Development of smart nanoparticles for experimental treatment of cancer
Failid
Kuupäev
2024-11-18
Autorid
Ajakirja pealkiri
Ajakirja ISSN
Köite pealkiri
Kirjastaja
Abstrakt
Glioblastoom on kõige sagedasem pahaloomuline ajukasvaja, mis on ebasoodsa prognoosi ja kõrge suremusmääraga. Glioblastoomi standardravi koosneb peamiselt kasvaja kirurgilisest eemaldamisest, millele järgneb kiiritusravi ja samaaegne keemiaravi temosolomiidiga. Üha suuremat tähelepanu pööratakse uudsete täppis-suunatud nanoosakestel põhinevate ravimeetodite väljatöötamisele, et parandada vähiravi tõhusust ja vähendada kõrvalmõjusid. Käesolevas doktoritöös esitatud uuringutes kasutati prekliiniliste vähktõve uuringute tööriistade ja ravimikandjatena kahte nanoosakeste platvormi: hõbeda nanoosakesi (AgNP, ingl silver nanoparticles) ja raudoksiid-nanousse (NW, ingl nanoworms). Demonstreerisime, et neid saab funktsionaliseerida kasvajaspetsiifiliste kullerpeptiididega ning kasutada tsütotoksiliste ja proapoptootiliste ravimite suunatud kohaletoimetamiseks. AgNP ja NW platvormid võimendavad ja laiendavad in vitro ja in vivo analüüsimeetodeid, mis hõlbustavad suunamisligandide uurimist ja valideerimist. Lisaks nanokandjate väljatöötamisele ja iseloomustamisele tuvastasime kasvajaspetsiifilise kullerpeptiidi PL3 (AGRGRLVR), mis seondub valkudega tenastsiin-C ja neuropiliin-1. PL3-peptiid suurendas nanoosakeste akumuleerumist kasvajakoes ja tõhustas eksperimentaalset vähiravi hiiredmudelites. PL3-peptiid omab vaba CendR-motiivi, mistõttu kaasneb sellega mõningane akumulatsioon tervetes kudedes, peamiselt kopsudes. Selle probleemi lahendamiseks kasutasime modifitseeritud faagidisplei meetodit, et tuvastada krüptilised proteolüütiliselt aktiveeritavad PL3 derivaatpeptiidid: SKLG (AGRGRLVRSKLG) ja PL3uCendR (AGRGRLVRSAGGSVA). Krüptiliste derivaatide lõhustamisel kasvajates üleekspresseeritud urokinaasiga (uPA) aktiveerus neuropiliin-1-st sõltuv penetratsioonimehhanism, kuid akumulatsioon terves kopsukoes vähenes olulisel määral. Töö tulemuste põhjal saab edasi arendada tõhusamaid suunatud vähiravimeetodeid glioblastoomile, vähendades ravi kõrvalmõjusid.
Glioblastoma is the most common malignant brain tumor with an unfavorable prognosis and high mortality rate. Standard treatment for glioblastoma consists primarily of tumor surgical resection followed by radiation therapy and concurrent chemotherapy with temozolomide. Increasing attention is being paid to the development of novel therapies based on precision-targeted nanoparticles to improve the efficacy of cancer treatment and reduce side effects. The research presented in this doctoral thesis focuses on the use of two nanoparticle platforms as tools and drug carriers for preclinical cancer research: silver nanoparticles (AgNP) and iron oxide nanoparticles (NW). We demonstrated that they can be functionalized with tumor homing peptides and used to deliver cytotoxic and proapoptotic drugs. AgNP and NW platforms can be used to enhance in vitro and in vivo assays for the study and validation of targeting ligands. In addition to the development and characterization of the nanocarriers, we identified a tumor homing peptide PL3 (AGRGRLVR) that interacts with the tenascin-C and neuropilin-1 proteins. PL3 peptide enhanced nanoparticle accumulation in tumor tissue and showed efficacy in experimental cancer mouse models. The PL3 peptide has an exposed CendR-motif, which results in healthy tissue accumulation, mainly in the lungs. To address this issue, we used a modified phage display method to identify cryptic proteolytically activatable PL3 derivative peptides: SKLG (AGRGRLVRSKLG) and PL3uCendR (AGRGRLVRSAGGSVA). Cleavage of cryptic derivatives by urokinase (uPA) overexpressed in tumors activated a neuropilin-1 dependent penetration mechanism, while accumulation in healthy lung tissue was reduced. The results of this work can help develop improved targeted cancer treatments for glioblastoma with reduced side effects.
Glioblastoma is the most common malignant brain tumor with an unfavorable prognosis and high mortality rate. Standard treatment for glioblastoma consists primarily of tumor surgical resection followed by radiation therapy and concurrent chemotherapy with temozolomide. Increasing attention is being paid to the development of novel therapies based on precision-targeted nanoparticles to improve the efficacy of cancer treatment and reduce side effects. The research presented in this doctoral thesis focuses on the use of two nanoparticle platforms as tools and drug carriers for preclinical cancer research: silver nanoparticles (AgNP) and iron oxide nanoparticles (NW). We demonstrated that they can be functionalized with tumor homing peptides and used to deliver cytotoxic and proapoptotic drugs. AgNP and NW platforms can be used to enhance in vitro and in vivo assays for the study and validation of targeting ligands. In addition to the development and characterization of the nanocarriers, we identified a tumor homing peptide PL3 (AGRGRLVR) that interacts with the tenascin-C and neuropilin-1 proteins. PL3 peptide enhanced nanoparticle accumulation in tumor tissue and showed efficacy in experimental cancer mouse models. The PL3 peptide has an exposed CendR-motif, which results in healthy tissue accumulation, mainly in the lungs. To address this issue, we used a modified phage display method to identify cryptic proteolytically activatable PL3 derivative peptides: SKLG (AGRGRLVRSKLG) and PL3uCendR (AGRGRLVRSAGGSVA). Cleavage of cryptic derivatives by urokinase (uPA) overexpressed in tumors activated a neuropilin-1 dependent penetration mechanism, while accumulation in healthy lung tissue was reduced. The results of this work can help develop improved targeted cancer treatments for glioblastoma with reduced side effects.
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