fl
Soleiman Jaferian
a, Babak Negahdari
b, Ali Eatemadi
b,c,*
aDepartmentofInternalMedicine,LorestanUniversityofMedicalSciences,Khoramabad,Iran
bDepartmentofMedicalBiotechnology,SchoolofAdvanceScienceinMedicine,TehranUniversityofMedicalSciences,Tehran,Iran
cDepartmentofMedicalBiotechnology,SchoolofMedicine,LorestanUniversityofMedicalSciences,Lorestan,Iran
ARTICLE INFO
Articlehistory:
Received25August2016
Receivedinrevisedform29September2016 Accepted1October2016
Keywords:
Drugdelivery Polymer 5-Flurouracil 5-FU Coloncancer
ABSTRACT
Therehasbeenseveralresearchworksonthedevelopmentofanoraldeliverysystemtodelivercytotoxic andchemopreventiveagentsdirectlyatthetargetedsiteofactionwithreducedunwantedsideeffects.
Theefficacyofthesite-specificdeliverysystemofadrugtocolonhasbeenproventoincreasethedrugs concentrationatthetargetsite,andthusrequiresareduceddoseofthedrugwithminimizedsideeffects.
Thisreviewincludesdiscussionofthedeliverysystemsof5-FUusingbiodegradablematerialsandsome significantoutcomesinthepre-clinicaldevelopmentof5-fluorouracilcarriersforthecoloncancer.
ã2016ElsevierMassonSAS.Allrightsreserved.
Contents
1. Introduction ... 780
2. Coloncancer:causesandetiology ... 781
2.1. Deliveryroutes ... 782
2.2. 5-Fluorouracil ... 782
2.3. Fluorouracildeliverysystems ... 783
2.4. Biodegradablematerials ... 783
2.5. Alginatebeads... 783
2.6. Poly(E-caprolactone)(PCL) ... 784
2.7. EUDRAGIT1 ... 784
2.8. Guargum ... 784
3. Bovineserumalbumin(BSA)nanoparticle ... 785
3.1. Poly(D,L-lactide)(PLA)andpoly(D,L-lactide-co-glycolide)(PLGA) ... 785
4. Preclinicalresearchstudieswith5-fluorouracildeliverysystems ... 785
5. Deliverysystem ... 785
6. Conclusion ... 786
Declarationofinterest ... 786
Acknowledgments ... 786
References ... 786
1.Introduction
Colorectal cancer (CRC) is the third deadliest and widely diagnosedcancerintheworld,accountingfor10%ofallcancers[1].
Around55%ofcoloncancercaseswerediagnosedinAustraliaand NewZealandwithitshighprevalenceamongelderswithamedian ageof69yearsold[2].Approximatelyinayear,5,60,000peopleare losttocoloncancerworldwide.Coloncancerhasahighmetastatic andit’sinsensitivetometastaticintheliverandassuch,thereisa
*Correspondingauthorat:DepartmentofMedicalBiotechnology,Schoolof AdvancedTechnologiesinMedicine,TehranUniversityofMedicalSciences,Tehran, Postaladdress:6997118544,Iran.
E-mailaddress:[email protected](A.Eatemadi).
http://dx.doi.org/10.1016/j.biopha.2016.10.004
0753-3322/ã2016ElsevierMassonSAS.Allrightsreserved.
need to develop a new resistance mechanism [3–7]. Cytotoxic drugsaremadeofheterogeneouschemicalcompoundsthatare toxicorharmfultocancerouscellsthathavetheabilitytorapidly growanddivideandassuchtheseagentspreferentiallykillthem [8–12].Thesecytotoxicdrugsareroutinelyadministeredintrave- nouslyintheformoffreedrugbutfailureisstillbeingrecorded especiallyforpatientswithahistoryofmalignanciesthathavean allergytochemotherapeuticagents[7,13–16].Whencomparedto otherclasses of drugs, cytotoxic drugs, lack specificity in their systemic delivery of their effects which eventually results in subsequentsideeffectscausedbythedrugattackingbothhealthy and target cells [17]. In addition, due to their antagonistic pharmacokinetics,there is aneed toadministera highdoseof the drugs. Several past types of research have shown that Fluoropyrimidines,Irinotecan,andOxaliplatinhaveemergedhas potentdrugsofchemotherapyforCRC[18].However,asaresultof unevenandunspecificdeliveryintotheliver[8],intestinalmucosa andother vitalhealthytissues theyare usuallydiagnosed with severemucositis, myelosuppression,and hematologicaladverse reactions[19].
