delivering on nano's promise

8/14/2019 Delivering on Nano's Promise

1/6

liv ring_ on.Nano's on . . .PromiseSeveral nanotechnology-enab led drugs are on themarket and researchers are investigating the nextgeneration of nanoparticles for drug delivery.

Patr ick McGee Senior E

n 1995,several years before

the word nanotechnologyi began creatingabuzz,Doxil

(doxorubicin HCLHpoKonu;injec-tion) received accelerated approvalfor the treatm ent of chem otherapy-refractive AIDS-relat(id Kaposi's sar-com a. The fact that Doxil was areformulation of an earlier drug,Adriamycin (doxorubicin), did notmake it unique:. What did, however,was how it was reformulated byDoxil's developer, Alza Corp., M oun-tain View,Calif. a subsidiary of John -son Johnson, New Brunswick, N.J.

While Adriamycin was effective, itwas,like other chemotherapy drugs,very toxic. Alza's goal was to m ain-tain the drug's effectiveness wbilereducing that toxicity. They did tbisby placing the active agent of dox-orubicin Into a liposome with a layerof hair-like strand s m ade ofmethoxypolyethylene glycol. Thiscarrier allows Doxil to evade thebody's immu ne system, thusincreasing the time tbe drug is in thehody. At least 90% ofthe activi;agent remains in tbe liposomc while


2/6

An image of rhodam ine-encapsulated inpolyethylene oxide-modifiecl polyepsiloncaprolactone administered to SKOV-3ovarian cancer cells after four h ours ofincubation. The image shows uptake andendosome/lysosome localization ofthenanoparticles upon intracellular delivery.(Source: Man soorAmiji,PhD)

in the blood, giving Doxil more timeto reach tum or tissue and reducingsystemic toxicity. It has since beenapproved for other indications.

Although it was not highly toutedat tbe time, Doxil represented a newwave of therapies, those that sougbtto improve drug efficacy and safetyby manipulation at tbe nanometerlevel. Drug deliveiy is just one ofthemany applications for nanotechnolo-gy, a muUidiscipIinary field rangingfrom biology to cbemistry to physicsto engineering. The National Nanote-chology Initiative defines nanotecb-nology as "research and technologydevelopm ent at the atomic, molecu-lar, or macromolecular scale leadingto the controlled creation a nd use ofstructures, devices, and systems witha length scale of approxim ately to100 nanom eters (nm )." Other defini-tions expand that to 1 to 1,000nanometers.Mansoor Am iji, PhD, an a ssociateprofessor of pharmaceu tical sciencesin the school of pharmacy at North-eastern University, Boston, bas doneextensive researcb in nanotecbnolo-gy and believe s the fie ld offers a"tremendous opp ortunity" for thepbarmaceutical and biotechnologyindustries. "Because of nanotechnol-ogy and the role of these various par-ticles and delivery systems, we have

an opportunity to strategically thinkabout ways to incorporate more tbanone drug into the nano systems sothat you can get beneficial therapeu-tic aspects. W e could overcome drugresistance botb in cancer and infec-tious disease hy strategically design-ing nanoparticles so that they canprovide multiple therap euticavenues and synergistic effects. Wecan also develop strategies to get var-ious kinds of drug molecules into thebrain to treat some o fthe debilitatingbrain disorders," be says.

Nanotechnology bas been the sub-ject ofa great deal of hype, and tbepharmaceutical and biotechnologyindustries are no exception. However,there is a good deal of baixl science tohack the hy pe. Nanoparticles such asliposomes, dendrim ers, goldriiinoshelis, quantu m dots, andfullerenes have a num ber of potentialadvantages over classical drug deliv-ery methods, proponen ts say. Theseinclude greatly altering the absorp-tion, distribution, and length of timedrugs stay in th e body, as well asallowing for targeted delivery ofdrugs to diseased sites.

