Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

External triggering and triggered targeting strategies for drug delivery

Nature Reviews Materials volume 2, Article number: 17020 (2017) Cite this article

Subjects

Abstract

Drug delivery systems that are externally triggered to release drugs and/or target tissues hold considerable promise for improving the treatment of many diseases by minimizing nonspecific toxicity and enhancing the efficacy of therapy. These drug delivery systems are constructed from materials that are sensitive to a wide range of external stimuli, including light, ultrasound, electrical and magnetic fields, and specific molecules. The responsiveness conferred by these materials allows the release of therapeutics to be triggered on demand and remotely by a physician or patient. In this Review, we describe the rationales for such systems and the types of stimuli that can be deployed, and provide an outlook for the field.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Drug delivery systems.
Figure 2: Light-triggered systems.
Figure 3: Actuation mechanisms for magnetically triggered systems.
Figure 4: An ultrasound-triggered drug delivery system.
Figure 5: Microchip-based drug delivery device.
Figure 6: A pharmacologically triggered system.

Similar content being viewed by others

References

  1. Lu, Y., Aimetti, A. A., Langer, R. & Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 2, 16075 (2016).

    Article  CAS  Google Scholar 

  2. Maeda, H. Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv. Drug Deliv.Rev. 91, 3–6 (2015).

    Article  CAS  Google Scholar 

  3. Fang, J., Nakamura, H. & Maeda, H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev. 63, 136–151 (2011).

    Article  CAS  Google Scholar 

  4. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  CAS  Google Scholar 

  5. Zhang, P. et al. Near infrared-guided smart nanocarriers for microRNA-controlled release of doxorubicin/siRNA with intracellular ATP as fuel. ACS Nano 10, 3637–3647 (2016).

    Article  CAS  Google Scholar 

  6. Liu, Q., Wang, W., Zhan, C., Yang, T. & Kohane, D. S. Enhanced precision of nanoparticle phototargeting in vivo at a safe irradiance. Nano Lett. 16, 4516–4520 (2016).

    Article  CAS  Google Scholar 

  7. Kohane, D. S. Microparticles and nanoparticles for drug delivery. Biotechnol. Bioeng. 96, 203–209 (2007).

    Article  CAS  Google Scholar 

  8. Dvir, T., Banghart, M. R., Timko, B. P., Langer, R. & Kohane, D. S. Photo-targeted nanoparticles. Nano Lett. 10, 250–254 (2010). A nanoparticulate system that targets cells selectively on illumination.

    Article  CAS  Google Scholar 

  9. Timko, B. P. et al. Near-infrared-actuated devices for remotely controlled drug delivery. Proc. Natl Acad. Sci. USA 111, 1349–1354 (2014).

    Article  CAS  Google Scholar 

  10. Kost, J., Wolfrum, J. & Langer, R. Magnetically enhanced insulin release in diabetic rats. J. Biomed. Mater. Res. 21, 1367–1373 (1987).

    Article  CAS  Google Scholar 

  11. Tong, R. & Kohane, D. S. Shedding light on nanomedicine. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 4, 638–662 (2012).

    Article  CAS  Google Scholar 

  12. Petersen, R. C. et al. American National Standard for Safe Use of Optical Fiber Communication Systems Utilizing Laser Diodes LED Sources, ANSI Z136.2-2012 (Laser Institute of America, 2012).

    Google Scholar 

  13. Klan, P. et al. Photoremovable protecting groups in chemistry and biology: reaction mechanisms and efficacy. Chem. Rev. 113, 119–191 (2013).

    Article  CAS  Google Scholar 

  14. Olejniczak, J., Carling, C.-J. & Almutairi, A. Photocontrolled release using one-photon absorption of visible or NIR light. J. Control. Release 219, 18–30 (2015).

    Article  CAS  Google Scholar 

  15. Gohy, J. F. & Zhao, Y. Photo-responsive block copolymer micelles: design and behavior. Chem. Soc. Rev. 42, 7117–7129 (2013).

    Article  CAS  Google Scholar 

  16. Jiang, J., Tong, X., Morris, D. & Zhao, Y. Toward photocontrolled release using light-dissociable block copolymer micelles. Macromolecules 39, 4633–4640 (2006).

