Is targeting your target?

Warren Chan’s group published in June a perspective in Nature Reviews Materials entitled “Analysis of nanoparticle delivery to tumours” (Wilhelm et al). A key finding of their analysis of the literature is the absence of increase in the (very small) amount of nanoparticles delivered to tumours in the past 10 years. In a welcome departure from the usually overly diplomatic and confused style that is the trademark of most scientific writing, Wilhelm et al write the following:

 “These advantages [of nanoparticles] have been dampened by the lack of translation to patient care, despite the large investment (more than $1 billion in North America in the past 10 years) and success in imaging and treating tumours in mouse models. As a result, nanomedicine has acquired a reputation of being “hype” that cannot deliver and has not transformed patient care as it promised 15 years ago”


“We must admit that our current approach is broken, and that is why we have not observed significant clinical translation of cancer nanomedicines. Many academic studies focused on the potential of nanoparticles for in vivo applications and showed that nanoparticles may be delivered to tumours by the EPR effect. However, publishing ‘proof of concept’ studies will only lead to curing mice and will unlikely translate to cancer care, irrespective of the number of nanoparticle design permutations used for cancer targeting studies.”

Recognising the magnitude of the challenge, Wilhelm et al propose a thirty year strategy for nanomedicine.

Not surprisingly the publication sparked a debate; see for example Derek Lowe’s blog “Nanoparticles Mix It Up With Reality” and the comments therein, and the article by Michael Torrice for Chemical and Engineering News “Does nanomedicine have a delivery problem?” which features a number of quotes by various nanomedicine players, some of whom contesting Wilhelm et al’s findings, or their relevance to the development of nanomedicine. The debate has also continued in the scientific literature with a comment by McNeil “Evaluation of nanomedicines: stick to the basics” and a response by Chan.

Another comment by Lammers et al has been published 10 days ago “Cancer Nanomedicine: Is targeting our target?”. The implicit answer of the authors is no, targeting is not our target and therefore the absence of progress noted by Wilhelm et al matters little. Lammers et al’s argument is first that the percentage of the injected dose reaching the tumour is not a good indicator of the potential of a therapy, and second, that nanomedicine has in fact had some successes even without targeting. To illustrate this latter point, their first example is Doxil, a liposomal formulation of the anti-cancer drug Doxurubicin.

It is rather unconvincing that Lammers et al would use Doxil as an indication of the success of nanomedicine given that it was developed in the 80s and 90s, i.e. one or two decades before the “nanomedicine” word had been coined and Clinton had announced the $500M National Nanotechnology Initiative (January 2000). A bibliography search for the word “nanomedicine” suggests that it started to be used in the year 2000, with this MIT Technology Review being one of the very first examples:

Nanomedicine Nears the Clinic

Minuscule “smart bombs” that find cancer cells, kill them with the help of lasers and report the kills. Sound crazy? Guess again. That treatment scenario may be less than a decade away.

by David Voss
January 1, 2000

Since this infamous MIT technology review, we have seen so many similar promises and so little translation that Chan’s review and the debate that it provoked are indeed an incredibly positive and much needed development.

There is another amusing thing about Lammers et al’s review. The title suggesting that targeting is not our target is further echoed in the conclusion as follows:

“Patients do not benefit from targeting as such, and a reported tumour accumulation of 0.7%ID does not mean that nanomedicines do not work. We have to think beyond targeting, and beyond numbers, and focus on carrier-dependent drugs, combination therapies, protocols for patient selection and ways to enable rapid and more efficient clinical translation.”

Yet targeting as such seems very much to have been the target of these authors as the (non-exhaustive) list of articles below illustrate.

