June 27, 2012 - Mansoor Amiji, Distinguished Professor and Chair of the Department of Pharmaceutical Sciences at Northeastern University. Amiji's field of expertise includes Drug Delivery and Nanomedicine, the application of nanotechnology for medical diagnosis, imagining, and therapy.
Every avail?able cancer drug is sus?cep?tible to resis?tance, according to Man?soor Amiji, Dis?tin?guished Pro?fessor and chair of the Depart?ment of Phar?ma?ceu?tical Sci?ences. Tumors grow more quickly than blood ves?sels, so these unruly masses of cells receive very little oxygen and nutri?ents, which means they know just how to sur?vive under harsh con?di?tions. They make minia?ture pumps to actively dispel any?thing that doesn?t serve them well (like drugs), and they evade all the checks and bal?ances that nor?mally main?tain healthy cell populations.
Each of these super?cell powers is coded in the cancer?s DNA. In theory, turning off the right genes would turn off the super?powers, according to Amiji. A method called RNA inter?fer?ence does exactly that. By inhibiting pro?tein pro?duc?tion of spe?cific sec?tions of DNA, so-??called small inter?fering RNA, or siRNA, can shut down the activity of indi?vidual?genes.
But this is easier said than done. The siRNA mol?e?cules are incred?ibly finicky mol?e?cules, which Amiji likened to a picky house?guest who needs every?thing just so. ?They?re small, neg?a?tively charged, and extremely labile,? he said, and they degrade if you so much as breathe on them in the lab. All of these char?ac?ter?is?tics make it dif?fi?cult to get them where you want them inside the?body.
In a recent paper in the journal Bio?ma?te?rials, Amiji and col?lab?o?ra?tors at Novartis Insti?tutes for Bio?med?ical Research present a system that they believe will over?come some of these chal?lenges. Using their exper?tise in tar?geted drug delivery, Amiji?s team devel?oped a mod?ular system that can be used to deliver siRNA and any stan?dard drug directly to the cancer cells and nowhere else. This work is funded by the National Cancer Institute?s Alliance for Nan?otech?nology in Cancer Plat?form Part?ner?ship?grant.
?If we really want to take resis?tance head on, we need to address it in a mul?ti?fac?to?rial way,? said Amiji. The new mod?ular system is just that?a mul?ti?fac?eted approach that simul?ta?ne?ously addresses chemo tox?i?city and resis?tance, two of the most dif?fi?cult chal?lenges facing cancer drug developers.
In the research, spear?headed by Amiji?s former grad?uate stu?dent Shanthi Ganesh and cur?rent research assis?tant pro?fessor Arun Iyer, the team cre?ated a library of car?rier com?plexes, each spe?cial?ized for cer?tain prop?er?ties. Some of the com?plexes are good at car?rying neg?a?tively charged mol?e?cules (like siRNA) through the neg?a?tively charged cell mem?brane, which nor?mally repels them. Other com?plexes are good at engulfing hydrophobic drugs (which don?t dis?solve 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 pay?load, and then sub?se?quently target the right area of the body where it needs to be deliv?ered,? said?Amiji.
The assem?blies also dawn mol?e?cules that make them act like homing-??pigeons in the blood, car?rying their mes?sages of cel?lular destruc?tion to cancer cells?alone.
In this research, Amiji?s team focused on a mol?e?cule called hyaluronic acid, which many cancer cells rec?og?nize via spe?cial?ized recep?tors on their sur?face. In the lab, they were able to design sys?tems that deliv?ered drugs and siRNAs directly and solely to cancer cells, wherein 100 per?cent of the pay?load was released.
But once they tested the process in live mice, they had less suc?cess. That?s because two fac?tors that help ensure the com?plexes will reach their target aren?t an issue in the petri dish: plumbing and instruc?tions. If the tar?geted cancer cells have too few recep?tors on their sur?face, the com?plexes won?t find them in the rel?a?tively enor?mous organ?ismal system. But even if receptor expres?sion 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 bal?ance these fac?tors when using the team?s library to develop car?riers appro?priate for spe?cific drugs and cancer types, Amiji said. But the mod?u?larity of their system makes it espe?cially well-??suited to deal with a variety of unique chal?lenges. ?It allows us to cus?tomize this system for the right type of tumor,? he explained.
View selected pub?li?ca?tions of Man?soor Amiji in IRis, Northeastern?s dig?ital?archive.
Source: http://www.northeastern.edu/news/2013/03/kryptonite-for-cancer-cells/
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