    Article  CAS  Google Scholar 

  17. Lin, Q. et al. Highly discriminating photorelease of anticancer drugs based on hypoxia activatable phototrigger conjugated chitosan nanoparticles. Adv. Mater. 25, 1981–1986 (2013).

    Article  CAS  Google Scholar 

  18. Lin, Q. et al. Anticancer drug release from a mesoporous silica based nanophotocage regulated by either a one- or two-photon process. J. Am. Chem. Soc. 132, 10645–10647 (2010).

    Article  CAS  Google Scholar 

  19. Tong, R., Chiang, H. H. & Kohane, D. S. Photoswitchable nanoparticles for in vivo cancer chemotherapy. Proc. Natl Acad. Sci. USA 110, 19048–19053 (2013).

    Article  CAS  Google Scholar 

  20. Youssef, P. N., Sheibani, N. & Albert, D. M. Retinal light toxicity. Eye 25, 1–14 (2011).

    Article  CAS  Google Scholar 

  21. Weissleder, R. A clearer vision for in vivo imaging. Nat. Biotechnol. 19, 316–317 (2001).

    Article  CAS  Google Scholar 

  22. Rwei, A. Y., Wang, W. & Kohane, D. S. Photoresponsive nanoparticles for drug delivery. Nano Today 10, 451–467 (2015).

    Article  CAS  Google Scholar 

  23. Williams, R. M., Zipfel, W. R. & Webb, W. W. Interpreting second-harmonic generation images of collagen I fibrils. Biophys. J. 88, 1377–1386 (2005).

    Article  CAS  Google Scholar 

  24. Chen, G., Qiu, H., Prasad, P. N. & Chen, X. Upconversion nanoparticles: design, nanochemistry, and applications in theranostics. Chem. Rev. 114, 5161–5214 (2014).

    Article  CAS  Google Scholar 

  25. Wang, W. et al. Efficient triplet–triplet annihilation-based upconversion for nanoparticle phototargeting. Nano Lett. 15, 6332–6338 (2015).

    Article  CAS  Google Scholar 

  26. Vasdekis, A. E., Scott, E. A., O'Neil, C. P., Psaltis, D. & Hubbell, J. A. Precision intracellular delivery based on optofluidic polymersome rupture. ACS Nano 6, 7850–7857 (2012).

    Article  CAS  Google Scholar 

  27. Rwei, A. Y. et al. Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes. Proc. Natl Acad. Sci. USA 112, 15719–15724 (2015).

    CAS  Google Scholar 

  28. Jain, P. K., Lee, K. S., El-Sayed, I. H. & El-Sayed, M. A. Calculated absorption and scattering properties of gold nanoparticles of different size, shape, and composition: applications in biological imaging and biomedicine. J. Phys. Chem. B 110, 7238–7248 (2006).

    Article  CAS  Google Scholar 

  29. Link, S. & El-Sayed, M. A. Shape and size dependence of radiative, non-radiative and photothermal properties of gold nanocrystals. Int. Rev. Phys. Chem. 19, 409–453 (2000).

    Article  CAS  Google Scholar 

  30. Timko, B. P., Dvir, T. & Kohane, D. S. Remotely triggerable drug delivery systems. Adv. Mater. 22, 4925–4943 (2010).

    Article  CAS  Google Scholar 

  31. Huschka, R. et al. Gene silencing by gold nanoshell-mediated delivery and laser-triggered release of antisense oligonucleotide and siRNA. ACS Nano 6, 7681–7691 (2012).

    Article  CAS  Google Scholar 

  32. Wang, Q., Zhao, Y., Yang, Y., Xu, H. & Yang, X. Thermosensitive phase behavior and drug release of in situ gelable poly(N-isopropylacrylamide-co-acrylamide) microgels. Colloid Polym. Sci. 285, 515–521 (2007).

    Article  CAS  Google Scholar 

  33. Yavuz, M. S. et al. Gold nanocages covered by smart polymers for controlled release with near-infrared light. Nat. Mater. 8, 935–939 (2009). A study of drug release from gold nanocages triggered by near-infrared light.

    Article  CAS  Google Scholar 

  34. Leung, S. J. & Romanowski, M. NIR-activated content release from plasmon resonant liposomes for probing single-cell responses. ACS Nano 6, 9383–9391 (2012).

