Abstract
The interdependent relationship between pharmacology and toxicology is fundamental to the concepts of efficacy and safety of both drugs and xenobiotics. The traditional concept of establishing efficacious and tolerated doses to define a ‘therapeutic window’ appears simplistic in the context of an exponentially increasing database on molecular mechanisms and cell biology that inform our understanding of homeostasis. Recent advances in nano medicine illustrate the convergence of efficacy and safety considerations that are central to establishing a clear pathway for regulatory review. The following overview considers biological responses to the administration of nanoparticles and the scale of balanced, within a range that might be considered ‘normal’, to unbalanced, abnormal responses associated with health and disease.
Similar content being viewed by others
References
Dobrovolskaia MA, Germolec DR, Weaver JL. Evaluation of nanoparticle immunotoxicity. Nat Nanotechnol. 2009;4(7):411–4.
Dobrovolskaia, M.A. and S.E. McNeil, Immunological properties of engineered nanomaterials. Nature Nanotechnology, 2007. 2 (August).
Dreher KL. Health and environmental impact of nanotechnology: toxicological assessment of manufactured nanoparticles. Toxicol Sci. 2004;77:3–5.
Garcia-Contreras L et al. Immediate and short-term cellular and biochemical responses to pulmonary single-dose studies of insulin and H-MAP. Pharm Res. 2001;18:1685–93.
Li R et al. Surface charge and cellular processing of covalently functionalized multiwall carbon nanotubes determine pulmonary toxicity. ACS Nano. 2013;7(3):2352–68.
Schanen BC et al. Immunomodulation and T helper TH (1)/TH (2) response polarization by CeO (2) and TiO (2) nanoparticles. PLoS One. 2013;8(5):e62816.
Schanen BC et al. Exposure to titanium dioxide nanomaterials provokes inflammation of an in vitro human immune construct. ACS Nano. 2009;3(9):2523–32.
Lu D et al. Poly (lactide-co-glycolide) microspheres in respirable sizes enhance an in vitro T cell response to recombinant Mycobacterium tuberculosis antigen 85B. Pharm Res. 2007;24:1834–43.
Pettis RJ, Hickey AJ. Aerosol delivery of peptide immunomodulators to rodent lungs. In: Tam JP, Kaumaya PTP, editors. Peptides frontiers of peptide science. Norwell: Kluwer/ESCOM; 1999. p. 845–6.
Tsai MY et al. Effect of influenza vaccine on markers of inflammation and lipid profile. J Lab Clin Med. 2005;145(6):323–7.
Protection, I.C.o.R., Recommendations of the ICRP. 1964, International Commission on Radiation Protection Oxford.
Oberdörster, G., O. E., and J. Oberdörster, Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environmental Health Perspectives, 2005. 113(7): p. 823.
Kirchner C et al. Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles. Nano Lett. 2005;5(2):331–8.
Gopee N et al. Migration of intradermally injected quantum dots to sentinel organs in mice. Toxicol Sci. 2007;98(1):249–57.
Zhang L, Monteiro-Riviere N. Assessment of quantum dot penetration into intact, tape-stripped, abraded and flexed rat skin. Skin Pharmacol Physiol. 2008;21(3):166–80.
Zhang Y, Kohler N, Zhang M. Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials. 2002;23(7):1553–61.
Kukowska-Latallo JF et al. Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer. Cancer Res. 2005;65(12):5317–24.
Farokhzad OC et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A. 2006;103(16):6315–20.
Delehanty JB et al. Self-assembled quantum dot-peptide bioconjugates for selective intracellular delivery. Bioconjug Chem. 2006;17(4):920–7.
Gref R et al. 'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf B: Biointerfaces. 2000;18(3–4):301–13.
Moore A, Weissleder R, Bogdanov A. Uptake of dextran-coated monocrystalline iron oxides in tumor cells and macrophages. J Magn Reson Imaging. 1997;7(6):1140–5.
Zahr A, Davis C, Pishko M. Macrophage uptake of core-shell nanoparticles surface modified with poly (ethylene glycol). Langmuir. 2006;22:8178.
Berg JM et al. The relationship between pH and Zeta potential of ~30 nm metal oxide nanoparticle suspensions relevant to in vitro toxicological evaluations. Nanotoxicology. 2009;3(4):276–83.
Sayes CM, Reed KL, Warheit DB. Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci. 2007;97(1):163–80.
Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637–50.
St John AL, Abraham SN. Innate immunity and its regulation by mast cells. J Immunol. 2013;190(9):4458–63.
Tait Wojno ED, Artis D. Innate lymphoid cells: balancing immunity, inflammation, and tissue repair in the intestine. Cell Host Microbe. 2012;12(4):445–57.
Olive C. Pattern recognition receptors: sentinels in innate immunity and targets of new vaccine adjuvants. Ext Rev. 2012;11(2):237–56.
