Application of Dendrimers for the Treatment of Infectious Diseases

32 Pages·2017·6.9 MB·English

molecules
Review
Application of Dendrimers for the Treatment
of Infectious Diseases
ZandileMhlwatikaandBlessingAtimAderibigbe*
DepartmentofChemistry,UniversityofFortHare,AliceCampus,EasternCape5700,SouthAfrica;
[email protected]
* Correspondence:[email protected];Tel:[phone]
(cid:1)(cid:2)(cid:3)(cid:1)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:1)
(cid:1)(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)
Received:14May2018;Accepted:15June2018;Published:31August2018
Abstract: Dendrimers are drug delivery systems that are characterized by a three-dimensional,
star-shaped, branched macromolecular network. They possess ideal properties such as low
polydispersityindex,biocompatibilityandgoodwatersolubility. Theyaremadeupoftheinterior
andtheexteriorlayers. Theexteriorlayerconsistsoffunctionalgroupsthatareusefulforconjugation
ofdrugsandtargetingmoieties. Theinteriorlayerexhibitsimproveddrugencapsulationefficiency,
reduceddrugtoxicity,andcontrolledreleasemechanisms. Theseuniquepropertiesmakethemuseful
for drug delivery. Dendrimers have attracted considerable attention as drug delivery system for
thetreatmentofinfectiousdiseases. Thetreatmentofinfectiousdiseasesishamperedseverelyby
drugresistance. Severalpropertiesofdendrimerssuchastheirabilitytoovercomedrugresistance,
toxicityandcontrolthereleasemechanismoftheencapsulateddrugsmakethemidealsystemsfor
thetreatmentofinfectiousdisease. Theaimofthisreviewistodiscussthepotentialsofdendrimers
forthetreatmentofviralandparasiticinfections.
Keywords: dendrimers;polymers;antivirals;parasites;drugdelivery
1. Introduction
Infectiousdiseasesarecausedbymicroorganismssuchasbacteria,viruses,parasitesorfungi[1].
The diseases can be transmitted by bites from insects or animals; or they can be spread directly
or indirectly from one person to another or through contaminated food, plants, soil or water [2].
Peoplewithcompromisedimmunesystemsandchildrenarethemostaffectedbythediseases[3,4].
Infectiousdiseasescanbetreatedbuttheirtreatmentishinderedbysimultaneousresistancetomultiple
drugs[3,5]. Duetothedevelopmentofdrugresistancebyinfectiousagents,severalresearchershave
developeddrugdeliverysystemsforthetreatmentofinfectiousdiseases.
Viruses are microorganisms living cells that replicate only within living cells by using the
enzymesystemsofthecells. Viralinfectionsinhumanincludeherpes,influenza,HIV/AIDSetc.[6].
About7.7%ofdeathsinSouthAfricawerecausedbyinfluenzaandpneumoniain2011[7]. Astudy
conductedinSouthAfricaalsoshowedthatabout44%ofHIVpatientswerelikelytohaveinfluenza
co-infection[8]. AIDSstillremainsthetop10leadingcausesofdeathinSouthAfrica[9]. Althoughthe
numberofinfectiousdiseasesisstillhighglobally,theoveralldeathrateisdecreasing. Thismaybe
duetotheimprovedservicedelivery,improvedaccesstohealthcarecentre,goodnutrition,andbetter
educationaboutinfectiousdiseases[10]. However,in2010,thenumberofdeathcausedbyinfectious
diseaseshaddecreased[11]. TheWorldHealthOrganization(WHO)reportedthatthereisapossibility
ofamilliondeathsduetoinfectiousdiseasesby2050indicatingthatthereisapressingneedtodevelop
therapeuticsthatcantreatinfectiousdiseaseseffectively[12].
