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.

  • Opinion
  • Published:

A holistic approach to targeting disease with polymeric nanoparticles

An Erratum to this article was published on 30 April 2015

This article has been updated

Abstract

The primary goal of nanomedicine is to improve clinical outcomes. To this end, targeted nanoparticles are engineered to reduce non-productive distribution while improving diagnostic and therapeutic efficacy. Paradoxically, as this field has matured, the notion of targeting has been minimized to the concept of increasing the affinity of a nanoparticle for its target. This Opinion article outlines a holistic view of nanoparticle targeting, in which the route of administration, molecular characteristics and temporal control of the nanoparticles are potential design variables that must be considered simultaneously. This comprehensive vision for nanoparticle targeting will facilitate the integration of nanomedicines into clinical practice.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: A holistic perspective of nanoparticle targeting.
Figure 2: Temporal targeting of therapeutic windows.

Similar content being viewed by others

Change history

  • 30 April 2015

    In Box 1 on page 241, BIND-014 was described as being loaded with doxorubicin, when it is in fact loaded with docetaxel, as described in Table 1 on page 242. This has been corrected in the online version.

References

  1. Liu, X. M. et al. Syntheses of click PEG–dexamethasone conjugates for the treatment of rheumatoid arthritis. Biomacromolecules 11, 2621–2628 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kamaly, N., Xiao, Z., Valencia, P. M., Radovic-Moreno, A. F. & Farokhzad, O. C. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem. Soc. Rev. 41, 2971–3010 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shi, J., Xiao, Z., Kamaly, N. & Farokhzad, O. C. Self-assembled targeted nanoparticles: evolution of technologies and bench to bedside translation. Accounts Chem. Res. 44, 1123–1134 (2011).

    Article  CAS  Google Scholar 

  5. Bertrand, N., Wu, J., Xu, X., Kamaly, N. & Farokhzad, O. C. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Deliv. Rev. 66, 2–25 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Lammers, T., Kiessling, F., Hennink, W. E. & Storm, G. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J. Control. Release 161, 175–187 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Iyer, A. K., Khaled, G., Fang, J. & Maeda, H. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov. Today 11, 812–818 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Hrkach, J. et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl Med. 4, 128ra39 (2012).

    Article  PubMed  Google Scholar 

  9. Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Merki, E. et al. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation 118, 743–753 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Cheng, C. J. et al. MicroRNA silencing for cancer therapy targeted to the tumor microenvironment. Nature http://dx.doi.org/10.1038/nature13905 (2014).

  12. Salvati, A. et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nature Nanotechnol. 8, 137–143 (2013).

    Article  CAS  Google Scholar 

  13. Kunjachan, S. et al. Passive versus active tumor targeting using RGD- and NGR-modified polymeric nanomedicines. Nano Lett. 14, 972–981 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cheng, Z., Al Zaki, A., Hui, J. Z., Muzykantov, V. R. & Tsourkas, A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338, 903–910 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Crielaard, B. J., Lammers, T., Schiffelers, R. M. & Storm, G. Drug targeting systems for inflammatory disease: one for all, all for one. J. Control. Release 161, 225–234 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Bertrand, N. & Leroux, J. C. The journey of a drug-carrier in the body: an anatomo-physiological perspective. J. Control. Release 161, 152–163 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Bernal, G. M. et al. Convection-enhanced delivery and in vivo imaging of polymeric nanoparticles for the treatment of malignant glioma. Nanomedicine 10, 149–157 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Desai, P. R. et al. Topical delivery of anti-TNFα siRNA and capsaicin via novel lipid-polymer hybrid nanoparticles efficiently inhibits skin inflammation in vivo. J. Control. Release 170, 51–63 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vij, N. et al. Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis. J. Nanobiotechnol. 8, 22 (2010).

