Analog SFF, June 2011 (15 page)

The problem of targeting nanoparticles to cancer cells provides a good illustration of the issues involved in treating disease with nanoparticles. Such targeting can be passive, in which the drug delivery system takes advantage of natural characteristics of the tissue or of the tumor. Using the particle-trapping characteristics of the liver to passively target liver cancer would be an example. Nanoparticles can actually pass through the cells that line capillaries, or they can pass between the cells to enter the surrounding tissue. It turns out that tumors (and also inflamed tissues) have leakier blood vessel walls than normal healthy tissue, causing circulating nanoparticles to preferentially accumulate inside tumors in what is termed the “enhanced permeability and retention effect.” Tumors also have a higher metabolic rate due to increased cell division and may be poorly oxygenated as a result, so that the tumor becomes more acidic than the surrounding tissue. This fact can be used to enhance release of an anti-cancer drug at the site of the tumor by designing nanoparticles that release the drug in an acidic environment.

Often the objective is to have the nanoparticle internalized by the target cell. Binding to cell surface receptors often results in internalization as a result of the receptor's normal function. Cells will also engulf particles by the process of endocytosis without the involvement of a specific receptor. Active targeting can improve specificity but requires that the tumor cells express some molecule on their surface that is either unique to the tumor cells or is expressed more highly on tumor than on normal cells. If the molecule in question happens to be a receptor, then that receptor's natural ligand can be attached to nanoparticles to produce active targeting. Receptors for the vitamin, folate, and the iron-carrier transferrin have both been studied for tumor targeting. Alternatively, antibodies can be generated and attached to nanoparticles to target other types of cell-surface molecules. The technology has long existed to produce large quantities of antibodies that bind to a molecule of choice.

Nanoparticle toxicity and clearance from the body

Nanoparticle drug delivery systems pose a number of toxicity issues. There may be residual toxicity of the drug being delivered, which may not be completely masked by the nanoparticles. In this context, the rate of release of the drug and the conditions under which it is released may be relevant to nanoparticle design. There is also the matter of the body's response to the particles themselves, and finally there is the question of what happens to the nanoparticle drug carriers after they have served their function.

Obviously it is undesirable to make nanoparticles for drug delivery out of materials that are themselves toxic, but even materials that seem relatively inert may pose a health risk if present in the blood in the form of nanosized particles. This concern is raised by research on the health risks of particulate air pollution. Ultra-fine particles that are inhaled don't just cause problems in the lungs; they also cross into the bloodstream, and there is substantial evidence linking exposure to nano-sized particles in the air with atherosclerosis or “hardening of the arteries.” Presumably the particles can become lodged in atherosclerotic plaques that are forming on the walls of blood vessels and exacerbate the inflammation that is part of the disease process. This problem may be avoided by choosing materials for nanoparticle construction that are more “familiar” to the body—biologically derived polypeptides, lipids, and polysaccharides—or by altering the surface characteristics of the particles. Particles with negatively charged surfaces cause fewer problems than positively charged particles, for example.

Little is known about potential long-term health effects of using nanoparticle drug carriers. For a person receiving a single small dose, the risk may be minimal or may be outweighed by the benefits. For large doses and long-term treatment of chronic conditions, however, it becomes increasingly important to know how the nanoparticles will be cleared from the body. Particles that are less than 30 nm in diameter can be cleared by the kidneys, passing from the blood into the urine. The issue then remains of what impact the excreted nanoparticles might have in the environment. Larger particles will remain in the body unless they are broken down. Not surprisingly, current research runs heavily toward biodegradable nanoparticles. In many cases the particles are designed to be digested by the cells that take them up, and this may be planned as part of the mechanism of drug release. The trade-off for drug carriers that are too biologically “fragile” is that they may break down at inappropriate times and places in the body, causing toxicity or reducing their effectiveness. Despite these lingering issues, the great potential of nanoparticle drug delivery systems to improve drug effectiveness relative to drug toxicity means that research on these systems will surely continue, and in the future we are likely to see more use of nanoparticles in clinical applications.

Bibliography

Amir H Faraji and Peter Wipf. “Nanoparticles in cellular drug delivery.” (review) Bioorganic and Medicinal Chemistry 17: 2950-2962, 2009

Wim H De Jong and Paul JA Borm. “Drug delivery and nanoparticles: Applications and hazards.” (review) International Journal of Nanomedicine 3 (2): 133-149, 2008

Kwongjae Cho, Xu Wang, Shuming Nie, Zhou (Georgia) Chen, and Dong M. Shin. “Therapeutic Nanoparticles for Drug Delivery in Cancer.” (review) Clinical Cancer Research 14 (5): 1310-1316, 2008

Yogeshkumar Malam, Marilena Loizidou, and Alexander M Seifalian. “Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer.” (review) Trends in Pharmacological Sciences 30 (11): 592-599, 2009

Stephen J. Russell and Kah-Whye Peng. “Viruses as anticancer drugs.” (Review) Trends in Pharmacological Sciences 28 (7): 326-333, 2007

Andrew K. Udit, Christian P.R. Hackenberger, and Mary K. O'Reilly. “Chemically Tailored Multivalent Virus Platforms: From Drug Delivery to Catalysis.” (highlight) ChemBioChem 11: 481-484, 2010

Anupa R. Menjoge, Rangaramanujam M. Kannan, and Donald A. Tomalia. “Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications.” (review) Drug Discovery Today 15(5/6):171- 185, 2010

M. Talelli, C.J.F. Rijcken, C.F. van Nostrum, G. Storm, and W.E. Hennink. “Micelles based on HPMA copolymers.” Advanced Drug Delivery Reviews 62: 231-239, 2010

About the Author:

Carol Wuenschell originally set out to be a biological illustrator with a B.A. degree in biology and art (double major) from Occidental College and an M.A. in biological illustration from Cal. State University, Long Beach. Before even finishing the Master's, however, she had decided she wanted to be a scientist and went on to earn a Ph.D. in biology from UCLA. After postdoctoral work at Caltech and USC, she joined the faculty of the USC School of Dentistry. There she maintained an independent laboratory research program for seven years, working on nicotine receptors and the effects of nicotine exposure on fetal lung development in mice. While at USCSD, she also helped teach basic biomedical sciences to dental students by serving as a “facilitator” of small-group learning in the Dental School's problem-based learning program. Currently Dr. Wuenschell is employed as a scientific writer at the City of Hope National Medical Center in Duarte, California.