2.Coloncancer:causesandetiology
There are several causes of CRC, mostof theCRC casesare irregularwithnonoticeablefamilyhistoryorheritabletendency.
80%-85%ofCRCpatientswithnonhereditarysporadicadenoma- tous polyposis (SAP) exhibited a somatic mutation of the adenomatous polyposis Coli (APC) as a distinctive marker.
Furthermore,mutationoftheAPCgenewasearlieridentifiedas
thecauseofCRCbutseveralfactorshavebeenrecentlyidentifiedas causativeagentsofCRCthatincludesdiets,smoking,environmen- talhazards,viruses,andlifestylesofdifferentindividuals(Fig.1) [20–25].
Currently,mostofthechemotherapiesareIntravenoustherapy, whichinvolvesadministrationofchemotherapeuticagentsdirect- lyintothevein,however,intravenoustherapyexposesthepatient totheriskofbloodbacterialinfectionthroughthebreakoftheskin [22,27–31].Inaddition,intravenoustherapieshavenotprovento be potent to treat colon cancers as the administered drugs is responsiblenotonlyforthedeathofcancerouscellsbutalsothe healthyandvitalcellsinthebody,whichresultsinveryseriousand life-threatening side-effects [32]. The most commontreatment optionforCRCissurgerythatinvolvestheremovalofcancerous tissuesbyminimallyinvasivesurgeryfollowedbyradiotherapyto helpdecreasethesizeofthecoloncancertumorbyinducingDNA fragmentation processes and inhibits intracellular membranes therebycausingcellapoptosis[33–35].Therefore,thedesignofa morepotentdrugdeliverysystemstoreducetoxicityandimprove onthespecificdeliverytothecancerouscolonareaisofparamount importanceinthescientificcommunity[36–40].Itshouldbenoted thatcoloncancertreatmentselectionfullydependsonthespecific stageofthepatient’scancerandmedicalhistoryandconditions [41–45]. Over the years several polysaccharides have been demonstrated forcolon-specificdrugdelivery Table1. Itshould alsobenotedthatinadditiontopolymers,otherdrugcarriers,such as Microparticles,liposomes, solid lipidnanoparticleshavealso beendemonstrated effectivelytotargettheanti-cancerdrugto colon tumor (Table 1).For the purposeof this review, we will Fig.1.Showingsomecausesofcolorectalcancer.SeveralfactorshavebeenidentifiedascausativeagentsofCRCthatsuchasthedietwithhighfatandredmeat,smoking, aging,familyhistory,obesity,ulcerativecolitisandpolyps.Thisfigurewas.(Forinterpretationofthereferencestocolourinthisfigurelegend,thereaderisreferredtotheweb versionofthisarticle.)
Reproducedwithpermissionfrom[26].
discusstheuseofpolymerconjugatesorcopolymersinthedesign of5-FUdeliverysystems.
2.1.Deliveryroutes
There are several routes to achieve drug targeting to colon amongstthemisdirectadministrationfromtherectum(Fig.2)and oral route (Fig. 3).Each of these routes offers advantages and disadvantages for its use. Administration via the rectum, has showntobeeffectiveintherectumbecauseoftheireffectiveness in spreading across the colon but limited to the sigmoid and descendingcolon[55].
The direct rectal administration is in its way ineffective in distributing the precise drug dose to the entire area of colon making it a non-preferred method for a drug delivery in the managementofcoloncancer[40].