    Article  CAS  Google Scholar 

  20. Weiser, J. R. & Saltzman, W. M. Controlled release for local delivery of drugs: barriers and models. J. Control. Release 190, 664–673 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fleming, A. B. & Saltzman, W. M. Pharmacokinetics of the carmustine implant. Clin. Pharmacokinet. 41, 403–419 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Sawyer, A. J. et al. Convection-enhanced delivery of camptothecin-loaded polymer nanoparticles for treatmeny of intracranial tumors. Drug Deliv. Transl Res. 1, 34–42 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhou, J. et al. Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proc. Natl Acad. Sci. USA 110, 11751–11756 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nance, E. A. et al. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci. Transl Med. 4, 149ra119 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Neeves, K. B., Sawyer, A. J., Foley, C. P., Saltzman, W. M. & Olbricht, W. L. Dilation and degradation of the brain extracellular matrix enhances penetration of infused polymer nanoparticles. Brain Res. 1180, 121–132 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sawyer, A. J., Piepmeier, J. M. & Saltzman, W. M. New methods for direct delivery of chemotherapy for treating brain tumors. Yale J. Biol. Med. 79, 141–152 (2006).

    CAS  PubMed  Google Scholar 

  27. Allard, E., Passirani, C. & Benoit, J. P. Convection-enhanced delivery of nanocarriers for the treatment of brain tumors. Biomaterials 30, 2302–2318 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Lam, M. F., Thomas, M. G. & Lind, C. R. Neurosurgical convection-enhanced delivery of treatments for Parkinson's disease. J. Clin. Neurosci. 18, 1163–1167 (2011).

    Article  PubMed  Google Scholar 

  29. Stiles, D. K. et al. Widespread suppression of huntingtin with convection-enhanced delivery of siRNA. Exp. Neurol. 233, 463–471 (2012)

    Article  CAS  PubMed  Google Scholar 

  30. Wang, Y. C. et al. Sustained intraspinal delivery of neurotrophic factor encapsulated in biodegradable nanoparticles following contusive spinal cord injury. Biomaterials 29, 4546–4553 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Li, H. et al. A PEDF N-terminal peptide protects the retina from ischemic injury when delivered in PLGA nanospheres. Exp. Eye Res. 83, 824–833 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Kaur, I. P. & Kakkar, S. Nanotherapy for posterior eye diseases. J. Control. Release 193, 100–112 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Baroli, B. Penetration of nanoparticles and nanomaterials in the skin: fiction or reality? J. Pharm. Sci. 99, 21–50 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Hadam, J., Aoun, E., Clarke, K. & Wasko, M. C. Managing risks of TNF inhibitors: an update for the internist. Cleve. Clin. J. Med. 81, 115–127 (2014).

    Article  PubMed  Google Scholar 

  35. Moghimi, S. M. & Bonnemain, B. Subcutaneous and intravenous delivery of diagnostic agents to the lymphatic system: applications in lymphoscintigraphy and indirect lymphography. Adv. Drug Deliv. Rev. 37, 295–312 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Irvine, D. J., Swartz, M. A. & Szeto, G. L. Engineering synthetic vaccines using cues from natural immunity. Nature Mater. 12, 978–990 (2013).

    Article  CAS  Google Scholar 

  37. Moghimi, S. M. & Rajabi-Siahboomi, A. R. Advanced colloid-based systems for efficient delivery of drugs and diagnostic agents to the lymphatic tissues. Prog. Biophys. Mol. Biol. 65, 221–249 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Hawley, A. E., Illum, L. & Davis, S. S. Lymph node localisation of biodegradable nanospheres surface modified with poloxamer and poloxamine block co-polymers. FEBS Lett. 400, 319–323 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Kreuter, J., Nefzger, M., Liehl, E., Czok, R. & Voges, R. Distribution and elimination of poly(methyl methacrylate) nanoparticles after subcutaneous administration to rats. J. Pharm. Sci. 72, 1146–1149 (1983).

    Article  CAS  PubMed  Google Scholar 

  40. Toita, R. et al. Biodistribution of 125I-labeled polymeric vaccine carriers after subcutaneous injection. Bioorg. Med. Chem. 21, 5310–5315 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Moghimi, S. M. et al. Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes. FEBS Lett. 344, 25–30 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. DeMuth, P. C. et al. Polymer multilayer tattooing for enhanced DNA vaccination. Nature Mater. 12, 367–376 (2013).