Copyright © 2011 Carol Wuenschell

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Is honesty always the best policy? Think twice before you answer. . . .

I was trying to fix my kitchen garbage disposal when my phone trilled. I put it on speaker. “Gary Shu,” I said, wiping my hands on a rag.

"Mr. Shu, this is Nnamdi Okonkwo from UNSA.” A low voice, cultured.

"UNSA? Really?” Why would anyone from the UN Space Agency be calling
me?
I was just a second-string newsblogger.

"Really. This concerns your application for the Citizen-Astronaut Program."

"Oh, that.” I'd made it as far as the semifinals, but when the finalists had been announced my name hadn't been on the list. That had been over a year ago. I picked up my screwdriver and resumed poking at the clog. “What about it?"

"You have probably heard the terrible news about Kim Yeun-ja."

"Yeah.” She was the Korean painter who'd been selected as the first Citizen-Astronaut. Two weeks ago, less than two months before her scheduled launch, she'd broken her neck on a recreational hike in the Alps. She'd recover, but she wouldn't be up for a trip to Mars any time soon. A tragic story, and an excellent hook for a fundraising call. I kept trying to pry the whatever-it-was out of the disposal's blades.

"You are probably also aware of the difficulties we've been having with funding and public opinion.” We'd had people on Mars continuously for over eight years now. The initial discoveries of water and life—frozen, subsurface water and fossils of microscopic, long-extinct life—had been newsworthy, but after that, interest had declined steadily. And with declining public interest came a declining willingness by the UN's various governments to fund the ongoing mission.

"Uh-huh,” I said, squinting down the disposal's throat. By now I was just waiting for the pitch so I could hang up on the guy in good conscience. “So what's the purpose of this call?"

"My superiors have decided that the loss of Ms. Kim provides an opportunity for us to . . . reprioritize the Citizen-Astronaut Program. Rather than call on Ms. Kim's backup, we have been instructed to bring in someone who is in a better position to influence public opinion. Someone such as yourself."

The screwdriver clattered to the floor. “Guh?” I managed.

"Can you come to Geneva right away?"

"Uh?” I swallowed. “Uh, for how long?"

He chuckled. “In Geneva? Thirty-seven days. But after that it might be quite a bit longer. . . ."

Thirty-seven days? I checked my phone's calendar.

Thirty-seven days was the time until the Kasei 18 spacecraft launched for Mars.

The sixty-five-day voyage to Mars was about as exciting as a long bus trip, bracketed by the thundering, shuddering terrors of launch and aerobraking. Though I did what I could to make the trip interesting to my viewers, my ratings dropped steadily the whole time. I was handicapped by limited bandwidth—I couldn't embed even a single Spin or Jumbo3D frame in my reports, and was reduced to plain text and flat, still images—and by the fact that every day was the same. Although we were going almost two hundred thousand kilometers per hour, from inside the ship there was no way to tell we were moving at all.

But as I lay on my back after touchdown, heart pounding and sweat pooling in the small of my space-suited back, I knew everything had changed. I was
on Mars
! I couldn't wait to step out of the lander, to see the endless red desert spread out before me, to feel the dry, lifeless dust crunch under my boots.

The exit protocol was one of the things we'd had plenty of time to negotiate during the long trip out. The commander of our craft, the American-born Flemish climatologist Lynne Ann Morse, had graciously ceded her commander's prerogative to me as Citizen- Astronaut. I would be the first one out of the lander: the sixty-seventh person to set foot on Mars.

But before I could even unstrap myself, the hatch clanged open and Nam Dae-jung's scratched helmet poked in. I recognized his face immediately—he was one of the three members of the current crew who would be staying on, and with our arrival he was now commander of
Expedition
18
. A Korean geochemist, he was a small man, built like a fireplug, and his face was just about as red as one. “Get your butts out here,” he shouted. “We've got a leak."

We four new arrivals got ourselves unstrapped and tumbled out of the hatch as quickly as we could, bouncing and stumbling in our haste. We immediately saw the problem: A pipe on the lander's underside had split open, and a white jet of steam and ice crystals was spewing out into the thin Martian atmosphere. Frost was already building up around the gap. I activated the camera in my helmet and began snapping pictures of the dramatic scene for my blog. Finally some excitement!

"That's just water,” said Kabir Abuja, our Nigerian engineer, and scuttled to the back of the lander where the main valve panel was located. A moment later the stream of vapor cut off.

Kabir, Lynne Ann, and Dae-jung ducked under the lander to inspect the damage. I joined them, mindful of the descent engine's bell-shaped nozzle, which was still nearly red-hot.

I saw a dusty red streak leading up to the damaged pipe. “Look at that,” I said, pointing. “Looks like a rock got kicked up by the descent engine.” I took pictures of that too.

"Easily repaired,” said Kabir, and started backing out of the confined space. “It's only water anyway. No shortage of that.” Even through his faceplate I could see the confident smile that almost never left his dark, handsome face.