  1. Blume, G.; Cevc, G.; Crommelin, M.; Bakkerwoudenberg, I.; Kluft, C.;Storm, G.,Specific targeting with poly(ethylene glycol)-modified liposomes – coupling of homing devices to the ends of the polymeric chains combines effective target binding with long circulation times. Biochimica Et Biophysica Acta 1993, 1149 (1), 180-184.
  2. Vingerhoeds, M. H.; Steerenberg, P. A.; Hendriks, J.; Dekker, L. C.; vanHoesel, Q.;Crommelin, D. J. A.; Storm, G., Immunoliposome-mediated targeting of doxorubicin to human ovarian carcinoma in vitro and in vivo. British Journal of Cancer 1996, 74 (7), 1023-1029.
    3. Storm, G.; Crommelin, D. J. A., Colloidal systems for tumor targeting. Hybridoma 1997, 16 (1), 119-125.
    4. Mastrobattista, E.; Koning, G. A.; Storm, G., Immunoliposomes for the targeted delivery of antitumor drugs. Advanced Drug Delivery Reviews 1999, 40 (1-2), 103-127.
    5. Mastrobattista, E.; Kapel, R. H. G.; Eggenhuisen, M. H.; Roholl, P. J. M.; Crommelin, D. J. A.; Hennink, W. E.; Storm, G., Lipid-coated polyplexes for targeted gene delivery to ovarian carcinoma cells. Cancer Gene Therapy 2001, 8 (6), 405-413.
    6. Mastrobattista, E.; Crommelin, D. J. A.; Wilschut, J.; Storm, G., Targeted liposomes for delivery of protein-based drugs into the cytoplasm of tumor cells. Journal of Liposome Research 2002, 12 (1-2), 57-65.
    7. Metselaar, J. M.; Bruin, P.; de Boer, L. W. T.; de Vringer, T.; Snel, C.; Oussoren, C.; Wauben, M. H. M.; Crommelin, D. J. A.; Storm, G.; Hennink, W. E., A novel family of L-amino acid-based biodegradable polymer-lipid conjugates for the development of long-circulating liposomes with effective drug-targeting capacity. Bioconjugate Chemistry 2003, 14 (6), 1156-1164.
    8. Metselaar, J. M.; Wauben, M. H. M.; Wagenaar-Hilbers, J. P. A.; Boerman, O. C.; Storm, G., Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. Arthritis and Rheumatism 2003, 48 (7), 2059-2066.
    9. Schiffelers, R. M.; Koning, G. A.; ten Hagen, T. L. M.; Fens, M.; Schraa, A. J.; Janssen, A.; Kok, R. J.; Molema, G.; Storm, G., Anti-tumor efficacy of tumor vasculature-targeted liposomal doxorubicin. Journal of Controlled Release 2003, 91 (1-2), 115-122.
    10. Schmidt, J.; Metselaar, J. M.; Wauben, M. H. M.; Toyka, K. V.; Storm, G.; Gold, R., Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis. Brain 2003, 126, 1895-1904.
    11. van Steenis, J. H.; van Maarseveen, E. M.; Verbaan, F. J.; Verrijk, R.; Crommelin, D. J. A.; Storm, G.; Hennink, W. E., Preparation and characterization of folate-targeted pEG-coated pDMAEMA-based polyplexes. Journal of Controlled Release 2003, 87 (1-3), 167-176.
    12. Mulder, W. J. M.; Strijkers, G. J.; Griffioen, A. W.; van Bloois, L.; Molema, G.; Storm, G.; Koning, G. A.; Nicolay, K., A liposomal system for contrast-enhanced magnetic resonance imaging of molecular targets. Bioconjugate Chemistry 2004, 15 (4), 799-806.
    13. Schiffelers, R. M.; Ansari, A.; Xu, J.; Zhou, Q.; Tang, Q. Q.; Storm, G.; Molema, G.; Lu, P. Y.; Scaria, P. V.; Woodle, M. C., Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Research 2004, 32 (19).