    Article  CAS  Google Scholar 

  43. Reddy, L. H., Sharma, R. K. & Murthy, R. S. Enhanced tumour uptake of doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles in mice bearing Dalton's lymphoma tumour. J. Drug Target. 12, 443–451 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Cartiera, M. S. et al. Partial correction of cystic fibrosis defects with PLGA nanoparticles encapsulating curcumin. Mol. Pharm. 7, 86–93 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gugulothu, D., Kulkarni, A., Patravale, V. & Dandekar, P. pH-sensitive nanoparticles of curcumin–celecoxib combination: evaluating drug synergy in ulcerative colitis model. J. Pharm. Sci. 103, 687–696 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Yoo, M. K. et al. Targeted delivery of chitosan nanoparticles to Peyer's patch using M cell-homing peptide selected by phage display technique. Biomaterials 31, 7738–7747 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Gundogdu, E. & Yurdasiper, A. Drug transport mechanism of oral antidiabetic nanomedicines. Int. J. Endocrinol. Metab. 12, e8984 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Pridgen, E. M. et al. Transepithelial transport of Fc-targeted nanoparticles by the neonatal Fc receptor for oral delivery. Sci. Transl Med. 5, 213ra167 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Mohammad, A. K., Amayreh, L. K., Mazzara, J. M. & Reineke, J. J. Rapid lymph accumulation of polystyrene nanoparticles following pulmonary administration. Pharm. Res. 30, 424–434 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Woodrow, K. A. et al. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA. Nature Mater. 8, 526–533 (2009).

    Article  CAS  Google Scholar 

  51. Steinbach, J. M., Weller, C. E., Booth, C. J. & Saltzman, W. M. Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection. J. Control. Release 162, 102–110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lai, S. K., Wang, Y. Y. & Hanes, J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv. Drug Deliv. Rev. 61, 158–171 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Ensign, L. M. et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci. Transl Med. 4, 138ra79 (2012).

    Article  PubMed  Google Scholar 

  54. Navath, R. S. et al. Injectable PAMAM dendrimer-PEG hydrogels for the treatment of genital infections: formulation and in vitro and in vivo evaluation. Mol. Pharm. 8, 1209–1223 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang, M. et al. Vaginal delivery of paclitaxel via nanoparticles with non-mucoadhesive surfaces suppresses cervical tumor growth. 3, 1044–1052 Adv. Healthc. Mater. (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Blum, J. S. et al. Topical treatment of K-ras and Pten mediated intravaginal cancer with camptothecin-loaded nanoparticles. Drug Deliv. Transl Res. 1, 383–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. das Neves, J. et al. Biodistribution and pharmacokinetics of dapivirine-loaded nanoparticles after vaginal delivery in mice. Pharm. Res. 31, 1834–1845 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Cu, Y., Booth, C. J. & Saltzman, W. M. In vivo distribution of surface-modified PLGA nanoparticles following intravaginal delivery. J. Control. Release 156, 258–264 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lai, S. K. et al. Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc. Natl Acad. Sci. USA 104, 1482–1487 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. das Neves, J., Amiji, M. & Sarmento, B. Mucoadhesive nanosystems for vaginal microbicide development: friend or foe? Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 3, 389–399 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Cu, Y. & Saltzman, W. M. Drug delivery: stealth particles give mucus the slip. Nature Mater. 8, 11–13 (2009).

