In 1980, two papers on nanotechnology were published. In 2011 and 2012, that number soared to 14,000 papers, each year.
The Era of “The Small” will be big.
That was the message at the nanotechnology session at the New York World Science Festival. Nanotech—the big science of building wee things—has permeated many areas of research. In medicine, the approach may be particularly effective, since it builds on the structures and functions of hugely effective nanoparticles already in the body—then improves upon them.
Medical nano-engineers are, in rapid succession, studying, co-opting, and reinventing improvements in human physiology wrought by eons of evolution.
The session’s translational segment focused on the cancer work of Omid Farokhzad, Harvard Medical School associate professor, and head of the Brigham and Women’s Hospital Laboratory of Nanomedicine and Biomaterials. Farokhzad noted that nano-sized drug delivery vehicles, in preclinical and pioneering clinical trials, are yielding encouraging results in oncology. Their tiny size lets them slip chemotherapy (chemo) payloads into leaky tumor blood vessels, and avoid immune detection (aided by a coating of water-friendly molecules).
Then there are ligands, molecules in nature on the surface of, say, T cells, that recognize and lock onto corresponding molecules on cancer cells—letting the T cells kill them. Nanotechnologists can create single molecules displaying many different ligands. These man-made missiles can thus lock onto many more receptors, at varying levels of intensity, in and on tumor cells—than can T cells.
And, as noted, unlike more natural tumor-killing monoclonal antibodies like Herceptin (which targets the Her-2 receptor on breast cancer cells), nanoparticles can hold and discharge large quantities of anti-cancer drugs. Standard chemos suffuse the body, killing many normal cells alongside their cancer targets. Like T cells, more natural monoclonal antibodies are better at targeting. But they can't deliver massive anti-cancer payloads.
Nanomolecules can do all of the above, unleashing massive chemo payloads in a highly targeted way.
In an April 2012 Science Translation Medicine paper, Farokhzad's group, in conjunction with the MIT lab of biological engineer Robert Langer, described results of a Phase 1 clinical trial that began in January 2011.
This first-in-human testing of a targeted polymeric nanoparticle for chemotherapy found that, in patients with advanced solid tumors, the nano-drug displays “remarkable pharmacological properties,” shrinking some tumors. Phase 2 clinical trials for lung, bladder and prostate cancers have begun.
Said Farokhzad by email after the talk: "Monoclonal antibodies are targeted, but don't carry a drug molecule. There are newer monoclonal antibody platforms called Antibody Drug Conjugates. A great example is the recently approved T-DM1, which is a cytotoxic drug conjugated to Herceptin."
However, said Farokhzad, "in this case, the monoclonal antibody can only carry two to eight drug molecules. And antibodies typically target antigens on the surface of cancer cells. Nanoparticles offer more flexibility. They can have many ligands on their surface, in the tens to hundreds. These multiple ligands create a velcro effect and make nanoparticles enormously sticky to their target site. Also, multiple ligands can cross-link receptors on the cell surface which can induce a process called "receptor mediated endocytosis" that results in the uptake of the nanoparticles--although some monoclonal antibodies also get in the cell this way."
He continued: "So nanoparticles can carry thousands of drug molecules. Every bio-recognition event (ligand finding its target) results in the delivery of a massive load of drug. Nanoparticles can be designed to target extracellular matrix proteins, too. This can get nanoparticles "stuck" in tumor tissue and locally deliver a large depot of drug.2, 3 Monoclonal antibodies are not used in this way. They are biologic, and relatively more expensive to manufacture. Nanoparticles are synthetic. The cost of manufacturing is similar to that of small molecule drugs. "
Other advantages may include intellectual property protection.4
"Antibodies and biologics represents a $30 billion market," concluded the researcher, a cofounder of three nanotech start-ups. "I expect nanoparticle technologies will become a very important class of therapeutics analogous to, or perhaps even more pronounced than, antibody technologies."
Farokhzad's three start-ups are BIND Therapeutics, Selecta Biosciences, and Blend Therapeutics. All three are commercializing nano-particle innovations.
1) Hrkach, J., et. al. “Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile,” Science Translational Medicine, Vol 4, Iss 128, April 4, 2013: p128ra39.
2) Chan, M., et. al. "Spatiotemporal controlled delivery of nanoparticles to injured vasculature," Proceedings of the National Academy of Sciences," Vol 107, Iss 5, February 2, 2010: p2213-2218.
3) Chan, J. M., et. al. "In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles," Proceedings of the National Academy of Sciences, Vol 108, Iss 48, November 29, 2011: p19347-19352.
4) Burgess, P., et. al. "On firm ground: IP protection of therapeutic nanoparticles," Nature Biotechnology, Vol 28, Iss 12, December 2010: p1267-1270.