Drugdeliverysystemsarepotentialtherapeuticcarrierswhichofferseveraladvantageswhen
comparedtotheconventionaldrugsusedforthetreatmentofinfectiousdiseases. Someexamplesof
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deliverysystemsusedforthetreatmentofinfectiousdiseasesarepolymer-drugconjugates,micelles,
nanogels,hydrogel,emulsion,dendrimersetc. Theuniquepropertiesofdendrimersasdrugdelivery
systems make them potential devices for the treatment of infectious diseases [13]. Some of the
advantagesare: reducedtoxicity,increasedspecificitywhichresultsintheprotectionofthehealthy
cell, tissuesandorgansfromthetoxicsideeffectsofthedrug; improvedbioavailability; extended
half-liferesultinginreducedkidneyclearanceandprotectionoftheincorporateddrugsfrompremature
degradationbyenzymaticreactionsandotherscavengingmechanisms. Thisreviewwillreportthe
biologicalefficacyofdendrimersinthetreatmentofinfectiousdiseases.
2. ParasiticInfections
Aparasiteisanorganismthatliveswithinoronahost,anditssurvivalisdependentonthehost.
Someparasiticdiseasesareeasilytreated,whilesomearenot. Commonparasiticdiseasesaremalaria,
leishmaniasis,schistosomiasisandtoxoplasmosis[14,15].
2.1. Malaria
MalariaisaparasiticdiseasecausedbythegenusPlasmodiumparasitecarriedbyfemaleAnopheles
mosquitoes[16]. TherearefivetypesofPlasmodiumparasitethatinfecthumans,including: P.ovale,
P.malariae,P.knowlesi,P.vivaxandP.falciparum[17]. Plasmodiumfalciparumisthespeciesthatcauses
themostlife-threateningformofmalaria. Thediseaseistransmittedtoapersonbyabiteofaninfected
femaleAnophelesmosquito[18]. Itcanalsobetransmittedfromonepersontoanotherthroughblood
transfusion,anorgantransplant,andsharingofneedlesorsyringes[18,19]. Itcanalsobetransmitted
fromaninfectedmothertoachildatbirth. Thisdiseaseiscommoninthetropicalandsubtropical
regionsacrosstheworld,whichincludesub-SaharanAfrica,AsiaandLatinAmerica[19,20]. Malaria
hasamajornegativeimpactoneconomicdevelopment,thusleadingtopoverty[21]. Thesymptoms
usuallybeginabouttentofifteendaysafteramosquitobite[21]. Typical,symptomsofmalariainclude:
fever, headaches, and vomiting, but in severe cases it can cause seizures, anemia, abnormal pains
andcoma[22].
2.2. Leishmaniasis
LeishmaniasisiscausedbytheLeishmaniaparasitethatusuallylivesininfectedsandflies. Itcan
betransmittedfromabiteofafemaleinfectedsandfly[23]. Thisdiseasecanalsobetransmittedfrom
onepersontoanotherthroughbloodtransfusionorbysharingofneedles[24]. Leishmaniasisisfound
inpartsoftropicandsubtropicalregionswhichinclude: EastAfrica,SouthAmericaandAsia[25].
Thereareseveraldifferentformsofleishmaniasisbutthemostcommoninhumansare: cutaneousand
visceral[26]. Themainsymptomofcutaneousleishmaniasisisskinsores. Commonsymptomsfor
visceralleishmaniasisareweightloss,fever,enlargedspleenandenlargedliver[27].
2.3. Schistosomiasis
Schistosomiasisisthethirdmostdevastatingparasiticdiseaseintheworld[28]. Itisthecauseof
mortalityandmorbidityindevelopingcountriessuchasAfrica,SouthAmericaandAsia[29]. In2014,
anestimated61.6millionpeoplewereinfectedwithschistosomiasis[30]. Itiscausedbyaparasite
called Schistosoma and the parasite is a fluke [31]. The parasite affects the intestines and bladder,
butbecauseitlivesintheblood,thusitcanalsoaffectothersystems. Afterinfection,thepersonmay
developarashoritchyskinwithin1–2monthswithsymptomssuchasmuscleaches,fatigue,cough,
weightloss,feverandchills[32].
2.4. Toxoplasmosis
ToxoplasmosisisaninfectioncausedbyaparasitecalledToxoplasmagondii[33]. Theinfection
usually occurs from the exposure to infected cat faeces, by eating undercooked meat, or it can be
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transmitted from mother to child during pregnancy [33]. It can also be found in contaminated
water[34]. Peoplewhoareatahighriskoftheinfectionarethosewithcompromisedimmunesystems
andinfantsborntomotherswithactiveinfectionduringpregnancy[35]. Toxoplasmosiscancause
seriouscomplicationstothosewithweakenedimmunesystemssuchasinfants,pregnantwomenand
peoplelivingwithHIV/AIDS[35]. Mosthealthypeoplewhoareinfectedwithtoxoplasmosisshowno
signsorsymptomsbutsomemaydevelopsymptomssimilartoflu,fever,bodyaches,headacheand
fatigue[36]. Toxoplasmosisislife-threateninginpeoplewithlowimmunesystemsandtheyareatrisk
ofdevelopingseizures,confusion,pooreyevision,andlunginfection[36,37].
