.

    Article  CAS  PubMed  Google Scholar 

  14. Klibanov AL, Maruyama K, Beckerleg AM, Torchilin VP, Huang L. Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. Biochim Biophys Acta. 1991;1062(2):142–8.

    Article  CAS  PubMed  Google Scholar 

  15. Mullen DG, Fang M, Desai A, Baker JR, Orr BG, Banaszak Holl MM. A quantitative assessment of nanoparticle-ligand distributions: implications for targeted drug and imaging delivery in dendrimer conjugates. ACS Nano. 2010;4(2):657–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hrkach J, Von Hoff D, Mukkaram Ali M, Andrianova E, Auer J, Campbell T, et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med. 2012;4(128):128ra39.

    Article  PubMed  Google Scholar 

  17. Jokerst JV, Lobovkina T, Zare RN, Gambhir SS. Nanoparticle PEGylation for imaging and therapy. Nanomedicine (Lond). 2011;6(4):715–28.

    Article  CAS  Google Scholar 

  18. Smith MC, Crist RM, Clogston JD, McNeil SE. Quantitative analysis of PEG-functionalized colloidal gold nanoparticles using charged aerosol detection. Anal Bioanal Chem. 2015;407(13):3705–16.

    Article  CAS  PubMed  Google Scholar 

  19. Makan AC, Spallek MJ, du Toit M, Klein T, Pasch H. Advanced analysis of polymer emulsions: particle size and particle size distribution by field-flow fractionation and dynamic light scattering. J Chromatogr A. 2016;1442:94–106.

    Article  CAS  PubMed  Google Scholar 

  20. Perry JL, Reuter KG, Kai MP, Herlihy KP, Jones SW, Luft JC, et al. PEGylated PRINT nanoparticles: the impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics. Nano Lett. 2012;12(10):5304–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Baer DR, Engelhard MH, Johnson GE, Laskin J, Lai J, Mueller K, et al. Surface characterization of nanomaterials and nanoparticles: important needs and challenging opportunities. J Vac Sci Technol A. 2013;31(5):50820.

    Article  PubMed  Google Scholar 

  22. Rabanel JM, Hildgen P, Banquy X. Assessment of PEG on polymeric particles surface, a key step in drug carrier translation. J Controlled Release. 2014;185:71–87.

    Article  CAS  Google Scholar 

  23. Ilinskaya AN, Dobrovolskaia MA. Nanoparticles and the blood coagulation system. Part II: safety concerns. Nanomedicine (Lond). 2013;8(6):969–81.

    Article  CAS  Google Scholar 

  24. (USP) USP. <729> Globule size distribution in lipid injectable emulsions. Physical tests. Rockville, MD 2013.

  25. Joubert MK, Hokom M, Eakin C, Zhou L, Deshpande M, Baker MP, et al. Highly aggregated antibody therapeutics can enhance the in vitro innate and late-stage T-cell immune responses. J Biol Chem. 2012;287(30):25266–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. den Engelsman J, Garidel P, Smulders R, Koll H, Smith B, Bassarab S, et al. Strategies for the assessment of protein aggregates in pharmaceutical biotech product development. Pharm Res. 2011;28(4):920–33.

    Article  Google Scholar 

  27. Driscoll DF, Etzler F, Barber TA, Nehne J, Niemann W, Bistrian BR. Physicochemical assessments of parenteral lipid emulsions: light obscuration versus laser diffraction. Int J Pharm. 2001;219(1–2):21–37.

    Article  CAS  PubMed  Google Scholar 

  28. Kotarek J, Stuart C, De Paoli SH, Simak J, Lin TL, Gao Y, et al. Subvisible particle content, formulation, and dose of an erythropoietin peptide mimetic product are associated with severe adverse postmarketing events. J Pharm Sci. 2016;105(3):1023–7.

    Article  CAS  PubMed  Google Scholar 

  29. Weaver JL, Boyne M, Pang E, Chimalakonda K, Howard KE. Nonclinical evaluation of the potential for mast cell activation by an erythropoietin analog. Toxicol Appl Pharmacol. 2015;287(3):246–52.

    Article  CAS  PubMed  Google Scholar 

  30. Wolfram J, Suri K, Yang Y, Shen J, Celia C, Fresta M, et al. Shrinkage of pegylated and non-pegylated liposomes in serum. Colloids Surf B Biointerfaces. 2014;114:294–300.

    Article  CAS  PubMed  Google Scholar 

  31. Capomaccio R, Jimenez IO, Colpo P, Gilliland D, Ceccone G, Rossi F, et al. Determination of the structure and morphology of gold nanoparticle-HSA protein complexes. Nanoscale. 2015;7(42):17653–7.

    Article  CAS  PubMed  Google Scholar 

  32. Aramesh M, Shimoni O, Ostrikov K, Prawer S, Cervenka J. Surface charge effects in protein adsorption on nanodiamonds. Nanoscale. 2015;7(13):5726–36.

    Article  CAS  PubMed  Google Scholar 

  33. Cedervall T, Lynch I, Lindman S, Berggard T, Thulin E, Nilsson H, et al. Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci U S A. 2007;104(7):2050–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Modi S, Anderson BD. Determination of drug release kinetics from nanoparticles: overcoming pitfalls of the dynamic dialysis method. Mol Pharm. 2013;10(8):3076–89.

    Article  CAS  PubMed  Google Scholar 

  35. Ambardekar VV, Stern ST. NBCD pharmacokinetics and drug release methods. In: Crommelin DJA, de Viegler JSB, editors. Non-biological complex drugs; the science and the regulatory landscape. Springer; 2015. p. 261–87.

