Homing peptides for targeting of brain diseases
Kuupäev
2020-04-06
Autorid
Ajakirja pealkiri
Ajakirja ISSN
Köite pealkiri
Kirjastaja
Abstrakt
Ühiskonna keskmise eluea suurenemise tulemusel kasvab vananemisega seotud kesknärvisüsteemi haiguste, näiteks Alzheimeri ja Parkinsoni tõve, sagedus. Nende haiguste puhul puudub tõhus ravi haiguse kulu peatamiseks või patsientide terveks ravimiseks. Neurodegeneratiivsed haigused pole iseenesest letaalsed, kuid haiguse progresseeruv kulg muudab patsiendid kõrvalabist sõltuvaks. Seevastu ajukasvajad on väga kehva prognoosiga – hoolimata ravist ei ületa agressiivsemate ajukasvajate korral patsiendide elulemus 1,5 aastat.
Kesknärvisüsteemi haiguste ravi on keeruline, kuna seda kaitsevad erinevad füüsilised ja funktsionaalsed barjäärid, mille eesmärgiks on takistada patogeenide, toksiinide ja vererakkude sisenemist ajukoesse. Olulisimad nendest mehhanismidest on vere-aju barjäär ning vere-tserebrospinaalvedeliku barjäär, millest vaid väga kindlate omadustega molekulid on võimelised läbi tungima. Enamikele molekulidele ning ka 99% ravimitele on need tõkked läbipääsmatud.
Vananemisega seotud neuroloogiliste haiguste ravi parandamiseks on oluline parendada nende haiguste diagnoosimist. Selleks on vaja identifitseerida ja valideerida molekulaarseid markereid, mis võimaldavad haigusi diagnoosida varasemas staadiumis. Eelistatult juba enne kliiniliste sümptomite avaldumist. Järgmine oluline samm neuroloogiliste haiguste ravis on leida molekulaarsed transportsüsteemid, mille abil saaks ravimeid viia läbi kaitsva barjääri, et need jõuaksid haigusest haaratud koeni. Üks strateegia, mis võiks parandada ajuhaiguste ravi, on nanotehnoloogia rakendamine. Vere-aju barjääri läbivad kullermolekulid on võimalik kinnitada ravimitega laaditud nanoosakeste pinnale. Sel viisil oleks võimalik ajukoesse transportida ka ravimeid, mis on koekultuuri süsteemis näidanud efektiivsust kasvajarakkude hävitamisel või neuronite kaitsmisel, kuid vereringesse süstituna ei suuda iseseisvalt aju kaitsvaid tõkkeid läbida.
Käesoleva prekliinilise töö eesmärgiks oli leida peptiidid, mis akumuleeruvad ajus ning mida saab rakendada kullermolekulidena kontrastainete ja/või ravimite transportimiseks. Parimate kullermolekulide välja valimiseks töötasime välja väga täpse kvantitatiivse metoodika, mis võimaldab erinevaid kullerpeptiide raku- ja loomkatsetes omavahel võrrelda.
Neurological diseases, especially age-related disorders, are widespread and due to aging population their frequency is expected to rise rapidly. The most common age-related brain diseases are neurodegenerative disorders - Alzheimer's disease and Parkinson's disease, and brain tumors. For all of these diseases, there is no effective treatment that could cure patients or stop the disease progression. Neurodegenerative diseases are not lethal, but the progressive course of the disease makes patients dependent on their caregivers and healthcare system. On the contrary, brain tumors have a very poor prognosis despite multimodal treatment, patients with most aggressive type of tumors live less than 1.5 years. The treatment of neurological diseases is hampered because the central nervous system is protected by a variety of molecular mechanisms that prevent pathogens, toxins and blood cells from entering the brain tissue. The most important protective mechanisms are the blood-brain barrier and blood-cerebrospinal fluid barrier. These barriers are impermeable to most molecules, including 99% of drugs. In order to improve the treatment of age-related neurological disorders, it is important to advance the diagnosis. New molecular markers are needed to make the diagnosis at a earlier stage, before the onset of clinical symptoms. The next crucial step is to find molecules that are able to transport drugs across the protective barriers to reach the affected brain tissue. An important strategy that could improve the treatment of brain diseases is application of nanotechnology. Brain targeting ligands can be attached to the surface of nanoparticles and drugs could be encapsulated inside the nanoparticles. In this way, it is possible to deliver drugs that have shown efficacy in cell assays by killing tumor cells or protecting neurons, but cannot, by themselves, pass through protective barriers in the brain when injected into the bloodstream. The aim of this preclinical work was to find peptides that would be able to accumulate in the brain and could be used as targeting ligands in various neurological diseases to deliver contrast agents or drugs into affected tissue. To select the best targeting ligands, we developed a highly sensitive quantitative methodology that allows to compare targeting peptides in cell and animal experiments.
Neurological diseases, especially age-related disorders, are widespread and due to aging population their frequency is expected to rise rapidly. The most common age-related brain diseases are neurodegenerative disorders - Alzheimer's disease and Parkinson's disease, and brain tumors. For all of these diseases, there is no effective treatment that could cure patients or stop the disease progression. Neurodegenerative diseases are not lethal, but the progressive course of the disease makes patients dependent on their caregivers and healthcare system. On the contrary, brain tumors have a very poor prognosis despite multimodal treatment, patients with most aggressive type of tumors live less than 1.5 years. The treatment of neurological diseases is hampered because the central nervous system is protected by a variety of molecular mechanisms that prevent pathogens, toxins and blood cells from entering the brain tissue. The most important protective mechanisms are the blood-brain barrier and blood-cerebrospinal fluid barrier. These barriers are impermeable to most molecules, including 99% of drugs. In order to improve the treatment of age-related neurological disorders, it is important to advance the diagnosis. New molecular markers are needed to make the diagnosis at a earlier stage, before the onset of clinical symptoms. The next crucial step is to find molecules that are able to transport drugs across the protective barriers to reach the affected brain tissue. An important strategy that could improve the treatment of brain diseases is application of nanotechnology. Brain targeting ligands can be attached to the surface of nanoparticles and drugs could be encapsulated inside the nanoparticles. In this way, it is possible to deliver drugs that have shown efficacy in cell assays by killing tumor cells or protecting neurons, but cannot, by themselves, pass through protective barriers in the brain when injected into the bloodstream. The aim of this preclinical work was to find peptides that would be able to accumulate in the brain and could be used as targeting ligands in various neurological diseases to deliver contrast agents or drugs into affected tissue. To select the best targeting ligands, we developed a highly sensitive quantitative methodology that allows to compare targeting peptides in cell and animal experiments.
Kirjeldus
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Märksõnad
brain diseases, treatment, diagnostics, drug delivery systems, cell-penetrating peptides, nanoparticles