3. ViralInfection
Viruses are microorganisms that replicate only within living cells by using the cells’ enzyme
systems[38]. TheycausediseasessuchasHIV,herpes,cervicalcancer(HPV),meningitis,hepatitis,
andinfluenzaetc.[39].
3.1. HIV
HIVisahumanimmunevirusthatcausesacquiredimmunodeficiencysyndrome(AIDS)over
time[40]. HIVattacksimmunesystemofthebody,causinglowCD4count. AIDSisthefinalstage
of HIV infection, but not everyone with HIV develop AIDS [41]. When HIV has manifested into
AIDS,itbecomeslife-threateningbydestroyingthewhitebloodcellsthatusuallyfightinfections[42].
Thiscancauseseriousinfectionsanddiseasesliketuberculosis,candidiasisandmeningitisetc.[43].
HIVistransmittedthroughsexualintercoursewithaninfectedperson,throughbloodtransfusion
from an infected person, and from an infected mother to her baby through breastfeeding, during
pregnancy[44]. ThesymptomsofHIVusuallydevelopseveralmonthsorevenyearsafterinfection
withthevirus[45]. TheearlysymptomsofHIVinfectioninclude: fever,chill,jointpain,andrashes.
IfHIVhasmanifestedintoAIDS,thenthesymptomsmayincludediarrhea,drycough,weightloss,
nightsweatsandseriousfever[45,46].
3.2. Influenza
Influenzaisacontagiousrespiratoryinfectionwhichaffectspeopleofallages[47]. Thevirusis
transmittedthroughtheairbycoughsandsneezesandinfectsthenose, throat, mouth, andlungs.
It can also be transferred by touching surfaces that are already contaminated with the virus [48].
Theviruscanbedeadlyinindividualswithlowimmunesystem(i.e.,newbornbabies,elderlypeople
andpeoplelivingwithchronicdiseases)[49]. Therearethreecommonformsofinfluenza,namely:
typeA,BandC[50]. TypeAfluvirusesarethemostdangerousandexhibitdeadlycomplications
andareresponsibleforthelargehumaninfluenzapandemics[51]. Thevirusmostlyaffectshumans
butanimalsandwildbirdsarealsoknownhostsforthefluvirus[51]. TypeBvirusislesscommon
thanAanditonlyaffectshumans[52]. AlthoughtypeBisveryharmful,butitislessseverethantype
A[53]. TypeBinfluenzadoesnotcausehumanpandemics[54]. InfluenzatypeCcausesmilddiseases
andislesscommonthanothertypes,therearenoepidemicsassociatedwithinfluenzatypeC[55].
Symptomsincludecough,chills,headaches,sorethroatandbodymuscleaches[56].
3.3. Meningitis
Meningitisisaviralinfectionofthemeninges,thetoughlayeroftissuesurroundingthespinal
cordandthebrain[57]. Meningitiscanleadtobrainswellingcausingpermanentdisabilitiessuch
as coma, and can lead to death if not treated [58]. There are four common type of meningitis
which include bacterial, viral, fungal and aseptic meningitis [59]. Bacterial meningitis is the most
life-threateningandcanleadtodeathinfewhours[59].ItiscausedbythebacterialsuchasStreptococcus,
Streptococcuspneumonia,NeisseriameningitidesandListeriamonocytogenes[60]. Mostpeopleareluckyto
recoverfromit,buttheyarelikelytogetpermanentdisabilitiessuchashearingloss,braindamageand
coma[60]. Viralmeningitisiscausedbyvirusessuchasenteroviruses,herpesvaricellaandmumps
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viruses[61]. FungalmeningitisiscausedbypathogenssuchasCandidaspp.-Histoplasmacapsulatum
andCryptococcusneoformans. Fungalmeningitisismostcommoninpeoplewithlowimmunesystems,
and it is more severe in people with impaired immune systems (e.g., organ transplantation) [62].