    14. Verbaan, F. J.; Oussoren, C.; Snel, C. J.; Crommelin, D. J. A.; Hennink, W. E.Storm, G., Steric stabilization of poly(2-(dimethylamino)ethyt methacrytate)-based polyplexes mediates prolonged circulation and tumor targeting in mice. Journal of Gene Medicine 2004, 6 (1), 64-75.
    15. Visser, C. C.; Stevanovic, S.; Voorwinden, L. H.; van Bloois, L.; Gaillard, P. J.; Danhof, M.; Crommelin, D. J. A.; de Boer, A. G., Targeting liposomes with protein drugs to the blood-brain barrier in vitro. European Journal of Pharmaceutical Sciences 2005, 25 (2-3), 299-305.
    16. Zhang, C. F.; Jugold, M.; Woenne, E. C.; Lammers, T.; Morgenstern, B.; Mueller, M. M.; Zentgraf, H.; Bock, M.; Eisenhut, M.; Semmler, W.; Kiessling, F., Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner. Cancer Research 2007, 67 (4), 1555-1562.
    17. Dolman, M. E. M.; Fretz, M. M.; Segers, G. W.; Lacombe, M.; Prakash, J.; Storm, G.; Hennink, W. E.; Kok, R. J., Renal targeting of kinase inhibitors. International Journal of Pharmaceutics 2008, 364 (2), 249-257.
    18. Lammers, T.; Hennink, W. E.; Storm, G., Tumour-targeted nanomedicines: principles and practice. British Journal of Cancer 2008, 99 (3), 392-397.
    19. Lammers, T.; Subr, V.; Peschke, P.; Kuhnlein, P.; Hennink, W. E.; Ulbrich, K.; Kiessling, F.; Heilmann, M.; Debus, J.; Huber, P. E.; Storm, G., Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy. British Journal of Cancer 2008, 99 (6), 900-910.
    20. Rijcken, C. J. F.; Schiffelers, R. M.; van Nostrum, C. F.; Hennink, W. E., Long circulating biodegradable polymeric micelles: Towards targeted drug delivery. Journal of Controlled Release 2008, 132 (3), E33-E35.
    21. Crommelin, D. J. A., Nanotechnological approaches for targeted drug delivery: hype or hope? New Biotechnology 2009, 25, S34-S34.
    22. Mulder, W. J. M.; Castermans, K.; van Beijnum, J. R.; Egbrink, M.; Chin, P. T. K.; Fayad, Z. A.; Lowik, C.; Kaijzel, E. L.; Que, I.; Storm, G.; Strijkers, G. J.; Griffioen, A. W.; Nicolay, K., Molecular imaging of tumor angiogenesis using alpha v beta 3-integrin targeted multimodal quantum dots. Angiogenesis 2009, 12 (1), 17-24.
    23. Talelli, M.; Rijcken, C. J. F.; Lammers, T.; Seevinck, P. R.; Storm, G.; van Nostrum, C. F.; Hennink, W. E., Superparamagnetic Iron Oxide Nanoparticles Encapsulated in Biodegradable Thermosensitive Polymeric Micelles: Toward a Targeted Nanomedicine Suitable for Image-Guided Drug Delivery. Langmuir 2009, 25 (4), 2060-2067.
    24. Dolman, M. E. M.; Harmsen, S.; Storm, G.; Hennink, W. E.; Kok, R. J., Drug targeting to the kidney: Advances in the active targeting of therapeutics to proximal tubular cells. Advanced Drug Delivery Reviews 2010, 62 (14), 1344-1357.
    25. Lammers, T.; Subr, V.; Ulbrich, K.; Hennink, W. E.; Storm, G.; Kiessling, F., Polymeric nanomedicines for image-guided drug delivery and tumor-targeted combination therapy. Nano Today 2010, 5 (3), 197-212.
    26. Lammers, T.; Subr, V.; Ulbrich, K.; Peschke, P.; Huber, P. E.; Hennink, W. E.; Storm, G.; Kiessling, F., Long-Circulating and Passively Tumor-Targeted Polymer-Drug Conjugates Improve the Efficacy and Reduce the Toxicity of Radiochemotherapy. Advanced Engineering Materials 2010, 12 (9), B413-B421.