    Article  CAS  Google Scholar 

  35. Zhan, C. Y. et al. Phototriggered local anesthesia. Nano Lett. 16, 177–181 (2016).

    Article  CAS  Google Scholar 

  36. Jain, P. K., Qian, W. & El-Sayed, M. A. Ultrafast cooling of photoexcited electrons in gold nanoparticle–thiolated DNA conjugates involves the dissociation of the gold–thiol bond. J. Am. Chem. Soc. 128, 2426–2433 (2006).

    Article  CAS  Google Scholar 

  37. Huang, X. et al. Modular plasmonic nanocarriers for efficient and targeted delivery of cancer-therapeutic siRNA. Nano Lett. 14, 2046–2051 (2014).

    Article  CAS  Google Scholar 

  38. Wu, G. et al. Remotely triggered liposome release by near-infrared light absorption via hollow gold nanoshells. J. Am. Chem. Soc. 130, 8175–8177 (2008).

    Article  CAS  Google Scholar 

  39. Saito, K., Tsubouchi, K., Takahashi, M. & Ito, K. Practical evaluations on heating characteristics of thin microwave antenna for intracavitary thermal therapy. Proc. IEEE Eng. Med. Biol. Soc. 2755–2758 (2010).

  40. Peng, H. et al. A multifunctional β-CD-modified Fe3O4@ZnO:Er3+,Yb3+ nanocarrier for antitumor drug delivery and microwave-triggered drug release. Mater. Sci. Eng. C 46, 253–263 (2015).

    Article  CAS  Google Scholar 

  41. Kotagiri, N., Sudlow, G. P., Akers, W. J. & Achilefu, S. Breaking the depth dependency of phototherapy with Cerenkov radiation and low radiance responsive nanophotosensitizers. Nature Nanotechnol. 10, 370–379 (2015). Photosensitization triggered by Cherenkov radiation resulting in tumour killing.

    Article  CAS  Google Scholar 

  42. Needham, D., Park, J. Y., Wright, A. M. & Tong, J. Materials characterization of the low temperature sensitive liposome (LTSL): effects of the lipid composition (lysolipid and DSPE–PEG2000) on the thermal transition and release of doxorubicin. Faraday Discuss. 161, 515–534; discussion 161, 563–589 (2013).

    Article  CAS  Google Scholar 

  43. Rwei, A. Y., Zhan, C., Wang, B. & Kohane, D. S. Multiply repeatable and adjustable on-demand phototriggered local anesthesia. J. Control. Release 251, 68–74 (2017).

    Article  CAS  Google Scholar 

  44. Rudolf, H., Silvio, D., Robert, M. & Matthias, Z. Magnetic particle hyperthermia: nanoparticle magnetism and materials development for cancer therapy. J. Phys. Condens. Matter 18, S2919–S2934 (2006).

    Article  CAS  Google Scholar 

  45. Golovin, Y. I. et al. Towards nanomedicines of the future: remote magneto-mechanical actuation of nanomedicines by alternating magnetic fields. J. Control. Release 219, 43–60 (2015).

    Article  CAS  Google Scholar 

  46. Advisory Group on Non-ionising Radiation. Health effects from radiofrequency electromagnetic fields http://webarchive.nationalarchives.gov.uk/20140714084352/http://www.hpa.org.uk/Publications/Radiation/DocumentsOfTheHPA/RCE20HealthEffectsfromRFElectromagneticFields/ (Health Protection Agency, 2012).

  47. Cole, A. J., Yang, V. C. & David, A. E. Cancer theranostics: the rise of targeted magnetic nanoparticles. Trends Biotechnol. 29, 323–332 (2011).

    Article  CAS  Google Scholar 

  48. Rosensweig, R. E. Heating magnetic fluid with alternating magnetic field. J. Magn. Magn. Mater. 252, 370–374 (2002).

    Article  CAS  Google Scholar 

  49. Katagiri, K. et al. Magnetoresponsive on-demand release of hybrid liposomes formed from Fe3O4 nanoparticles and thermosensitive block copolymers. Small 7, 1683–1689 (2011).

    Article  CAS  Google Scholar 

  50. Ruiz-Hernández, E., Baeza, A. & Vallet-Regí, M. Smart drug delivery through DNA/magnetic nanoparticle gates. ACS Nano 5, 1259–1266 (2011).