  36. Skoczen S, McNeil SE, Stern ST. Stable isotope method to measure drug release from nanomedicines. J Controlled Release. 2015;220(Pt A):169–74.

    Article  CAS  Google Scholar 

  37. Levin AA. A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta. 1999;1489(1):69–84.

    Article  CAS  PubMed  Google Scholar 

  38. Tamilvanan S, Raja NL, Sa B, Basu SK. Clinical concerns of immunogenicity produced at cellular levels by biopharmaceuticals following their parenteral administration into human body. J Drug Target. 2010;18(7):489–98.

    Article  CAS  PubMed  Google Scholar 

  39. Weiszhar Z, Czucz J, Revesz C, Rosivall L, Szebeni J, Rozsnyay Z. Complement activation by polyethoxylated pharmaceutical surfactants: Cremophor-EL, Tween-80 and Tween-20. Eur J Pharm Sci. 2012;45(4):492–8.

    Article  CAS  PubMed  Google Scholar 

  40. Dobrovolskaia MA. Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: challenges, considerations and strategy. J Controlled Release. 2015;220(Pt B):571–83.

    Article  CAS  Google Scholar 

  41. Dobrovolskaia MA, McNeil SE. Immunological properties of engineered nanomaterials. Nat Nano. 2007;2(8):469–78.

    Article  CAS  Google Scholar 

  42. Dobrovolskaia MA, McNeil SE. Understanding the correlation between in vitro and in vivo immunotoxicity tests for nanomedicines. J Controlled Release. 2013;172(2):456–66.

    Article  CAS  Google Scholar 

  43. Dobrovolskaia MA, Neun BW, Clogston JD, Ding H, Ljubimova J, McNeil SE. Ambiguities in applying traditional Limulus amebocyte lysate tests to quantify endotoxin in nanoparticle formulations. Nanomedicine (Lond). 2010;5(4):555–62.

    Article  CAS  Google Scholar 

  44. Dobrovolskaia MA, Neun BW, Clogston JD, Grossman JH, McNeil SE. Choice of method for endotoxin detection depends on nanoformulation. Nanomedicine (Lond). 2014;9(12):1847–56.

    Article  CAS  Google Scholar 

  45. International A. ASTM F756 - 13 standard practice for assessment of hemolytic properties of materials. West Conshohocken, PA2013

  46. Adiseshaiah PP, Hall JB, McNeil SE. Nanomaterial standards for efficacy and toxicity assessment. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2(1):99–112.

    Article  CAS  PubMed  Google Scholar 

  47. Szebeni J, Muggia F, Gabizon A, Barenholz Y. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev. 2011;63(12):1020–30.

    Article  CAS  PubMed  Google Scholar 

  48. Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer. 2001;84(10):1424–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gould SE, Junttila MR, de Sauvage FJ. Translational value of mouse models in oncology drug development. Nat Med. 2015;21(5):431–9.

    Article  CAS  PubMed  Google Scholar 

  50. Snipstad S, Hak S, Baghirov H, Sulheim E, Morch Y, Lelu S, et al. Labeling nanoparticles: dye leakage and altered cellular uptake. Cytometry A. 2016.

  51. Mamidi RN, Weng S, Stellar S, Wang C, Yu N, Huang T, et al. Pharmacokinetics, efficacy and toxicity of different pegylated liposomal doxorubicin formulations in preclinical models: is a conventional bioequivalence approach sufficient to ensure therapeutic equivalence of pegylated liposomal doxorubicin products? Cancer Chemother Pharmacol. 2010;66(6):1173–84.

    Article  CAS  PubMed  Google Scholar 

  52. Wei A, Mehtala JG, Patri AK. Challenges and opportunities in the advancement of nanomedicines. J Controlled Release. 2012;164(2):236–46.

    Article  CAS  Google Scholar 

  53. Hansen M, Smith MC, Crist RM, Clogston JD, McNeil SE. Analyzing the influence of PEG molecular weight on the separation of PEGylated gold nanoparticles by asymmetric-flow field-flow fractionation. Anal Bioanal Chem. 2015;407(29):8661–72.

    Article  CAS  PubMed  Google Scholar 

  54. Hinterwirth H, Wiedmer SK, Moilanen M, Lehner A, Allmaier G, Waitz T, et al. Comparative method evaluation for size and size-distribution analysis of gold nanoparticles. J Sep Sci. 2013;36(17):2952–61.

    Article  CAS  PubMed  Google Scholar 

  55. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9(3):203–14.

    CAS  PubMed  Google Scholar 

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Acknowledgments

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. The authors thank the scientists and staff of the Nanotechnology Characterization Lab (NCL), with special thanks to Scott McNeil, Stephan Stern, Marina Dobrovolskaia, and Magdalena Scully for helpful discussions and Allen Kane for assistance with figures.

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Authors and Affiliations

  1. Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, 8560 Progress Drive, Wing D, Rm 1003, Frederick, Maryland, 21702, USA

    Jennifer H. Grossman, Rachael M. Crist & Jeffrey D. Clogston

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  1. Jennifer H. Grossman
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  2. Rachael M. Crist
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  3. Jeffrey D. Clogston
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Correspondence to Jennifer H. Grossman.

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Guest Editors: Katherine Tyner, Sau (Larry) Lee, and Marc Wolfgang

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Grossman, J.H., Crist, R.M. & Clogston, J.D. Early Development Challenges for Drug Products Containing Nanomaterials. AAPS J 19, 92–102 (2017). https://doi.org/10.1208/s12248-016-9980-4

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  • DOI: https://doi.org/10.1208/s12248-016-9980-4

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