The oral route would have been an alternative way of administeringchemotherapydrugsvia colon-targetedoraldrug deliverysystemsbutthesedrugsaremostlyabsorbedorbroken
downinthestomachwallandsmallintestinepriortosuccessful deliveryofthedrugstothecolonregion(Fig.2).However,knowing andunderstandingthechemicalandphysiologicalfactorsaffecting drugdeliveryacrossthedigestivetractcanovercomethismajor setback[56].Theuseofaselectivedeliverysystemhasalsobeen instrumentalinpointdeliveryofdrugsdirectlytocolonathigh concentrationsofthechemotherapeuticdrugtothecolonrectal region,however,thereisaneedtoadministerareduceddoseofthe druginothertodecreasetheoccurrenceofsideeffects[57].
2.2.5-Fluorouracil
5-Fluorouracil (5-FU or 5-fluoro-2, 4-pyrimidinedione) is an antimetabolite of the pyrimidine analogue type, with a broad spectrumofactivityagainstsolidtumors,aloneorincombination chemotherapy regimens [58]. Due to 5-FU structure, 5-FU obstructs withnucleoside metabolismand can beincorporated intoRNAandDNAsingleanddoublehelix respectively,thereby leadingtocytotoxicityandfinallycelldeath.5-fluorouracil(5-FU)
localefficacyattumorsitemediatedbyrIL-2fromasingle doseofmicrospheresthanthatofmultiplerIL-2solution injections
Pectin 5-fluorouracil(5-FU) Zincpectinatepellets Insituintracapsularwettingofpectincoatbydissolution mediumresultedintheformationofethylcelluloseplug interconnectingwithpelletsthroughthebindingactionof pectin.Lessthan25%ofthedrugwasreleasedintheupper gastrointestinaltract.Themajorityofdrugwasreleased uponprolongeddissolutionandinresponsetocolonic enzymepectinase,whichdigestedcorepellets
[49]
Guargum Piroxicam Tablettedguargummicrospheres Crosslinkedguargummicrospheresofpiroxicamwere directlycompressedintomatrixtabletandcoatedwith EudragitS100.Theoptimizedtabletthatdisplayed0%
releaseinsimulatedgastricfluid,15%insimulatedintestinal fluidand97.1%insimulatedcolonicfluidunderwent roentgenographicstudyinrabbitstocheckitssafetransitto thecolon.Thiscouldbeusedastargetedadjuvanttherapy forcolonicadenocarcinomas
[50]
Alginate Iron-saturatedbovine lactoferrin(Fe-bLf) protein
Alginate-enclosedchitosan-calcium phosphate-loadediron-saturatedbovine lactoferrinnanocarriers(Fe-bLf-loaded NCs)
Afteroraldelivery,thepharmacokineticandbioavailability studiesindicatedthatnanoformulatedFe-bLfwas predominantlypresentontumorcells(Caco-2)comparedto non-nanoformulatedFe-bLf.Fe-bLf-loadedNCswerefound tohelpinabsorptionofiron
[51]
Hyaluronicacid Anear-infrared fluorescenceimaging dye(Cy5.5)and irinotecan
Poly(ethyleneglycol)-conjugated hyaluronicacidnanoparticles(P-HA-NPs)
Cy5.5-P-HA-NPsandIRT-P-HA-NPsshowedtheranosticand therapeuticmonitoringpotentialforcoloncancer
[52]
Copolymerof2- hydroxyethyl methacrylatewith4- methacryloyloxy
5-FU Hydrogel Drugreleasewasfasterandgreaterinhumanfecalmedia
comparedtosimulatedgastricandintestinalfluids.Faster releaseduetothecleavageoftheazocrosslinksinthe hydrogelbytheazoreductase
[53]
Triglycerideesters 5-FU Solidlipidnanoparticlesbyevaporation technique
SLNssystemhasahighpotentialtoimprovetheuptakeof anticancerdrugsinsidecolontumors.Thereleaseprofileof thedruginsimulatedcolonicmediumshowedaprolonged patternthatmayallowspreadingofthedruginsidethe colontocovermostofthecolonicareawhereverthetumors mayexist
[54]
isconsideredoneofthemostpotentchemotherapydrugagentsfor thetreatmentofCRC.
