Is dit de sleutel tot kankergenezing? Gerichte mitochondriale afgifte!
Kanker - een woord dat we allemaal vrezen en respecteren. Het is momenteel een van de meest voorkomende oorzaken van vroegtijdige sterfte wereldwijd. Het vinden van effectieve behandelingen voor kanker kan levens redden en lijden verminderen. In deze voortdurende zoektocht naar effectieve therapieën tegen kanker, duikte ik in de complexe wereld van nanomedicijnen om een nieuwe benadering te ontwikkelen waarbij therapieën gericht toegediend worden op subcellulair niveau, met name op het niveau van de mitochondriën.
De link tussen mitochondriën en kanker
Je zou je kunnen afvragen waarom het belangrijk is om therapieën specifiek in de mitochondriën van de cel te krijgen voor de behandeling van kanker. Wel, mitochondriën functioneren (onder andere) als energiefabriek van de cel en spelen een rol bij de regulatie van zowel celdood als celoverleving. Als we deze subcellulaire organellen specifiek kunnen targetten in kankercellen, kunnen we hun energievoorziening verstoren en de ontwikkeling en groei van kankercellen remmen.
Hoe geraken we in de mitochondriën?
Geneesmiddelen op een gerichte manier in de mitochondriën van kankercellen brengen vormt een grote uitdaging gezien de complexe structuur van de cellen, maar ook van de subcellulair organellen. Naast vele barrières zoals weefselspecifieke barrières en cellulaire barrières zoals het celmembraan, moeten nu ook barrières op het niveau van de structuren binnen de cel worden overwonnen.
Nanomedicijnen vormen een veelbelovende oplossing voor de gerichte toediening van therapieën op het subcellulair niveau. Het zijn minuscule boodschappers, veel kleiner dan een cel, die geneesmiddelen kunnen dragen en ervoor zorgen dat ze op de juiste plek in ons lichaam terechtkomen. Nanomedicijnen zijn al jaren een ‘hot field’ vanwege hun vele voordelen, waaronder het vermogen om gerichter te werken, zoals uitsluitend op kankercellen, zonder schade aan gezonde cellen te veroorzaken. Wat resulteert in minder bijwerkingen in vergelijking met traditionele behandelingen.
In de wereld van nanogeneeskunde, zijn er nanogeneesmiddelen genaamd polymeer-geneesmiddel conjugaten. In deze gevallen wordt het geneesmiddel verbonden aan een polymeer via een chemische verbinding genaamd een "linker". Dit is anders dan sommige andere nanogeneesmiddelen waarbij het geneesmiddel niet chemisch gebonden is, maar iets eromheen is gewikkeld of wanneer het geneesmiddel zelf gereduceerd is tot nanoschaal. Een polymeer is eigenlijk een soort chemische structuur die is opgebouwd uit herhaalde eenheden, vergelijkbaar met LEGO-blokjes. Bijvoorbeeld, in het geval van polypeptide-geneesmiddel conjugaten, bestaat het polymeer uit een polypeptide, met herhaalde eenheden die aminozuren worden genoemd.
De kunst van het nanomedicijn: ontwerp en synthese
Een polypeptide-geneesmiddel conjugaat, dat bekend staat als ‘trivalent’ werd gedesignd en gesynthetiseerd. Het systeem is genaamd 'trivalent', omdat het bestaat uit drie belangrijke onderdelen. Ten eerste is er trifenylphophonium (TPP), dat als een soort richtpunt fungeert en zorgt voor accumulatie in de mitochondriën van kankercellen. Dan hebben we polyornithine (PLO), een soort drager die helpt bij het afleveren van het geneesmiddel in het cytosol (het binnenste gedeelte van de cel) nadat deze door de cel is opgenomen. Ten slotte is er het geneesmiddel zelf dat moet worden afgeleverd. Om deze componenten te verbinden, wordt een disulfidelinker gebruikt.
Het systeem werd gesynthetiseerd in een complex proces van acht stappen, waarbij een fluorescerende stof genaamd cy5 amine werd gebruikt als een substituut voor een mogelijk geneesmiddel, om visualisatie via microscopie mogelijk te maken. Na een uitgebreide karakterisering van het uiteindelijke trivalente systeem werd bevestigd dat de juiste structuur was gesynthetiseerd. Bovendien werd een geoptimaliseerde opzuiveringsmethode ontwikkeld aangezien er na opzuivering nog steeds nevenproducten aanwezig waren.
Het verminderen van de toxiciteit is cruciaal
Vanwege de positieve ladingen, kan het trivalent systeem van nature schadelijk zijn voor alle cellen. Dit komt doordat deze ladingen de elektrische balans van de cel verstoren, wat schade kan veroorzaken aan de celmembraan structuur, normale cel processen kan verstoren en zelfs tot celdood kan leiden. Hierdoor is het testen en verminderen van de cel toxiciteit in borstkankercellen een belangrijk aspect in de ontwikkeling van een effectief nanomedicijn.
Om de schadelijke effecten van het trivalent systeem te verminderen, hebben we de positieve ladingen bedekt met een stof genaamd VLC3, die van nature negatief geladen is. Er is ook gebruik gemaakt van plasmide DNA om een soort stabiel "pakketje" te vormen met het trivalent nanosysteem, genaamd polyplexes.
Toekomst?
Als we erin slagen om de schade aan cellen met succes te verminderen toont het trivalente systeem potentieel voor het leveren van geneesmiddelen of zelf genetisch materiaal (aangezien plasmide DNA werd gebruikt in de polyplexes) in mitochondria van de kankercellen. Het is echter noodzakelijk om verder te testen hoe het trivalente systeem presteert wanneer het daadwerkelijk wordt gebruikt om geneesmiddelen in de mitochondria te krijgen in plaats van de fluorescerende stof.
Bovendien toont het trivalente systeem niet alleen potentieel voor kankerbehandeling, maar ook voor de behandeling van een breed scala aan ziekten die verband houden met mitochondriale disfuncties, zoals neurodegeneratieve aandoeningen (zoals Alzheimer en Parkinson), metabole ziekten (waaronder diabetes en obesitas), evenals degeneratieve aandoeningen (zoals hart- en nierfalen).
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