ParasiticmeningitisiscausedbyparasitessuchasAngiostrongyluscantonensis,Schistosoma,Toxocariasis
and Gnathostoma spinigerum. The infection is believed to occur when there is a predominance of
eosinophiliaintheCSF[63]. Symptomsofmeningitisincludefever,stiffnessofneck,nausea,headache
andvomiting[64].
3.4. Herpes
Herpesisasexuallytransmitteddisease[65].OralherpesisalsoknownasHSV-1,ortype1herpes
simplex[66]. Itcanbetransmittedviainfectedsaliva,mucousmembranesorskin[67]. Thisvirus
causessoresinthemouth,gums,tongue,faceornose.Itcausessymptomssuchasfever,swollenlymph
nodesandmuscleaches[68]. GenitalherpesisalsoknownasHSV-2,ortype2herpessimplex[69].
Thisviruscausessoresaroundthegenitalareas. Thevirusistransmittedthroughskin-to-skincontact
withsores[69]. GenitalherpesismostlikelytoaffectwomenthanmenandwomenwithHIVare
difficult to treat resulting in the administration of higher doses of antiviral drugs [70]. The virus
sometimeshidesinthenervescausingnosymptoms. Ifthesymptomsarevisible,thenapersonmay
experienceitchypainfulblisterswhichcouldresultsinulcers[71].
3.5. Hepatitis
Hepatitisistheinflammationofthelivertissueresultingfromalcoholabuse,certainmedications
and toxins [72]. Common types of hepatitis are Hepatitis A, B and C. Hepatitis A is a virus that
causes liver infection [72]. It is transmitted through the digestion of food or water that is already
contaminatedwiththefaecesofaninfectedperson[73]. SymptomsofhepatitisAincludevomiting,
tiredness,jointpains,darkurineandintenseitching[74]. HepatitisBiscausedbythevirushepatitis
Banditistransmittedfrombloodandbodyfluidsofaninfectedperson. Itisalsotransmittedfrom
mother-to-unbornbabyifthemotherisinfected[75]. HepatitisBcanbepreventedbyvaccination.
SymptomsaresimilartothoseoftypeA;theyincludeheadache,darkurine,andvomitingetc.[76].
HepatitisCcausesseriouslivercancer,whichcouldleadtolivertransplant[77]. Approximately80%
ofpatientswithhepatitisCdevelopchronicliverinfection[78]. Itistransmittedviasharingneedles
withaninfectedperson,throughingestingdrugsandthroughmothertochildtransmissionduring
pregnancy. Symptomsincludefever,fatigue,nausea,abdominalpainandjaundice[79].
3.6. CervicalCancer
Cervicalcanceriscausedbyaviruscalledhumanpapillomavirus(HPV)andthisviruscauses
thegrowthofabnormalcellsonthecervixwhichiscancerous[80]. HPVistransmittedviasexual
intercourse[81]. TherearefactorsthatcontributetothedevelopmentofHPV,suchashavingmany
sexualpartners,peoplelivingwithHIVIarelikelytobeinfectedwiththedisease,long-termuseof
contraceptives,havingseveralpregnanciesandgivingbirthatayoungage[82]. Symptomsofcervical
cancerincludeabnormalvaginalbleeding,abnormalvaginaldischarge,andvaginalbleedingafter
menopause,heavyperiodsandvaginalbleedingaftersex[83].
4. ApplicationofDendrimersintheTreatmentofInfectiousDiseases
Infectious diseases are caused by microorganisms, such as bacteria, viruses, parasites or
fungi[84]. Infectiousdiseasesarecurrentlybeingtreatedbytherapeuticssuchasantibiotics,antiviral,
anti-parasiticandantifungal[85]. Mostofthesetherapeuticssufferfromseverelimitationssuchas
drugresistance,toxicityandtheirroutesofadministrationresultinpoorpatientcompliance[86,87].
Thedrug-resistantproblemisduetodifferentmechanismsuchasincreasedeffluxsystem;reduced
membranepermeabilityorincreaseofdrugdegradation[88]. Duetotheselimitations,theapplication
oftargeteddrugdeliverysystemisanattractivecarrierforthetreatmentofinfectiousdiseases[89].