    27. Oerlemans, C.; Bult, W.; Bos, M.; Storm, G.; Nijsen, J. F. W.; Hennink, W. E., Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release. Pharmaceutical Research 2010, 27 (12), 2569-2589.
    28. Talelli, M.; Iman, M.; Rijcken, C. J. F.; van Nostrum, C. F.; Hennink, W. E., Targeted core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin. Journal of Controlled Release 2010, 148 (1), E121-E122.
    29. van Rooy, I.; Cakir-Tascioglu, S.; Couraud, P. O.; Romero, I. A.; Weksler, B.; Storm, G.; Hennink, W. E.; Schiffelers, R. M.; Mastrobattista, E., Identification of Peptide Ligands for Targeting to the Blood-Brain Barrier. Pharmaceutical Research 2010, 27 (4), 673-682.
    30. Talelli, M.; Hennink, W. E., Thermosensitive polymeric micelles for targeted drug delivery. Nanomedicine 2011, 6 (7), 1245-1255.
    31. Talelli, M.; Rijcken, C. J. F.; Oliveira, S.; van der Meel, R.; Henegouwen, P.; Lammers, T.; van Nostrum, C. F.; Storm, G.; Hennink, W. E., Nanobody – Shell functionalized thermosensitive core-crosslinked polymeric micelles for active drug targeting. Journal of Controlled Release 2011, 151 (2), 183-192.
    32. van Rooy, I.; Mastrobattista, E.; Storm, G.; Hennink, W. E.; Schiffelers, R. M., Comparison of five different targeting ligands to enhance accumulation of liposomes into the brain. Journal of Controlled Release 2011, 150 (1), 30-36.
    33. Crielaard, B. J.; Lammers, T.; Schiffelers, R. M.; Storm, G., Drug targeting systems for inflammatory disease: One for all, all for one. Journal of Controlled Release 2012, 161 (2), 225-234.
    34. Crielaard, B. J.; Rijcken, C. J. F.; Quan, L. D.; van der Wal, S.; Altintas, I.; van der Pot, M.; Kruijtzer, J. A. W.; Liskamp, R. M. J.; Schiffelers, R. M.; van Nostrum, C. F.; Hennink, W. E.; Wang, D.; Lammers, T.; Storm, G., Glucocorticoid-Loaded Core-Cross-Linked Polymeric Micelles with Tailorable Release Kinetics for Targeted Therapy of Rheumatoid Arthritis. Angewandte Chemie-International Edition 2012, 51 (29), 7254-7258.
    35. Dolman, M. E. M.; Harmsen, S.; Pieters, E. H. E.; Sparidans, R. W.; Lacombe, M.; Szokol, B.; Orfi, L.; Keri, G.; Storm, G.; Hennink, W. E.; Kok, R. J., Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells. International Journal of Nanomedicine 2012, 7, 417-433.
    36. Joshi, M. D.; Unger, W. J.; Storm, G.; van Kooyk, Y.; Mastrobattista, E., Targeting tumor antigens to dendritic cells using particulate carriers. Journal of Controlled Release 2012, 161 (1), 25-37.
    37. Kunjachan, S.; Jayapaul, J.; Mertens, M. E.; Storm, G.; Kiessling, F.; Lammers, T., Theranostic Systems and Strategies for Monitoring Nanomedicine-Mediated Drug Targeting. Current Pharmaceutical Biotechnology 2012, 13 (4), 609-622.
    38. Lammers, T.; Kiessling, F.; Hennink, W. E.; Storm, G., Drug targeting to tumors: Principles, pitfalls and (pre-) clinical progress. Journal of Controlled Release 2012, 161 (2), 175-187.
    39. van der Meel, R.; Oliveira, S.; Altintas, I.; Haselberg, R.; van der Veeken, J.; Roovers, R. C.; Henegouwen, P.; Storm, G.; Hennink, W. E.; Schiffelers, R. M.; Kok, R. J., Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment. Journal of Controlled Release 2012, 159 (2), 281-289.