    Article  CAS  Google Scholar 

  51. Hoare, T. et al. Magnetically-triggered composite membrane for on-demand drug delivery. Nano Lett. 9, 3651–3657 (2009). Drug release from a composite membrane triggered by an oscillating magnetic field.

    Article  CAS  Google Scholar 

  52. Hoare, T. et al. Magnetically-triggered nanocomposite membranes: a versatile platform for triggered drug release. Nano Lett. 11, 1395–1400 (2011).

    Article  CAS  Google Scholar 

  53. Campbell, S., Maitland, D. & Hoare, T. Enhanced pulsatile drug release from injectable magnetic hydrogels with embedded thermosensitive microgels. ACS Macro Lett. 4, 312–316 (2015).

    Article  CAS  Google Scholar 

  54. Derfus, A. M. et al. Remotely triggered release from magnetic nanoparticles. Adv. Mater. 19, 3932–3936 (2007).

    Article  CAS  Google Scholar 

  55. Mahmoudi, M., Sant, S., Wang, B., Laurent, S. & Sen, T. Superparamagnetic iron oxide nanoparticles (SPIONs): development, surface modification and applications in chemotherapy. Adv. Drug Deliv. Rev. 63, 24–46 (2011).

    Article  CAS  Google Scholar 

  56. Salunkhe, A. B., Khot, V. M. & Pawar, S. H. Magnetic hyperthermia with magnetic nanoparticles: a status review. Curr. Top. Med. Chem. 14, 572–594 (2014).

    Article  CAS  Google Scholar 

  57. Laurent, S. et al. Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev. 108, 2064–2110 (2008).

    Article  CAS  Google Scholar 

  58. Peng, X. H. et al. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy. Int. J. Nanomed. 3, 311–321 (2008).

    CAS  Google Scholar 

  59. Schleich, N., Danhier, F. & Preat, V. Iron oxide-loaded nanotheranostics: major obstacles to in vivo studies and clinical translation. J. Control. Release 198, 35–54 (2015).

    Article  CAS  Google Scholar 

  60. Peiris, P. M. et al. Enhanced delivery of chemotherapy to tumors using a multicomponent nanochain with radio-frequency-tunable drug release. ACS Nano 6, 4157–4168 (2012). Nanochain-controlled drug release, triggered by a radio frequency field.

    Article  CAS  Google Scholar 

  61. Bertoglio, P., Jacobo, S. E. & Daraio, M. E. Preparation and characterization of PVA films with magnetic nanoparticles: the effect of particle loading on drug release behavior. J. Appl. Polym. Sci. 115, 1859–1865 (2010).

    Article  CAS  Google Scholar 

  62. Qin, J. et al. Injectable superparamagnetic ferrogels for controlled release of hydrophobic drugs. Adv. Mater. 21, 1354–1357 (2009).

    Article  CAS  Google Scholar 

  63. Thevenot, J., Oliveira, H., Sandre, O. & Lecommandoux, S. Magnetic responsive polymer composite materials. Chem. Soc. Rev. 42, 7099–7116 (2013).

    Article  CAS  Google Scholar 

  64. Shapiro, B. et al. Open challenges in magnetic drug targeting. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 7, 446–457 (2015).

    Article  CAS  Google Scholar 

  65. Schleich, N. et al. Comparison of active, passive and magnetic targeting to tumors of multifunctional paclitaxel/SPIO-loaded nanoparticles for tumor imaging and therapy. J. Control. Release 194, 82–91 (2014).

    Article  CAS  Google Scholar 

  66. Nelson, B. J., Kaliakatsos, I. K. & Abbott, J. J. Microrobots for minimally invasive medicine. Annu. Rev. Biomed. Eng. 12, 55–85 (2010).

    Article  CAS  Google Scholar 

  67. Kost, J., Leong, K. & Langer, R. Ultrasound-enhanced polymer degradation and release of incorporated substances. Proc. Natl Acad. Sci. USA 86, 7663–7666 (1989).

    Article  CAS  Google Scholar 

  68. Ferrara, K. W. Driving delivery vehicles with ultrasound. Adv. Drug Deliv. Rev. 60, 1097–1102 (2008).

    Article  CAS  Google Scholar 

  69. Rosenthal, I., Sostaric, J. Z. & Riesz, P. Sonodynamic therapy — a review of the synergistic effects of drugs and ultrasound. Ultrason. Sonochem. 11, 349–363 (2004).