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Drugdeliverysystemisusedtotransportpharmaceuticalcompoundsdirectlytothetargetedorgans
or tissue with less toxic effects on the organs/tissue [90]. There are many different types of drug
deliverysystems,suchasdendrimers,micelles,liposomes,nanospheres,nanocapsules,hydrogelsand
polymer-drugconjugates[91]. Anidealdrugdeliverysystemmustbeabletoreducedrugtoxicity,
improvebioavailability,biocompatibility,enhancedrugsolubility,non-immunogenic,biodegradable,
enhancepatients’complianceandbeabletoovercomedrugresistance[92,93].
Dendrimers are synthetic polymers with three-dimensional, star-shaped and branched
macromolecules[94]. Theyaremadeupoftheinteriorlayersandtheexteriorlayers. Theexterior
layer is composed of functional groups which are useful for conjugation of drugs and targeting
moieties[95]. Theinteriorlayersaresuitableforencapsulationofdrugmoleculeswithimproveddrug
efficacy,reducingdrugtoxicityandcontrolreleasemechanismsofdrugs[96]. Theyarewater-soluble,
biocompatible, polyvalence, and biodegradable [96]. These properties make them useful for drug
delivery and they are being investigated by several scientists [97]. Figure 1 shows a schematic
diagramofdendrimersfromgenerationonetofour. Thisreviewwilldemonstratetheimportanceof
dendrimersasatargeteddeliverysystemforthetreatmentofinfectiousdiseasespreciselyviraland
parasiticinfections.
Figure1.Schematicdiagramofdendrimers(G1–G4).
4.1. VariousDendrimersandTheirApplications
Dendrimershaveseveralmedicalandpracticalapplications;theycanbeusedfordrugdelivery,
genedelivery,tissueengineeringandfordiagnosis[98]. Severaldendrimershavebeendeveloped
for biomedical applications [98]. Polyamidoamine (PAMAM) has been used extensively for drug
delivery(Figure2a)andtissueengineering(Figure2b),becauseoftheirbiocompatibility,hydrophilic
nature and non-immunogenic effect [99]. PAMAM dendrimers consist of ethylenediamine core,
theirbranchingunitsconsistofaminegroupsthatcanbeusedtoloaddrugs,antibodies,enzymes
and other bioactive agents [100,101]. Poly-L-lysine (PLL, Figure 2c) dendrimers are mostly used
as gene carriers; they contain two primary amines which are often modified to enhance their
therapeuticeffects[102]. Poly-L-Lysinedendrimersarebiocompatible,flexible,biodegradableand
water-soluble[102]. Poly(propyleneimine)(PPI,Figure2d)dendrimersareusedfordiagnosis[103].
ThecoreofPPIisusuallybasedona1,4-diaminobutaneorethylenediamineandthebranchingunits
consistsofpropyleneiminemonomers[103].
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Figure2.Cont.
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Figure2.Cont.
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Figure2.Schematicrepresentationofdendrimersandtheirapplications,(a)PAMAM-G3dendrimers
fordrugdelivery;(b)PAMAM-G1dendrimersfortissueengineering;(c)PLLdendrimersforgene
delivery;and(d)PPIdendrimersfordiagnosis.