    40. Talelli, M.; Oliveira, S.; Rijcken, C. J. F.; Pieters, E. H. E.; Etrych, T.; Ulbrich, K.; van Nostrum, R. C. F.; Storm, G.; Hennink, W. E.Lammers, T., Intrinsically active nanobody-modified polymeric micelles for tumor-targeted combination therapy. Biomaterials 2013, 34 (4), 1255-1260.
    41. van der Meel, R.; Vehmeijer, L. J. C.; Kok, R. J.; Storm, G.; van Gaal, E. V. B., Ligand-targeted particulate nanomedicines undergoing clinical evaluation: Current status. Advanced Drug Delivery Reviews 2013, 65 (10), 1284-1298.
    42. Heukers, R.; Altintas, I.; Raghoenath, S.; De Zan, E.; Pepermans, R.; Roovers, R. C.; Haselberg, R.; Hennink, W. E.; Schiffelers, R. M.; Kok, R. J.; Henegouwen, P., Targeting hepatocyte growth factor receptor (Met) positive tumor cells using internalizing nanobody-decorated albumin nanoparticles. Biomaterials 2014, 35 (1), 601-610.
    43. Kunjachan, S.; Pola, R.; Gremse, F.; Theek, B.; Ehling, J.; Moeckel, D.; Hermanns-Sachweh, B.; Pechar, M.; Ulbrich, K.; Hennink, W. E.; Storm, G.; Lederle, W.; Kiessling, F.; Lammers, T., Passive versus Active Tumor Targeting Using RGD- and NGR-Modified Polymeric Nanomedicines. Nano Letters 2014, 14 (2), 972-981.
    44. Novo, L.; Mastrobattista, E.; van Nostrum, C. F.; Hennink, W. E., Targeted Decationized Polyplexes for Cell Specific Gene Delivery. Bioconjugate Chemistry 2014, 25 (4), 802-812.
    45. Theek, B.; Gremse, F.; Kunjachan, S.; Fokong, S.; Pola, R.; Pechar, M.; Deckers, R.; Storm, G.; Ehling, J.; Kiessling, F.; Lammers, T., Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging. Journal of Controlled Release 2014, 182, 83-89.
    46. Liu, J.; Jiang, X. L.; Hennink, W. E.; Zhuo, R. X., A modular approach toward multifunctional supramolecular nanopolyplexes for targeting gene delivery. Journal of Controlled Release 2015, 213, E123-E124.
    47. Novo, L.; Takeda, K. M.; Petteta, T.; Dakwar, G. R.; van den Dikkenberg, J. B.; Remaut, K.; Braeckmans, K.; van Nostrum, C. F.; Mastrobattista, E.; Hennink, W. E., Targeted Decationized Polyplexes for siRNA Delivery. Molecular Pharmaceutics 2015, 12 (1), 150-161.
    48. Shi, Y.; Lammers, T.; van Nostrum, C.; Hennink, W. E., Long circulating and stable polymeric micelles for targeted delivery of paclitaxel. Journal of Controlled Release 2015, 213, E127-E128.
    49. Shi, Y.; van der Meel, R.; Theek, B.; Blenke, E. O.; Pieters, E. H. E.; Fens, M.; Ehling, J.; Schiffelers, R. M.; Storm, G.; van Nostrum, C. F.; Lammers, T.; Hennink, W. E., Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Pi-Pi Stacking Stabilized Polymeric Micelles. Acs Nano 2015, 9 (4), 3740-3752.
    50. Ashton, S.; Song, Y. H.; Nolan, J.; Cadogan, E.; Murray, J.; Odedra, R.; Foster, J.; Hall, P. A.; Low, S.; Taylor, P.; Ellston, R.; Polanska, U. M.; Wilson, J.; Howes, C.; Smith, A.; Goodwin, R. J. A.; Swales, J. G.; Strittmatter, N.; Takats, Z.; Nilsson, A.; Andren, P.; Trueman, D.; Walker, M.; Reimer, C. L.; Troiano, G.; Parsons, D.; De Witt, D.; Ashford, M.; Hrkach, J.; Zale, S.; Jewsbury, P. J.; Barry, S. T., Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo. Science Translational Medicine 2016, 8 (325).