A great deal of work is being doneexploring its application to cancertberapeutics in an efibrt to make

t h e m m o K - ; t a r g r i i M I D L I , i \ n d t o x i csystemic effects, but scientists areexploring applications in severalothe r areas as well, such as cardiolo-gy and infectious d iseases. But tbefield is not witbout its challenges.Some cite concerns with toxicity andmany are skittish when it comes tonanoparticles, arming tbat therecould be liability con cern s. Stillanotber cballenge is taking tbesetypes of particles from the lab to scal-ing tbem up for clinical studies andcommercial production. irst generationAithougb tbere are a few lipid-baseddrugs and otbers using nanopow-ders, some consider tbese approacb-es as first generation nano drugdelivery. "Tb me, n ano tech is reallysomething that bas to do witb built-in multiple functionalities in a verysmall spaGe," sa ys Mauro Ferrari,P h D , a professor of nanotechno logyat tbe University of Texas Healtb Sci-ence Center in Houston, "Makingyour pow ders finer or larger orsmaller or wbatever. to me that'sexciting, that's important. It can giveyou some short-term advantages andperbaps even some long-termadvantages, hut it's not a revolution


3/6

in medicine. Nanotech is the notionof incorporating more tasks intosom ething the size ot'a m olecule ora small sub-cellular organism."

It is not difficult tosee the appealof nanopa rticles tbat allow for mu lti-ple functionalities, and it is clear whyliposomes, wbicb have been aroundfbr nearly2 years,were the firstnanoparficlestobe bamesse d fordrug delivery. Liposomes are pbos-pbolipids, and pbospholipids sucb aspo ylactic-co-glycolic acid and o tbershavebeen used in the pharmaceuti-ca indus try and bave a proven sati; tyrecord, Amijisays."Tbere are o tberswbo are sjmtbesizing newer poly-mers,but tbose will havetogothrough tbe safety screens."

In addition to Doxil, ano the r lipo-some-hased drug is Ahraxane, fromAbraxis BioScience Inc., Los Ange-les,wbicb was approved last year formetastatic breast cancer after failureof combination chemotherapy orrelapse within six months of adju-vant chemo therapy. A braxane is aformulation ofthe cancer drug pacli-taxe that uses nanoparticles madeof tbe human protein albumin.Because the na noparticles interactwith two biochemical processescommon in tumors, tbey are capableof boosting tbe am ount of paclitaxeldelivered into tbe body at a50%bigber dose over3 minutes. Tbatcompares to standard paclitaxel,whicb must be given in infusions forup to tbree bours.

In addition, binding tbe paclitaxelto album in allows patients to avoidthe toxic side effects of paclitaxel.

Because ofitspoor soluhility inblood, paclitaxel must be

mixed witb varioussolvents that can

result in seri-ous hyper-

sensitivityreactions

and other side effects. Tbis necessi-tates steroid treatm ent beforecbemotherapy, som ething tbat basbeen suspected to result in byper-glycemia, immunosuppression, andinsom nia. Because it is less toxic,Abraxane can be given in bigherdoses,sometbing tbat may explain aresponse rate that was almost doubletbat of patients receiving paclitaxel inclinical studies.

Nanopowders are ano tberapproach to enhancing drug delivery.The re are four drugs on tbe m arket,all reformulations, tbat useNanoCrystal tecbnology from ElanPbarmaceuticals, Dublin, wbicbdecreases drug particle size to typical-ly less tban 1,000 n ano me ters indiameter This increases surface areaand dissolution rates for poorlywater-soluble compounds, thusimproving compound activity, saysPaul Breen, PhD, executive vice pres-ident and head of nanotechnology atElan. The NanoCrystals are producedby milling the drug substance using aproprietary, wet-milling techn ique.Tbey are tben stabilized againstagglomeration by surface adsorptionof selected stabilizers, resu lting in anaqueous dispersion of tbt; drug sub-stance that behaves like a solution.

Tbe first drug to be app roved intbe U nited States using NanoCrystaltecbnology was a solid-dose formu-lation ofthe immunosuppressantRapamune (sirolimus) from W yeth,Madison, N.J., in 2000. Rapamunewas previously availahle only as anoral solution tbat had to be refriger-ated and then mixed with water ororange juice p rior to ad ministration.Breen said a NanoCrystal reformula-tion tbat is a favorite of his in term sof patie nt benefit is Megace ES(megestrol) from Par Pbarmaceuti-cal Companies Inc., Woodclitf Lake,N.J.MegaceES,whicb wasapproved in 2004, is a conc entrated

A worker producing NanoCrystals attbe Elan Pharmaceuticals plant inAthlone, Ireland. Tbe man ufacturingprocess reduces d rug particle sizeto typically less tban 1,000 nan ome -ters in diameter, thus impro vingcom pou nd activity. (Source: ElanPharmaceuticals)oral suspension for the treatm ent ofanorexia, cachexia, or an unex-plained, significant weight loss inpatients with AIDS.