    CAS  Google Scholar 

  70. ter Haar, G. Therapeutic applications of ultrasound. Prog. Biophys. Mol. Biol. 93, 111–129 (2007).

    Article  Google Scholar 

  71. Schroeder, A. et al. Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility. Langmuir 23, 4019–4025 (2007).

    Article  CAS  Google Scholar 

  72. Ahmadi, F., McLoughlin, I. V., Chauhan, S. & ter-Haar, G. Bio-effects and safety of low-intensity, low-frequency ultrasonic exposure. Prog. Biophys. Mol. Biol. 108, 119–138 (2012).

    Article  Google Scholar 

  73. Epstein-Barash, H. et al. A microcomposite hydrogel for repeated on-demand ultrasound-triggered drug delivery. Biomaterials 31, 5208–5217 (2010).

    Article  CAS  Google Scholar 

  74. Sirsi, S. R. & Borden, M. A. Microbubble compositions, properties and biomedical applications. Bubble Sci. Eng. Technol. 1, 3–17 (2009).

    Article  CAS  Google Scholar 

  75. Hernot, S. & Klibanov, A. L. Microbubbles in ultrasound-triggered drug and gene delivery. Adv. Drug Deliv. Rev. 60, 1153–1166 (2008).

    Article  CAS  Google Scholar 

  76. Chen, H., Kreider, W., Brayman, A. A., Bailey, M. R. & Matula, T. J. Blood vessel deformations on microsecond time scales by ultrasonic cavitation. Phys. Rev. Lett. 106, 034301 (2011).

    Article  CAS  Google Scholar 

  77. Lentacker, I., De Smedt, S. C. & Sanders, N. N. Drug loaded microbubble design for ultrasound triggered delivery. Soft Matter 5, 2161–2170 (2009).

    Article  CAS  Google Scholar 

  78. Sirsi, S. R. & Borden, M. A. State-of-the-art materials for ultrasound-triggered drug delivery. Adv. Drug Deliv.Rev. 72, 3–14 (2014).

    Article  CAS  Google Scholar 

  79. De Cock, I. et al. Ultrasound and microbubble mediated drug delivery: acoustic pressure as determinant for uptake via membrane pores or endocytosis. J. Control. Release 197, 20–28 (2015).

    Article  CAS  Google Scholar 

  80. Yan, F. et al. Paclitaxel–liposome–microbubble complexes as ultrasound-triggered therapeutic drug delivery carriers. J. Control. Release 166, 246–255 (2013). Ultrasound-triggered drug delivery from liposome–microbubble complexes.

    Article  CAS  Google Scholar 

  81. Brudno, Y. & Mooney, D. J. On-demand drug delivery from local depots. J. Control. Release 219, 8–17 (2015). A review of triggered local delivery strategies.

    Article  CAS  Google Scholar 

  82. Krasovitski, B., Frenkel, V., Shoham, S. & Kimmel, E. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proc. Natl Acad. Sci. USA 108, 3258–3263 (2011).

    Article  Google Scholar 

  83. Oerlemans, C., Deckers, R., Storm, G., Hennink, W. E. & Nijsen, J. F. W. Evidence for a new mechanism behind HIFU-triggered release from liposomes. J. Control. Release 168, 327–333 (2013).

    Article  CAS  Google Scholar 

  84. Dromi, S. et al. Pulsed-high intensity focused ultrasound and low temperature-sensitive liposomes for enhanced targeted drug delivery and antitumor effect. Clin. Cancer Res. 13, 2722–2727 (2007).

    Article  CAS  Google Scholar 

  85. Ranjan, A. et al. Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model. J. Control. Release 158, 487–494 (2012).

    Article  CAS  Google Scholar 

  86. Rapoport, N. Phase-shift, stimuli-responsive perfluorocarbon nanodroplets for drug delivery to cancer. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 4, 492–510 (2012).

    Article  CAS  Google Scholar 

  87. Sheeran, P. S. & Dayton, P. A. Phase-change contrast agents for imaging and therapy. Curr. Pharm. Design 18, 2152–2165 (2012).

    Article  CAS  Google Scholar 

  88. Wang, C.-H. et al. Aptamer-conjugated and drug-loaded acoustic droplets for ultrasound theranosis. Biomaterials 33, 1939–1947 (2012).