    Article  CAS  Google Scholar 

  62. Cu, Y. & Saltzman, W. M. Controlled surface modification with poly(ethylene)glycol enhances diffusion of PLGA nanoparticles in human cervical mucus. Mol. Pharm. 6, 173–181 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. GuhaSarkar, S. & Banerjee, R. Intravesical drug delivery: challenges, current status, opportunities and novel strategies. J. Control. Release 148, 147–159 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Barthelmes, J., Perera, G., Hombach, J., Dunnhaupt, S. & Bernkop-Schnurch, A. Development of a mucoadhesive nanoparticulate drug delivery system for a targeted drug release in the bladder. Int. J. Pharm. 416, 339–345 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Martin, D. T. et al. Surface-modified nanoparticles enhance transurothelial penetration and delivery of survivin siRNA in treating bladder cancer. Mol. Cancer Ther. 13, 71–81 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Peppas, N. A. & Huang, Y. Nanoscale technology of mucoadhesive interactions. Adv. Drug Deliv. Rev. 56, 1675–1687 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Wang, Y. Y. et al. Mucoadhesive nanoparticles may disrupt the protective human mucus barrier by altering its microstructure. PLoS ONE 6, e21547 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kirpotin, D. B. et al. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res. 66, 6732–6740 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Pirollo, K. F. & Chang, E. H. Does a targeting ligand influence nanoparticle tumor localization or uptake? Trends Biotechnol. 26, 552–558 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. He, C., Hu, Y., Yin, L., Tang, C. & Yin, C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31, 3657–3666 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Sahay, G., Alakhova, D. Y. & Kabanov, A. V. Endocytosis of nanomedicines. J. Control. Release 145, 182–195 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Loverde, S. M., Klein, M. L. & Discher, D. E. Nanoparticle shape improves delivery: rational coarse grain molecular dynamics (rCG-MD) of taxol in worm-like PEG–PCL micelles. Adv. Mater. 24, 3823–3830 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Perry, J. L., Herlihy, K. P., Napier, M. E. & Desimone, J. M. PRINT: a novel platform toward shape and size specific nanoparticle theranostics. Acc. Chem. Res. 44, 990–998 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Verma, A. & Stellacci, F. Effect of surface properties on nanoparticle-cell interactions. Small 6, 12–21 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Kolhar, P. et al. Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium. Proc. Natl Acad. Sci. USA 110, 10753–10758 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Perry, J. L. et al. PEGylated PRINT nanoparticles: the impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics. Nano Lett. 12, 5304–5310 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Deng, Y. et al. The effect of hyperbranched polyglycerol coatings on drug delivery using degradable polymer nanoparticles. Biomaterials 35, 6595–6602 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Huhn, D. et al. Polymer-coated nanoparticles interacting with proteins and cells: focusing on the sign of the net charge. ACS Nano 7, 3253–3263 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Tenzer, S. et al. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nature Nanotechnol. 8, 772–781 (2013).

    Article  CAS  Google Scholar 

  80. Monopoli, M. P., Aberg, C., Salvati, A. & Dawson, K. A. Biomolecular coronas provide the biological identity of nanosized materials. Nature Nanotechnol. 7, 779–786 (2012).

    Article  CAS  Google Scholar 

  81. Crooke, S. T. et al. Pharmacokinetic properties of several novel oligonucleotide analogs in mice. J. Pharmacol. Exp. Ther. 277, 923–937 (1996).

    CAS  PubMed  Google Scholar 

  82. Wolfrum, C. et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nature Biotech. 25, 1149–1157 (2007).

    Article  CAS  Google Scholar 

  83. Rodriguez, P. L. et al. Minimal “self” peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 339, 971–975 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Panariti, A., Miserocchi, G. & Rivolta, I. The effect of nanoparticle uptake on cellular behavior: disrupting or enabling functions? Nanotechnol. Sci. Appl. 5, 87–100 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang, Y. & Huang, L. A window onto siRNA delivery. Nature Biotech. 31, 611–612 (2013).

    Article  CAS  Google Scholar 

  86. Bumcrot, D., Manoharan, M., Koteliansky, V. & Sah, D. W. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nature Chem. Biol. 2, 711–719 (2006).

    Article  CAS  Google Scholar 

  87. Dominska, M. & Dykxhoorn, D. M. Breaking down the barriers: siRNA delivery and endosome escape. J. Cell Sci. 123, 1183–1189 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Zhou, J., Patel, T. R., Fu, M., Bertram, J. P. & Saltzman, W. M. Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors. Biomaterials 33, 583–591 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Lee, J. S. et al. Gold, poly(β-amino ester) nanoparticles for small interfering RNA delivery. Nano Lett. 9, 2402–2406 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dahlman, J. E. et al. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nature Nanotechnol. 9, 648–655 (2014).