However,itsefficacyhasbeengreatlyimpededbybeenableto bemetabolizedbydihydropyrimidinedehydrogenaseenzymein the gut wall immediately after oral administration [58]. The clinicalapplicationof5-FUhasnotbeenmaximallychanneledasa result of the ability of tumorcells to develop drug resistance, furthermore,5-FUchemotherapyneeds/requiresacontinuousand regularadministrationofhighdosesbecauseof itshighrateof metabolisminthebody[59].Becauseofthesereasons,intravenous administrationof5-FUhasbeenpreferredtooraltherapybutnot with its own disadvantages like severe cardiac, neural and gastrointestinalsideeffects.
Anefficientandsuccessful5-FUdeliverysystemshouldpossess thefollowingcharacteristics:
a)Physicalstability b)Smallsize c)Degradation-proof
d)Nolowstorageanddrugleakageproblems e)Controllable
f)Biodegradability
2.3.Fluorouracildeliverysystems
Thefollowingarefewof thecommon5-FUcolloidalcarriers andstrategiesdevelopedforitsdeliverytocancer[60].
Biodegradablepolymericparticles
Hydrogels
Vesicularsystems:liposomesandniosomes Magneticdrugdeliverysystems
Lipoproteins
Claymineralsandanionicclays Metals
Ionexchangeresins
2.4.Biodegradablematerials
There are several types of biodegradable materials for the applicationofdrugdeliverysystembasedonthedegradationrate of thecoating materialsand thedeliveryrate of thedrugthey encapsulate[61].Poly(lactide-co-glycolide)(PLGA)isaprovenand approvedcommonlyusedbiomaterial.Belowarethesomeofthe biodegradablepolymericmaterialusedin5-FUdeliverytocolon cancerregion[62].
2.5.Alginatebeads
Alginateisacopolymerofglucuronicacidandmanuronicacid anditsusefulnessisharnessedinboththedrugandpharmaceuti- calindustry.Theabilityofsodiumalginatetoformagelformation inthepresenceofCa2+ionabilityhasbeenharnessedintheaspect ofdrugdelivery.5-FUiscoatedwithalginatebeadsofadiameterof about1–2mm throughtheprocess ofgelation ofalginatewith calciumcations.Thealginatebeadsarepreparedbytheprocessof extrusion[63].
Fig.2.Showingdeliveryof5-FUviaIVadministration.ThefiguredepictedtheI.V.administrationof5-FUinbloodvessel,whichthendefuseintotumorlocation.Thisfigure was.
Reproducedwithpermissionfrom[26].
Fig.3.ShowingOral/enterictargeteddeliveryof5-FUtothecolorectalcancerouscell.Thefiguredepictedentrapmentof5-FUinananoparticle,whichincolonthecoatingof nanoparticleremoveandthedrugreleaseincolorectalcancercelllocationThisfigurewas.
Reproducedwithpermissionfrom[26].
importantinbothinvitroandinvivoculturemediumandithas beenused over theyears for 5-FUdelivery systems for cancer treatment[65].Poly-e-caprolactonehasbeenusedasimplantable- loadedmatriceswith5-FU.Thebiodegradableblockwasmadeby reactingPCLblockwithpoly(ethyleneglycol)blockwithoutany reactive catalyst at a temperature of about 185C [66]. This copolymerstructurewasformedthroughaknownring-opening procedure, which uses an active hydrogen atom of the poly (ethyleneglycol) blockand thencauses a selectiveacyl-oxygen cleavageofanestergroupofthemonomerring.Thereportofthese scientistshasshownthatthereisa possibilityofusingPCLasa
“time-delayed” 5-FU releasing system: a fast release of the anticancerdrug in the first 10h is followed bya slow release phase,andfinallyreachesalimitingvalueafter24h[67].
