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Kryptonite for cancer cells

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March 18, 2013

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Every avail­able cancer drug is sus­cep­tible to resis­tance, according to Man­soor Amiji, Dis­tin­guished Pro­fessor and chair of the Depart­ment of Phar­ma­ceu­tical Sci­ences. Tumors grow more quickly than blood ves­sels, so these unruly masses of cells receive very little oxygen and nutri­ents, which means they know just how to sur­vive under harsh con­di­tions. They make minia­ture pumps to actively dispel any­thing that doesn't serve them well (like drugs), and they evade all the checks and bal­ances that nor­mally main­tain healthy cell populations.

Each of these super­cell powers is coded in the cancer's DNA. In theory, turning off the right genes would turn off the super­powers, according to Amiji. A method called RNA inter­fer­ence does exactly that. By inhibiting pro­tein pro­duc­tion of spe­cific sec­tions of DNA, so-​​called small inter­fering RNA, or siRNA, can shut down the activity of indi­vidual genes.

But this is easier said than done. The siRNA mol­e­cules are incred­ibly finicky mol­e­cules, which Amiji likened to a picky house­guest who needs every­thing just so. "They're small, neg­a­tively charged, and extremely labile," he said, and they degrade if you so much as breathe on them in the lab. All of these char­ac­ter­is­tics make it dif­fi­cult to get them where you want them inside the body.

In a recent paper in the journal Bio­ma­te­rials, Amiji and col­lab­o­ra­tors at Novartis Insti­tutes for Bio­med­ical Research present a system that they believe will over­come some of these chal­lenges. Using their exper­tise in tar­geted drug delivery, Amiji's team devel­oped a mod­ular system that can be used to deliver siRNA and any stan­dard drug directly to the cancer cells and nowhere else. This work is funded by the National Cancer Institute's Alliance for Nan­otech­nology in Cancer Plat­form Part­ner­ship grant.

"If we really want to take resis­tance head on, we need to address it in a mul­ti­fac­to­rial way," said Amiji. The new mod­ular system is just that—a mul­ti­fac­eted approach that simul­ta­ne­ously addresses chemo tox­i­city and resis­tance, two of the most dif­fi­cult chal­lenges facing cancer drug developers.

In the research, spear­headed by Amiji's former grad­uate stu­dent Shanthi Ganesh and cur­rent research assis­tant pro­fessor Arun Iyer, the team cre­ated a library of car­rier com­plexes, each spe­cial­ized for cer­tain prop­er­ties. Some of the com­plexes are good at car­rying neg­a­tively charged mol­e­cules (like siRNA) through the neg­a­tively charged cell mem­brane, which nor­mally repels them. Other com­plexes are good at engulfing hydrophobic drugs (which don't dis­solve in water), while still others work better with hydrophilic, or
water-​​loving," drugs.

"It's almost like Lego pieces that you can mix and match to create the right assembly for the right type of pay­load, and then sub­se­quently target the right area of the body where it needs to be deliv­ered," said Amiji.

The assem­blies also dawn mol­e­cules that make them act like homing-​​pigeons in the blood, car­rying their mes­sages of cel­lular destruc­tion to cancer cells alone.

In this research, Amiji's team focused on a mol­e­cule called hyaluronic acid, which many cancer cells rec­og­nize via spe­cial­ized recep­tors on their sur­face. In the lab, they were able to design sys­tems that deliv­ered drugs and siRNAs directly and solely to cancer cells, wherein 100 per­cent of the pay­load was released.

But once they tested the process in live mice, they had less suc­cess. That's because two fac­tors that help ensure the com­plexes will reach their target aren't an issue in the petri dish: plumbing and instruc­tions. If the tar­geted cancer cells have too few recep­tors on their sur­face, the com­plexes won't find them in the rel­a­tively enor­mous organ­ismal system. But even if receptor expres­sion is high, blood supply must also be high in the live mouse, or they won't even begin their journey in the first place.

Future researchers will need to bal­ance these fac­tors when using the team's library to develop car­riers appro­priate for spe­cific drugs and cancer types, Amiji said. But the mod­u­larity of their system makes it espe­cially well-​​suited to deal with a variety of unique chal­lenges. "It allows us to cus­tomize this system for the right type of tumor," he explained.

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