    Article  CAS  Google Scholar 

  91. Cheng, C. J. & Saltzman, W. M. Enhanced siRNA delivery into cells by exploiting the synergy between targeting ligands and cell-penetrating peptides. Biomaterials 32, 6194–6203 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Biswas, S. & Torchilin, V. P. Nanopreparations for organelle-specific delivery in cancer. Adv. Drug Deliv. Rev. 66, 26–41 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Madani, F. et al. Mechanisms of cellular uptake of cell-penetrating peptides. J. Biophys. 2011, 414729 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Schaffer, D. V. & Lauffenburger, D. A. Optimization of cell surface binding enhances efficiency and specificity of molecular conjugate gene delivery. J. Biol. Chem. 273, 28004–28009 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Boucher, Y., Baxter, L. T. & Jain, R. K. Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res. 50, 4478–4484 (1990).

    CAS  PubMed  Google Scholar 

  96. Torosean, S. et al. Nanoparticle uptake in tumors is mediated by the interplay of vascular and collagen density with interstitial pressure. Nanomedicine 9, 151–158 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Boucher, R. C. An overview of the pathogenesis of cystic fibrosis lung disease. Adv. Drug Deliv. Rev. 54, 1359–1371 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Suk, J. S. et al. Rapid transport of muco-inert nanoparticles in cystic fibrosis sputum treated with N-acetyl cysteine. Nanomedicine (Lond.) 6, 365–375 (2011).

    Article  CAS  Google Scholar 

  99. Yang, M. et al. Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angew. Chem. Int. Ed. Engl. 50, 2597–2600 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Prabhakar, U. et al. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res. 73, 2412–2417 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kelkar, S. S. & Reineke, T. M. Theranostics: combining imaging and therapy. Bioconjug. Chem. 22, 1879–1903 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Liu, Y. et al. Multifunctional pH-sensitive polymeric nanoparticles for theranostics evaluated experimentally in cancer. Nanoscale 6, 3231–3242 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Soppimath, K. S., Aminabhavi, T. M., Kulkarni, A. R. & Rudzinski, W. E. Biodegradable polymeric nanoparticles as drug delivery devices. J. Control. Release 70, 1–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Sengupta, S. et al. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature 436, 568–572 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Zhang, X. et al. Anti-tumor efficacy and biodistribution of intravenous polymeric micellar paclitaxel. Anticancer Drugs 8, 696–701 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Rupp, R., Rosenthal, S. L. & Stanberry, L. R. VivaGel (SPL7013 Gel): a candidate dendrimer — microbicide for the prevention of HIV and HSV infection. Int. J. Nanomedicine 2, 561–566 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Eliasof, S. et al. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle. Proc. Natl Acad. Sci. USA 110, 15127–15132 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Pittet, L. et al. Development and preclinical evaluation of SEL-068, a novel targeted synthetic vaccine particle (tSVP) for smoking cessation and relapse prevention that generates high titers of antibodies against nicotine. J. Immunol. 188, 75.11 (2012).

    Google Scholar 

  109. Weiss, G. J. et al. First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. Invest. New Drugs 31, 986–1000 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Werner, M. E. et al. Preclinical evaluation of Genexol-PM, a nanoparticle formulation of paclitaxel, as a novel radiosensitizer for the treatment of non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 86, 463–468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lee, K. S. et al. Multicenter phase II trial of Genexol-PM, a cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res. Treat. 108, 241–250 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Masserini, M. Nanoparticles for brain drug delivery. ISRN Biochem. 2013, 238428 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Foley, C. P., Nishimura, N., Neeves, K. B., Schaffer, C. B. & Olbricht, W. L. Real-time imaging of perivascular transport of nanoparticles during convection-enhanced delivery in the rat cortex. Ann. Biomed. Eng. 40, 292–303 (2012).

    Article  PubMed  Google Scholar 

  114. Papa, S. et al. Selective nanovector mediated treatment of activated proinflammatory microglia/macrophages in spinal cord injury. ACS Nano 7, 9881–9895 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Alqawlaq, S. et al. Preclinical development and ocular biodistribution of gemini-DNA nanoparticles after intravitreal and topical administration: towards non-invasive glaucoma gene therapy. Nanomedicine 8, 1637–1647 (2014).