Desmet CJ, Ishii KJ. Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat Rev Immunol. 2012;12(7):479–91.
Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;327(5963):291–5.
Marichal T et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med. 2011;17(8):996–1002.
Tewary P. Beta-defensin 2 and 3 promote the uptake of self or CpG DNA, enhance IFN-alpha production by human plasmacytoid dendritic cells, and promote inflammation. J Immunol. 2013;19(2):865–74.
Yasuda K et al. Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and -independent pathways. J Immunol. 2005;174(10):6129–36.
Chang H et al. Involvement of MyD88 in zinc oxide nanoparticle-induced lung inflammation. Exp Toxicol Pathol. 2013;65(6):887–96.
Sun, B., et al., Engineering an Effective Immune Adjuvant by Designed Control of Shape and Crystallinity of Aluminum Oxyhydroxide Nanoparticles. ACS Nano, 2013.
Katwa P et al. A carbon nanotube toxicity paradigm driven by mast cells and the IL-(3) (3)/ST (2) axis. Small. 2012;8(18):2904–12.
Worthington KL et al. Chitosan coating of copper nanoparticles reduces in vitro toxicity and increases inflammation in the lung. Nanotechnology. 2013;24(39):395101.
Noah TL et al. Nasal cytokine production in viral acute upper respiratory infection of childhood. J Infect Dis. 1995;171(3):584–92.
Moro MR et al. Clinical features, adenovirus types, and local production of inflammatory mediators in adenovirus infections. Pediatr Infect Dis J. 2009;28(5):376–80.
Laham FR et al. LDH concentration in nasal-wash fluid as a biochemical predictor of bronchiolitis severity. Pediatrics. 2010;125(2):e225–33.
Semmler-Behnke M et al. Efficient elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent reentrainment onto airway epithelium. Environ Health Perspect. 2007;115(5):728–33.
Oberdorster G, Elder A, Rinderknecht A. Nanoparticles and the brain: cause for concern? J Nanosci Nanotechnol. 2009;9(8):4996–5007.
Moller W et al. Deposition, retention, and translocation of ultrafine particles from the central airways and lung periphery. Am J Respir Crit Care Med. 2008;177(4):426–32.
Geiser M et al. The role of macrophages in the clearance of inhaled ultrafine titanium dioxide particles. Am J Respir Cell Mol Biol. 2008;38(3):371–6.
Hellstrand E et al. Complete high-density lipoproteins in nanoparticle corona. FEBS J. 2009;276(12):3372–81.
Lundqvist M et al. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. PNAS USA. 2008;105(38):14265–70.
Dawson KA, Salvati A, Lynch I. Nanoparticles reconstruct lipids. Nat Nanotechnol. 2009;4(2):84–5.
Gao D et al. Bioeliminable Nanohydrogels for drug delivery. Nano Lett. 2008;8(10):3320–4.
Hickey AJ, Smyth HDC. Pharmaco-complexity. New York: Springer; 2011.
Cheng J et al. Formulation of functionalized PLGA–PEG nanoparticles for in vivo targeted drug delivery. Biomaterials. 2007;28(5):869–76.
Wang X et al. Poly (γ-glutamic acid) nanoparticles as an efficient antigen delivery and adjuvant system: potential for an AIDS vaccine. J Med Virol. 2008;80(1):11–9.
Kalkanidis M et al. Methods for nano-particle based vaccine formulation and evaluation of their immunogenicity. Methods. 2006;40(1):20–9.
Conway MA et al. Protection against Bordetella pertussis infection following parenteral or oral immunization with antigens entrapped in biodegradable particles: effect of formulation and route of immunization on induction of Th1 and Th2 cells. Vaccine. 2001;19(15–16):1940–50.
Singh M, O’Hagan D. Advances in vaccine adjuvants. Nat Biotechnol. 1999;17:1075.
Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis. 1999;5(4):285–94.
Ankley G. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 2010;29(3):730–41.
Schultz, T.W., B. Diderich, and S. Enoch, The OECD adverse outcome pathway approach: A case study for skin sensitization, in AXLR8-2 Workshop Report, T. Seidle and H. Spielmann, Editors. 2011, OECD: http://axlr8.eu/assets/axlr8-progress-report-2011.pdf. p. 288–300.
Acknowledgments and Disclosures
CMS would like to thank the CDC National Institute for Occupational Safety and Health (NIOSH) and AJH would like to thank the National Institutes of Health (NIH) and the Nanomaterial Registry (www.nanomaterialregistry.org/) for financial support.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sayes, C.M., Staats, H. & Hickey, A.J. Scale of Health: Indices of Safety and Efficacy in the Evolving Environment of Large Biological Datasets. Pharm Res 31, 2256–2265 (2014). https://doi.org/10.1007/s11095-014-1415-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-014-1415-2