4.2. DendrimersfortheTreatmentofLeishmaniasis
Leishmaniasisisalife-threateningdiseasethatiscausedbyaLeishmaniaparasiteandtransmitted
through a bite of an infected sand-fly [104]. About 12 million cases of people are affected by
leishmaniasisacrosstheworldandtwomillioncasesofleishmaniasisoccurannually[105]. Forseveral
decades, leishmaniasis was being treated with drugs such as sodium stibogluconate (Pentostam,
Figure3b)andmeglumineantimoniate(Glucantime)[106]. Although,thesedrugshavebeenusedfor
severaldecades,theyhavebeenreportedtodevelopresistancetoleishmaniasiswithsideeffectssuch
ascardiotoxicityandpancreatitis[107]. AstudyinIndiarevealedthatabout65%ofpatientsrelapsed
aftertreatmentwithanantimonial[108]. Thereisanincreaseinthecasesofresistancetopentavalent
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antimonialreportedworldwide[108,109]. Duetoemergenceofresistanceoftheparasitetoantimonial
drugs,amphotericinB(AmB,Figure3c),Miltefosine(Figure3a),andparomomycin(Figure3d)are
beingusedasalternativetherapeuticsforthetreatmentofleishmaniasis[110]. However,thereare
severe side effects associated with their use and they are also expensive [111]. Amphotericin B is
usedasbothantifungalandantiparasite,althoughitshowsagoodefficacy,butitisexpensiveand
requiresoraldose[112]. Miltefosineisananticancerdrugbutithasbeenapprovedasanoraldrugfor
leishmaniasis[113]. Miltefosinealsoshowsgoodefficacy,butitisveryexpensivewithlimitationssuch
aslowbloodplatelets,nephrotoxicity,diarrheaetc.[113]. Recently,theuseofnanocarrierssuchas
dendrimershaveshownpromisingresultsinthetreatmentofleishmaniasis[114].Dendrimershavethe
abilitytotransportdrugstothetargetedsite,reducedrugtoxicity,increasedrugsolubilisation,protect
thedrugfromdegradationandultimatelykilltheprotozoa[115]. Jainetal.developedaformulation
ofmuramyldipeptideconjugatedwithpoly(propyleneimine)(PPI)dendrimersencapsulatedwith
amphotericin B (Figure 4). The synergistic antiparasitic activity of the formulation was evaluated
invivo. The invivo results showed that the formulation was active against the parasite infection
ofmacrophagecelllinesandbalb/cmice. Thetoxicityoftheformulateddrugloadeddendrimers
wascomparedtothemarketedformulationofamphotericinB.Thepreparedformulationexhibited
a reduction of (p < 0.01) in toxicity towards human erythrocytes cells and J774A.1 macrophage
cells[116],revealingthepotentialofthedendrimerstoreducethetoxicityassociatedwithamphotericin
B(Table1). Themacrophagetargetingabilityoftheformulationwasenhanced,resultinginthekilling
oftheparasites. Theseresultssuggestedthattheformulationsarepotentialimmunomodulatorywith
antileishmanial activity for targeted drug delivery of amphotericin B. Daftarian et al. developed
acomplexbetweenliposomeamphotericinBandPan-DR-bindingepitope-baseddendrimerstostudy
the therapeutic efficacy of low dose LAmB/PDD against full dose of LAmB via L. major mouse
method [117]. The formulation exhibited reduced toxicity which was visible by dose reduction.
Invitro toxicity of the formulation revealed reduced toxicity on Hep2 cells. The formulation was
alsodeliveredselectivelytoparasitereservoircells,phagocytes[117]. Theinvitroandinvivostudies
revealedan83%improvementindrugefficacywithasignificantreductionofparasiteburdenand
toxicity. Jainetal. preparedapoly(propyleneimine)dendrimerscontainingmannoseloadedwith
amphotericinB(Table1).Theformulationexhibitedgooddrugincorporationefficiencyandtheinvitro
results revealed pH-dependent drug release mechanism. The formulation also exhibited reduced
toxicityonhumanerythrocytesandmacrophagecellsandtheefficacyoftheloadeddrugwasnot
compromised[118]. Thesedendrimerswereobservedtohavesignificantantiparasiticactivitytowards
L.denovaniamastigoteswithapromisingantileishmanialactivity[118]. Furthermore,pharmacokinetic
andorgandistributionstudiesrevealedthecontrolleddeliverymechanismoftheformulationwhich
wascharacterizedbyanenhanceddruguptakeinmacrophage-richorgans.
Table1.Variousdendrimersforparasiticdiseases.
DendrimersClassification CombinationwithTypeofDrugs TypeofInfection References
PPI AmphotericinB Leishmaniasis [116,118]
Sulfadoxine,chloroquine
PAA Toxoplamosis [118,119]
andprimaquine
DNA Schistosomiasis [120]
PAMAM
Chloroquineandprimaquine Malaria [121]
Poly-L-lysine Chloroquine Malaria [122]
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Figure3. Antileishmaniasisdrugs(a)Miltefosine; (b)Sodiumstibogluconate; (c)AmphotericinB;
(d)Paromomycin.
Figure4.DendrimerloadedwithamphotericinB.