    Article  CAS  Google Scholar 

  89. Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013).

    Article  CAS  Google Scholar 

  90. Negishi, Y. et al. Systemic delivery systems of angiogenic gene by novel bubble liposomes containing cationic lipid and ultrasound exposure. Mol. Pharm. 9, 1834–1840 (2012).

    Article  CAS  Google Scholar 

  91. Riviere, J. E. & Heit, M. C. Electrically-assisted transdermal drug delivery. Pharm. Res. 14, 687–697 (1997).

    Article  CAS  Google Scholar 

  92. Murdan, S. Electro-responsive drug delivery from hydrogels. J. Control. Release 92, 1–17 (2003).

    Article  CAS  Google Scholar 

  93. Kagatani, S. et al. Electroresponsive pulsatile depot delivery of insulin from poly(dimethylaminopropylacrylamide) gel in rats. J. Pharm. Sci. 86, 1273–1277 (1997).

    Article  CAS  Google Scholar 

  94. George, P. M. et al. Electrically controlled drug delivery from biotin-doped conductive polypyrrole. Adv. Mater. 18, 577–581 (2006).

    Article  CAS  Google Scholar 

  95. Tang, Z., Wang, Y., Podsiadlo, P. & Kotov, N. A. Biomedical applications of layer-by-layer assembly: from biomimetics to tissue engineering. Adv. Mater. 18, 3203–3224 (2006).

    Article  Google Scholar 

  96. Zhao, Y., Tavares, A. C. & Gauthier, M. A. Nano-engineered electro-responsive drug delivery systems. J. Mater. Chem. B 4, 3019–3030 (2016).

    Article  CAS  Google Scholar 

  97. Ge, J., Neofytou, E., Cahill, T. J., Beygui, R. E. & Zare, R. N. Drug release from electric-field-responsive nanoparticles. ACS Nano 6, 227–233 (2012).

    Article  CAS  Google Scholar 

  98. Eltorai, A. E. M., Fox, H., McGurrin, E. & Guang, S. Microchips in medicine: current and future applications. Biomed. Res. Int. 7, 1743472 (2016).

    Google Scholar 

  99. Sutradhar, K. B. & Sumi, C. D. Implantable microchip: the futuristic controlled drug delivery system. Drug Delivery 23, 1–11 (2016).

    Article  CAS  Google Scholar 

  100. Santini, J. T., Cima, M. J. & Langer, R. A controlled-release microchip. Nature 397, 335–338 (1999).

    Article  CAS  Google Scholar 

  101. Farra, R. et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci. Transl. Med. 4, 122ra121 (2012). Programmable drug release from a microchip, triggered by electric pulses.

    Article  CAS  Google Scholar 

  102. Pillay, V. et al. A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications. J. Biomed. Mater. Res. A 102, 2039–2054 (2014).

    Article  CAS  Google Scholar 

  103. Murakami, Y. & Maeda, M. DNA-responsive hydrogels that can shrink or swell. Biomacromolecules 6, 2927–2929 (2005).

    Article  CAS  Google Scholar 

  104. Ma, Z. & Taylor, J.-S. Nucleic acid-triggered catalytic drug release. Proc. Natl Acad. Sci. USA 97, 11159–11163 (2000).

    Article  CAS  Google Scholar 

  105. Battig, M. R., Soontornworajit, B. & Wang, Y. Programmable release of multiple protein drugs from aptamer-functionalized hydrogels via nucleic acid hybridization. J. Am. Chem. Soc. 134, 12410–12413 (2012).

    Article  CAS  Google Scholar 

  106. Ehrbar, M., Schoenmakers, R., Christen, E. H., Fussenegger, M. & Weber, W. Drug-sensing hydrogels for the inducible release of biopharmaceuticals. Nat. Mater. 7, 800–804 (2008). A pioneering study on pharmacologically triggered drug release from hydrogels.

    Article  CAS  Google Scholar 

  107. Gübeli, R. J. et al. Pharmacologically triggered hydrogel for scheduling hepatitis B vaccine administration. Sci. Rep. 3, 2610 (2013).

