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Slipping Past Cancer's Barriers

Mauro Ferrari

A New Nano-Attack

Taking a fresh approach to fighting cancer forced me and a number of other researchers to look beyond the traditional world of oncology. The understanding of cancer growth dynamics, the mechanisms by which it diversifies, and its preferential adaptation of biological barriers and transport modes are generally the province of cancer biologists. Such researchers are used to working with pharmaceutical scientists in the development of suitable therapeutic agents. But expertise on the topic of mass transport generally resides within very different fields: physics, chemistry, mathematics, and engineering. Researchers in those fields also harbor the skills required to design, manufacture, and test synthetic vectors that could deliver therapeutic payloads to a diversity of cancers inside their protective barriers. That cross-disciplinary approach is known as transport oncophysics.

 There is a great opportunity for progress against cancer by redrawing the boundaries of science—which are most generally detrimental to breakthrough thinking anyway—and forming interdisciplinary teams, at the service of the clinician in the fight against cancer. Cancer is a disease of physics as much as it is a disease of biology. We need to counter it with a matched array of synergistic weapons.

One of the most important of these new weapons is nanotechnology, which involves devices at a scale much smaller than even the vesicles on cells. At the nanoscale, the distinctions among scientific disciplines are blurred; chemical and physical properties are related in ways not found at larger scales. This is also the scale at which the most basic mass-transport processes operate. Conceptually, then, nanotechnology is a promising domain in which to search for solutions in the delivery of agents to cancers.

Actually, the first nanodrugs entered the clinic about 20 years ago, long before the words cancer and nanotechnology were explicitly uttered in the same sentence. Those early nanodrugs were not identified as such by their creators, but they were based exactly on the notion that biological barriers protecting Kaposi’s sarcoma and metastastic breast and ovarian cancers are altered as the disease progresses.

In particular, the walls of the blood vessels feeding these tumors become more leaky, by way of the presence of gaps (or fenestrations) in vascular tissue. Several pioneering laboratories manufactured lipid-based nanoparticles (called liposomes) to exploit these vascular wall alterations. The liposomes were shown to deliver drugs preferentially to tumors in their angiogenic growth phase, while reducing the adverse action of the payload drug on healthy tissues. Liposomal formulations of drugs such as doxorubicin have since been used to treat thousands of cancer patients worldwide, based on this precursor principle to transport oncophysics, and have become one of the first mass-produced nanotechnologies.

Several other types of nanodrugs have since entered the cancer clinic—including nanoparticles made from the protein albumin and loaded with one of the current principal cancer drugs, paclitaxel—for the treatment of breast, ovarian, and pancreatic cancers. In 2001, German researcher Andreas Jordan of the Charité-Universitätsmedizin Berlin developed a new type of nanoparticle made from iron oxide, which does not carry a drug but is itself used as a heat source to cook away certain brain cancers. The iron nanoparticle binds to a specific cancer tissue, then an external magnetic field selectively heats them to kill the tissue. They are the first clinical example of a completely physics-based nanotherapy.

Despite their intriguing potential, none of the nanodrugs approved for clinical use to date possesses any means of molecularly recognizing cancer cells. Their ability to concentrate at cancer sites depends entirely on the mechanisms of preferential transport. There has been great interest in adding cancer-recognizing molecules to the surface of barrier-busting nanoparticles, to give them a targeting specificity. These efforts have featured antibodies, aptamers (nucleotides or peptides that bind to a specific molecule), and various biomolecular ligands (a type of chemical group), attached to the surface of many different nanoparticle types. But despite more than 20 years of work by many laboratories, no biomolecularly targeted nanoparticle has been approved for clinical use.

One fundamental reason for these failures is that the addition of surface modifiers generally renders the nanoparticles less likely to penetrate the cancer bunker—again a matter of transport across biological barriers. The development of effective new therapies requires a deep understanding of biobarriers, because they are the mechanisms that determine how drugs distribute in the body, much more so than the biological recognition afforded by cancer-recognizing molecules.

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