2.7.EUDRAGIT1
Eudragitdrug deliverysystem uses theprinciple of thepH- sensitiveapproacheslikemethacrylate/methacrylacidpolymers Eudragit1SandLinaslightlyacidictoneutralaqueousmediaat pH6and7.Furthermore,therehasbeenelaborateandextensive researchworks onEudragit1 P-4135Fand Eudragit1 RS100 on microencapsulationof5-FUintheoraltreatmentofcoloncancer andEudragit1RS100hasbeenprovenefficientformatricesspray- coatingwhenusedforthecolorectalcarcinomatreatment(Fig.4).
Eudragit1P-4135FapH-sensitivedrug,throughtheprocessofoil/
water emulsification has been used to develop 5-FU-loaded microspheres,throughthismethod,themicroparticlesmadefrom Eudragit1RS100within8hofadministration,5-FUwasdelivered
and with minimal systemic side effects. The Eudragit1 S100 coating has a protective function over the microspheres as it transitsviathedigestivesystempriortodegradationinthecolon and exposingthealginatecoretocolonicbacteriafor digestion (Fig.5).
Zambito Y et al. reported that controllable 5-FU designed matrices are effectivefor the oraldelivery system totreat and manage colon cancer tissue. The matrices with a diameter of 0.6mmcoatedwith5-FUweredesignedtobeplacedwithinan entericcoatedcapsuleforaspecifictargetingofthedrugtothe coloninadditionthematriceswerealsocoatedwithaprotective Eudragit1S100filmandcoveredinalayerofchitosanhydrochlo- ride. Which is responsible for dissolution and controlled the releaseof5-FUinthephysiologicalenvironmentofthecolon[70].
2.8.Guargum
Guar gum is a polysaccharide derived from Cyamopsis tetragonolobus (Leguminosae family).Developed for site-specific deliveryof5-FUtothecolonbyKrishnaiahetal.,80%ofguargum incompression-coatedtabletshavehighefficientofdelivery5-FU successfullytoacolorectalregion.Itremainsapotentialcarrierfor colon-specific drug delivery, delivery by guar gum shows no changes in physical appearance or dissolution pattern. Also, majorityofthe5-FUloadwasdelivereddirectlyintothehuman colon withminimaltozero amountof thedrugresidue in the intestinewhenadeliverysystemthatemploystheuseofa5-FU
Fig.4. SEMimagesofmicrospherespreparedwith Eudragit1 P-4135F(a)and Eudragit1(b)usinganoil/oilemulsificationprocess.Thisfigurewas.
Reproducedwithpermissionfrom[71].Eudragit1hasbeenprovenefficientfor matricesspray-coatingwhenusedforthecolorectalcarcinomatreatment.
Fig.5. SchematicstructureofEndragitS100coatedCitrusPectinNanoparticles(E- CPNs),whichloaded5-Fluorouracil.Thecoatinghasaprotectivefunctionoverthe microspheresasittransitsviathedigestivesystempriortodegradationinthecolon andexposingthealginatecoretocolonicbacteriafordigestion.
guargumcompression-coatedformulationswasused.Inregardsto thispreviousstudy,otherscientistshavefocusedonthisthearea by using a combination of various polysaccharide gum as a compressioncoatoverthecoretabletforacontrollabledelivery systemof5-FU[72].
3.Bovineserumalbumin(BSA)nanoparticle
GhazalFadaeianandcolleagueshavedemonstratedthedelivery efficiency of anti-HER2mAb-coupled BSA nanoparticles loaded withananticancerdrug,5-FU.Theyreportedthat this targeted deliverysystemwasabletoimprovethetherapeuticeffectof5-FU onHER2-positivecells.Thecombinationofspecifictargetingwith drugloadingintheseHSAbasednanoparticulatesystemsshould leadtoanimprovementincancertherapy(Fig.6)[73].