Breen says the original Megacewas a thick syrup y liquid tbatpatients bad to swallow 20 milli-liters of after ea ting a m eal. Byapplying NanoCrystal tecbnology.Elan reduced viscosity 16 times andcut tbe dose from 20 toSmilliliters."But more importantly, we tookaway tbe nee d for tbe pa tients totake food, so tbere was a substantialbenefit to tbe patient."Second generation nonoThe benefits provided by nanopow-ders and tbe use of liposomes areclear, but m any researche rs are look-ing to tbe future, to the next genera-tion of nano-enabled d rugs. One of


4/6

themisScott McNeil, PhD, directorofthe Nanotechnology Characteri7a-tion Laboratory (NCL), Frederick,Md.NCLwas establisbed by theNational Cancer Ins titute (NCi) toperform predinical efficacy and toxi-city testing of nanoparticles in orderto accelerate tbe transition ofniinoscale particles and devices intoclinical applications.

"On one level, it's jus t strict charac-terization, but on tbe next level manyof those folks are materials scientistswho are developing concepts thatcould be used for medicinal purpos-es,and more specifically for cancertherapeu tics or diagnostics.Sowe attheNCLhelp them understand and

navigate those waters that maybe un familiartothem."

McNeil saysNCLbas cbaracter-

ized about65differ-ent particles, and

Ferrari saystbere are about1 50nanoparti-cle cance r ther-apies in

developmentand thousands of

other potentialcandidates. Some

ofthekey pa rticlesheing investigated to

date include: Dend rimers: These

have well-defined chemicalstmctures and exhihit m onod is-persity and have potential appli-cations in targeting cancer cells,drug delivery, and imaging.

Gold Nanosbclis:Ago d shellsurrounding a semiconductor,tbese can be irradiated whenre'iaching their target. Tbis heatstbe nanoshell, which, in turn,kills cancer cells.

Fullerenes:Aform of carbon (C-HO),fullerenes are com posed of

carbon atom s arranged in a soc-cer ball-like sbape , bence theirother namehuckyballs. Easilymanufactured in quantity, tbeyseemtobe ideal drug deliveryvebicles due to their size andshape.Tbese particles and otbers have a

great deal of potenfial, bu t one con-cern tbat arises is tbe potential fortoxicity, sometbing that McNeil sayshe oflen encounters in tbe form ofaquestion: "Are tbese nanoparticlestbe next asbestos?" He doesn't believeso.Ofthe 65 particles characterizedso far by NCL, all but onebavebeenverybenign, very unrem arkable asfar as toxicity."

Ferrari says that it should beremem bered that many of tbenanoparticles are being developed foruse in cancer, a disease tbatistreatedwith some very toxic substances. "Ibave not found any nanotecb particlethatisanywhere nea r as toxic as tbecancer drugs that weuse,"be says."hi terms ofthe simple reactivity andtoxit;ity per imit mass, if you will, thecom pounds that are going to be usedin tbe particles delivering tbem aregoingto bemillions of times morepotent and more toxic than tbe parti-cles themselves."

Amijiisno tsosure, particularlywben it comes to carbon structuressuch as fullerenes. Wbile m ucb a tten-tion is focused on getting thesenanostructurestotbe p roper locationto do theirjob,be believes notenougb attentionisbeing paid towbat bap pen s after tbat job is com-pleted. Wedon 't want to bave tbesesystems accumulate in tbe hody aftertbey do their job because tbat's wheretoxicity s tartstodevelop. That'swhe re you start to get some hysteriain certain cases about the potentialfbr asbestos-like effects," be says. "Ifit's not applicable in vivo you reallybavetoquestion yourself as to wbat