    Article  Google Scholar 

  108. Versteegen, R. M., Rossin, R., ten Hoeve, W., Janssen, H. M. & Robillard, M. S. Click to release: instantaneous doxorubicin elimination upon tetrazine ligation. Angew. Chem. Int. Ed. 52, 14112–14116 (2013).

    Article  CAS  Google Scholar 

  109. Kämpf, M. M. et al. Gene therapy technology-based biomaterial for the trigger-inducible release of biopharmaceuticals in mice. Adv. Funct. Mater. 20, 2534–2538 (2010).

    Article  CAS  Google Scholar 

  110. Brudno, Y. et al. In vivo targeting through click chemistry. ChemMedChem 10, 617–620 (2015).

    Article  CAS  Google Scholar 

  111. Fang, W., Yang, J., Gong, J. & Zheng, N. Photo- and pH-triggered release of anticancer drugs from mesoporous silica-coated Pd@Ag nanoparticles. Adv. Funct. Mater. 22, 842–848 (2012).

    Article  CAS  Google Scholar 

  112. Han, D., Tong, X. & Zhao, Y. Block copolymer micelles with a dual-stimuli-responsive core for fast or slow degradation. Langmuir 28, 2327–2331 (2012).

    Article  CAS  Google Scholar 

  113. Nahire, R. et al. Ultrasound enhanced matrix metalloproteinase-9 triggered release of contents from echogenic liposomes. Mol. Pharm. 9, 2554–2564 (2012).

    Article  CAS  Google Scholar 

  114. Cheng, R., Meng, F., Deng, C., Klok, H.-A. & Zhong, Z. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 34, 3647–3657 (2013).

    Article  CAS  Google Scholar 

  115. Torchilin, V. P. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat. Rev. Drug Discov. 13, 813–827 (2014). A recent review of multifunctional pharmaceutical nanoparticles, discussing properties such as longevity, targetability, intracellular penetration, imaging and stimulus sensitivity.

    Article  CAS  Google Scholar 

  116. Guragain, S., Bastakoti, B. P., Malgras, V., Nakashima, K. & Yamauchi, Y. Multi-stimuli-responsive polymeric materials. Chem. Eur. J. 21, 13164–13174 (2015).

    Article  CAS  Google Scholar 

  117. Pacardo, D. B., Ligler, F. S. & Gu, Z. Programmable nanomedicine: synergistic and sequential drug delivery systems. Nanoscale 7, 3381–3391 (2015).

    Article  CAS  Google Scholar 

  118. Jiang, T. et al. Furin-mediated sequential delivery of anticancer cytokine and small-molecule drug shuttled by graphene. Adv. Mater. 27, 1021–1028 (2015).

    Article  CAS  Google Scholar 

  119. Liu, Q., Zhan, C. & Kohane, D. S. Phototriggered drug delivery using inorganic nanomaterials. Bioconjug. Chem. 28, 98–104 (2017).

    Article  CAS  Google Scholar 

  120. Kohane, D. S. & Langer, R. Biocompatibility and drug delivery systems. Chem. Sci. 1, 441–446 (2010). A discussion of the biocompatibility of drug-delivery systems.

    Article  CAS  Google Scholar 

  121. You, S. & Li, W. Administration of nanodrugs in proper menstrual stage for maximal drug retention in breast cancer. Med. Hypotheses 71, 141–147 (2008).

    Article  CAS  Google Scholar 

  122. Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).

    Article  CAS  Google Scholar 

  123. Youan, B.-B. C. Chronopharmaceutical drug delivery systems: hurdles, hype or hope? Adv. Drug Deliv. Rev. 62, 898–903 (2010).

    Article  CAS  Google Scholar 

  124. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT00617981 (2014).

  125. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02181075 (2016).

  126. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT00054951 (2005).

  127. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT00041808 (2005).

Download references

Acknowledgements

This work was funded by the US National Institutes of Health (NIH R01 GM 116920).

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Division of Critical Care Medicine, Laboratory for Biomaterials and Drug Delivery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Yanfei Wang & Daniel S. Kohane

Authors
  1. Yanfei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel S. Kohane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel S. Kohane.

Ethics declarations

Competing interests

The authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Kohane, D. External triggering and triggered targeting strategies for drug delivery. Nat Rev Mater 2, 17020 (2017). https://doi.org/10.1038/natrevmats.2017.20

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/natrevmats.2017.20

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research