3.1.Poly(D,L-lactide)(PLA)andpoly(D,L-lactide-co-glycolide)(PLGA) Poly(D,L-lactide-co-glycolide)(PLGA)andpoly(D,L-lactide)(PLA) are the most commonly and highly preferred biodegradable materialbecauseofbiocompatibilityandbiodegradabilityproper- tiesthey possess.Theby-productof thebreakdownofPLA and PLGAthroughtheprocessofhydrolysisarelacticandglycolicacids andarefinallyremovedascitricacid.Theprocessofemulsification and solvent evaporation are two processes involved in the preparation of PLA and PLGA nanoparticles. Poly(D,L-lactide) (PLA)polymerisunderinvestigationforthedesignofnovelblock copolymerloadedwith5-FU.
Severalresearchershavedevelopedseveralnanoparticlesthat havepH-responsiveandbiodegradablepropertiesthatworkonthe principle ofgrafting biodegradable PLA ontoN isopropylacryla- mideandmethacrylicacid.Themostcommonlyusedmethodis the preparation of PLA-PEG-PLA triblock copolymers. Several techniqueshavebeendevelopedtomaximize5-FUloadingtoPLA nanoparticlesamongstthemare[74]:
Oil-in-oilemulsionsolventevaporationtechnique Nanoprecipitation-solventdisplacementtechnique Atriphasicreleasetechnique
4.Preclinicalresearchstudieswith5-fluorouracildelivery systems
Atpresent,severaldrugsareavailableforthemanagementof CRC.5-Fluorouracil(5-FU)/Leucovorinisthefirst-linetreatment, and the most common chemotherapy for metastatic CRC by inhibitingthymidylatesynthase.5-fluorouracil(5-FU),combined withleucovorinasbeenidentifiedasa potentsystemicchemo- therapytreatmentforcoloncancer.Presently5-FUisadministered given as anintravenous injectionand is directlydelivered into tumors,gutmucosa,bonemarrow,andhepatictissueasuracil.5- FUeffectsitsactionbyblockingthesynthesisandtheactionofthe thymine nucleotides and the enzyme thymidylate synthase respectively[75].Inaddition,5-FUalsoundergobioinactivation byaliverenzymecalleddihydrouracildehydrogenase, however, bioactivation of 5-FU–5-uoro-20-deoxyuridine occurs mostly in colon cancer cases than in healthy tissue. The activity of this enzymehasbeenrecordedashighestandlowestintheliverand colonrespectively.If5-FUisdeliveredspecifically/directlytothe colon infected region, theactive metabolite of 5-FU(5-uoro-20- deoxyuridine) shouldbemostavailableincolon tumorandthe systemic side effects of 5-FU associated with the intravenous administrationwillbeminimized.
5.Deliverysystem
Colon targeted oral delivery system is one of many logical approachesinusingchemotherapyasatreatmentoptionforcolon cancer of any stage as it is able to provideboth systemic and regionaldeliveryof5-FU,oxaliplatin,capecitabineandirinotecan.
Thishypothesishasbeenbasedontheabilityofthecolonactingas apossiblesiteforsystemicandlocaldrugdelivery[76].Inotherto develop a colon-targeted oral drug delivery system in the treatment and preventionof colon cancer,it’sofimportanceto takenoteofthesiteofactionandmodeofactionof5-FUgiventhat 5-FUiswelldeliveredintotheintestinalmucosa,bonemarrow, liverafterbeenadministeredintravenouslyasuracil.Toovercome thechallengesofadversesideeffectsposedbychemotherapy,oral drug delivery systems has been developed to transport the therapeutic drugs fromgastrointestinal tract tothecolon area.
The oral drugdelivery systems canachieve the sustaineddrug releaseusingthebiodegradableencapsulationmaterials.Thisalso enablesthedrugdeliverycarrierstobecompatiblewiththehuman body. In other to reduce both systemic side effects and dose/
durationofCRCtherapy,aprecise-specificanddose/ratecontrolled deliverysystemmustbeadopted[74].