you 're doing. You c an't jus t treat cellsan dmice.At some point tbese haveto go to hum ans."Scale upch llengesAchiilltjiigc many cite is an issue thatcontinually vexes the pharmaceuticaland biotechnology industriesscale-up."We're seeing efficacy across theboard as far as success. What we'refinding tobe tbe rate-limiting stepfrom NCL's perspective is tbe scale-up of tbose concepts. Tbat's notunique to nanotechnology; it's com-mon to technology in general," saysMcNeil, wbo refers to scale-up as tbe"Acbillesheel" of nanotech, S(al(>upcan be difficult enough with processchemistry, butitbecomes even moredifficult when dealing witb tbingslike multifunctional nanoparticles."In addition to tbe particle itself suchas a dendrimer, we are attachingmany constituents onto the surfaceofthe nanoparticle, and each one oftbose has a cbem istry associated witbit. Doing tbat in a flow-througb scale-up process is a challenge. It's notinsurmountable, and in fact NCLassists witb tbat kind of tbing, hut it isa cballenge."

Another issueisthe lack of regula-tory gu idelines regarding tbe use ofnanopardcles from tbeUSFood andDrug Administration (FDA) and otheragencies. Amiji says that becausenanotech ranges across disciplines asdiverse as biology, cbem istry, andengineering and am be used for tber-apeutics as well as imaging, develop-ing guidance docum ents can be verydifficult. FDAcannot come up w itbone standard or one guidance docu-ment w bicb could apply across theboard. Tbisisgoingtobe a case bycase tbing."

Some guidance could come tromNCL'swork witb the FDA. NCL is afbrmal co llaboration betw een NCI,FDA, and the National Institute of


5/6

Standards and Tfccbnology, and NCLinteracts witb the FDA on three lev-els,McNeil says. Tbe first is scientistto scientist, with NCL and FDA staffaddressing specific issues of charac-terization and toxicity. The FDA alsosits on NCL's scientific oversight com-mittee to help with programmingissues. "They help to ensure thatwe're characterizing the full scope ofparticles and witb issues related topreclinica characterization, and alsowith ensuring that our assays are inline with IND requirements," McNeilsays.NCL has a seat on the nanotecbsubcx)mmittee ofthe interagencyoncology task force, a joint venturebetween NCI and FDA designed tofacilitate the development of cancerdiagnosdcs and therapeutics.

Wbile regulators wrestle witb tbecomplex and difficult questions tbatnanotechnology raises, scientists wilicontinue to wrestle witb it in tbe lab-orator\'. "Nanotec,bnolog\' is a wbole

new ball game compared to smallmolecule cbemistry characteriza-tion," says McNeil. "We find thatnanoparticles interfere with existingcommon off-the-shelf kits that areoften used for predinical characteri-zation. We find that nanoparticleshave inherent fluorescenceabsorbance. In some cases we findtbat tbey bave catalyfic activities, soas far as predinical characterizafionwe have to run lots and lots of con-trols just to make sure that we're notinterfering with the assay itself andwe are, in fact, monitoring resultsdue to the nanoparticle." McNeil saysthat when he speaks at meetings, herecommends that researchers useNCL's protocols because diey controlfor sucb factors as interference.

Addressing tbese scale-up, regu-latory, and scientific issues willmove the field along and increasethe involvement of pharma andhiotech companies, which have

largely stood on the sidelines whilework on next-generation nanoparti-cles has gone on. Ferrari believesthis involvement will increase fol-lowing a "gestational" period fornanotechnology. "You cannot havea baby in less than nine months;you cannot bring very novel tech-nologies into tbe clinic in less tban10 years. Tbat's just tbe way itworks." He finds tbe skepticism insome circles regarding tbe potentialof nanoparticles reminiscent oftheskepticism surrounding monoclon-al antibodies in the mid-1980s aftera great deal of hype in the earlyHOs.But once biologies began com-ing on the market, big pbarmacouldn't stand on tbe sidelines anylonger. "I tbink tbis is going to hap-pen with nano," Ferrari says. "Nanobrings in a revolution in the cultureof tbe potential pbarma world. It'sno longer chemical, it's no longerbiological-it's different." ]

Only Cellomics offers a p rove n, start-to-finishHCS p latfo rm for dru g discovery.Scientists arou nd the wor ldaremaking incredib le breakthroughsin p roduct iv i t y - thankst oHigh Content Screening solutionsfrom Cellomies.Noone offers faster, easier waysto obtain real cell data,soyou can make informe d decisions with confidence.Our integrated set of best'in


6/6

delivering on nano's promise

Documents