    Article  CAS  Google Scholar 

  116. Alvarez-Román, R., Naik, A., Kalia, Y. N., Guy, R. H. & Fessi, H. Enhancement of topical delivery from biodegradable nanoparticles. Pharm. Res. 21, 1818–1825 (2004).

    Article  PubMed  Google Scholar 

  117. Jean, M. et al. Chitosan–plasmid nanoparticle formulations for IM and SC delivery of recombinant FGF-2 and PDGF-BB or generation of antibodies. Gene Ther. 16, 1097–1110 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Kohane, D. S. et al. Biodegradable polymeric microspheres and nanospheres for drug delivery in the peritoneum. J. Biomed. Mater. Res. A 77, 351–361 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Kamei, T. et al. Spatial distribution of intraperitoneally administrated paclitaxel nanoparticles solubilized with poly (2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) in peritoneal metastatic nodules. Cancer Sci. 102, 200–205 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Huang, Y.-H. et al. Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice. Cancer Res. 69, 6184–6191 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kourtis, I. C. et al. Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice. PLoS ONE 8, e61646 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Nagahama, R. et al. Nanoparticle-mediated delivery of pioglitazone enhances therapeutic neovascularization in a murine model of hindlimb ischemia. Arterioscler. Thromb. Vasc. Biol. 32, 2427–2434 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. de Titta, A. et al. Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at low dose. Proc. Natl Acad. Sci. USA 110, 19902–19907 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Rothenfluh, D. A., Bermudez, H., O'Neil, C. P. & Hubbell, J. A. Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nature Mater. 7, 248–254 (2008).

    Article  CAS  Google Scholar 

  125. Roa, W. H. et al. Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model. J. Control. Release 150, 49–55 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Luo, Y. et al. An inhalable β2-adrenoceptor ligand-directed guanidinylated chitosan carrier for targeted delivery of siRNA to lung. J. Control. Release 162, 28–36 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Mott, B., Thamake, S., Vishwanatha, J. & Jones, H. P. Intranasal delivery of nanoparticle-based vaccine increases protection against S. pneumoniae. J. Nanopart. Res. 15, 1646 (2013).

    Article  CAS  Google Scholar 

  128. Malhotra, M., Tomaro-Duchesneau, C., Saha, S. & Prakash, S. Intranasal delivery of chitosan–siRNA nanoparticle formulation to the brain. Methods Mol. Biol. 1141, 233–247 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Ulery, B. D. et al. Design of a protective single-dose intranasal nanoparticle-based vaccine platform for respiratory infectious diseases. PLoS ONE 6, e17642 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Saffran, M. et al. A new approach to the oral administration of insulin and other peptide drugs. Science 233, 1081–1084 (1986).

    Article  CAS  PubMed  Google Scholar 

  131. Yun, Y., Cho, Y. W. & Park, K. Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv. Drug Deliv. Rev. 65, 822–832 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. des Rieux, A. et al. Targeted nanoparticles with novel non-peptidic ligands for oral delivery. Adv. Drug Deliv. Rev. 65, 833–844 (2013).

    Article  CAS  PubMed  Google Scholar 

  133. Mane, V. & Muro, S. Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice. Int. J. Nanomed. 7, 4223–4237 (2012).

    CAS  Google Scholar 

  134. Jin, Y. et al. Goblet cell-targeting nanoparticles for oral insulin delivery and the influence of mucus on insulin transport. Biomaterials 33, 1573–1582 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

C.J.C. is the recipient of a Ruth L. Kirschstein Postdoctoral Fellowship from the National Cancer Institute (NCI) and the US National Institutes of Health (NIH; F32 CA174247). G.T.T. is supported by a training grant from the US National Institute of Allergy and Infectious Diseases (NIAID) and NIH (T32 AI089704). The authors' original work on polymeric nanoparticles for drug delivery is supported by the NIH (grants AI112443, EB00487, CA149128 and AI106992).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W. Mark Saltzman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, C., Tietjen, G., Saucier-Sawyer, J. et al. A holistic approach to targeting disease with polymeric nanoparticles. Nat Rev Drug Discov 14, 239–247 (2015). https://doi.org/10.1038/nrd4503

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd4503

This article is cited by

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