Several studies have reportedsomenew approaches onthe developmentofcolon-targetedoral5-FUdeliverysystemsnamely suchas:
A new research based on pluronic block copolymers with multiple effects was reported to be potent as a drug delivery system.Inthereport,anewco-deliverysystem,pluronicP85block copolymers,responsiblefordeliveringchemotherapeuticagent5- Fu,oneoftheanticanceragentsusedinthetreatmentof colon cancer and anotherform of cancer, was developed in otherto reinforcethedrugcurativeeffect.
SimilarlyXuC,etal.[77]reportedthattheefficacyofpectinand its saltsin anin vivo studyasa carrier forcolon-specificdrug delivery,thisfurtherprovesrightearlierstudiesonthepotencyof pectin andcalcium pectinateas carriersforcolon-specificdrug delivery.Inanotherstudy,apectinbasedcolonspecificdelivery systemwasusedandthedeliveryofthe5-FUintothestomachand digestive system was minimizedby an enteric coating. Several studiesoninvitrodrugreleaseandinvivoorgandistributionhave shown the efficacy of enteric-coated pectin microspheres to deliver5-FUtothecolon.Studiesinratmodelhavealsoproventhe Fig.6.SEMmicrographof1F2-coupled5-FU-loadedBSAnanoparticlesat30000X
magnification.Thisfigurewas.
Reproducedwithpermissionfrom[73].
pellets,forthe5-FUtoappearintheplasmaandreachedareduced peakplasmaconcentration.However,theplasmaconcentrationfor uncoatedpelletswasrecordedhigherthanthecoatedpelletand tookalongertimetoappearintheplasma,therebysuggestingthat pectinandethylcellulose(1:2)coatedpelletsat30%thicknessof totalweightgaincandeliver5-FUtocolonforlocalaction.
Lamprecht A et al. combined 5-FU and leucovorin by microencapsulation using sensitive polymers, given leucovorin isapromoterfactorfortheactivityof5-FUfordeliveryindistal colon[71].Inanotherstudy,amultiparticulatetechniquewasused as an oral-delivery system that employs the use of a lectin- conjugatedChitosan-Ca-alginatemicroparticlesloadedwithacid- resistantparticlesforpotentialtreatmentofcoloncancertissue.
Hydrogels,aproductofmodificationofpsylliumwithacrylicacid with a responsive pH has been proven to be potent for 5-FU delivery to the colon. Oral Consumption of psyllium has the efficacytoreducetheriskofcoloncancerinhumansassuchithasa dual pivotal role by delivery and itself acting as an anticancer therapeuticagent[78].
6.Conclusion
Unfortunately, currentchemotherapeutictreatment forcolon cancer administers high doses of cytotoxic drugs, specifically combinationsof5-FUandIrinotecan,whichleavesthepatientwith serious health side effects. It is necessary to develop new nanomedicines withmultifunctional abilities that work onthe principle of different chemotherapeutic agents; with reduced systemicdosesandultimatelyreducingtheriskofserioushealth sideeffects.Furthermore,concomitantresearchapproachesaimed at overcoming the rapid metabolization and drug resistance associatedwith5-FUshould bedeveloped. Althoughseveral of these delivery approaches developed for 5-FU has led to an efficient improvement in the management and treatment of cancersat thepreclinicalstage,however, morestudiesare still neededtobetterdefinepotencyandestablishtheirefficiencyin clinicalpractice.Finally,moreresearchonphysicochemical and preclinical studies is still needed to investigate more on the developmentofsurface-functionalizeddeliverysystemsfor5-FU withmoreefficientandspecificdeliveryof5-FUatthecoloncancer regionandabletoimproveonthe5-FUuptakebycancercells.
Declarationofinterest
Theauthorshavenodeclarationofinterest.Theauthorsalone areresponsibleforthecontentandwritingofthepaper.
Acknowledgments
The authors thank the Department of Internal Medicine, LorestanUniversity of Medical Sciences, Khoramabad, Iran and DepartmentofMedicalBiotechnology,SchoolofAdvanceScience inMedicine,TehranUniversityofMedicalSciences,Tehran,Iran.
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