Ispitivanje antitumorskog delovanja 6-[trifenilstanil]-1-heksanola vezanog za mezoporozni nanomaterijal SBA-15 u modelu mišjeg melanoma in vitro i in vivo

Abstract

Uprkos razvoju imunoterapije i ciljanih terapija, globalna incidenca melanoma nastavlja da raste. Konvencionalna hemoterapija, naţalost, pokazuje ograniĉenu efikasnost u leĉenju metastatskog melanoma. Primenu najĉešće korišćenog hemoterapeutskog leka cisplatine, ograniĉava uroĊena rezistencija ovog tipa tumora, što sve naglašava potrebu za razvojem efikasnije hemoterapije melanoma. Progres u medicinskoj organometalnoj hemiji omogućio je racionalni dizajn novih, nekonvencionalnih platinskih kompleksa, kao i neplatinskih antitumorskih jedinjenja, ukljuĉujući organokalajna jedinjenja, ĉija aktivnost ne poĉiva na direktnoj interakciji sa DNK. MeĊutim, nedovoljna rastvorljivost i toksiĉnost organokalajnih jedinjenja ograniĉava kompleksnija istraţivanja i ulazak u kliniĉka ispitivanja. U tom kontekstu, primena nanotehnologije u svrhu povećanja rastvorljivosti lekova i njihove selektivnosti prema maligno transformisanim klonovima u hemoterapiji kancera ima vodeću ulogu. Inkapsulacija hidrofobnih antitumorskih lekova u mezoporozne nanomaterijale silike, predstavlja najperspektivniju strategiju u ovoj oblasti. Zbog visokog potencijala za adsorpciju, nosaĉ SBA-15 je najinteresantniji mezoporozni silikat za ciljanu isporuku lekova. U skladu sa tim, u ovoj studiji je po prvi put ispitivan antitumorski potencijal organokalajnog(IV) jedinjenja [Ph3Sn(CH2)6OH] skladištenog u mezoporozni materijal SBA-15 (SBA-15pSn) in vitro i in vivo u modelu mišjeg melanoma. Imajući u vidu izuzetnu heterogenost melanoma, ispitivan je i njihov uticaj na visoko invazivnu liniju humanog melanoma, A375. Analizirani su ćelijski i molekulski mehanizmi pokrenuti u odgovoru na tretman eksperimentalnim agensima u ćelijama melanoma, kao i mehanizam preuzimanja ĉestica SBA-15pSn u humane ćelije melanoma u sistemu in vitro. [Ph3Sn(CH2)6OH] u slobodnoj formi ali, mnogo potentnije, uskladišten u SBA-15 smanjio je vijabilitet ćelijskih linija melanoma poreklom od miša B16, i ĉoveka A375. Isti trend je zapaţen u singenom modelu mišjeg melanoma in vivo. Pokazalo se da A375 ćelije melanoma preuzimaju SBA-15pSn pasivnim putem i makropinocitozom.

Despite rapid development in immunotherapy and targeted therapies, the global incidence of melanoma continues to increase. Besides, conventional chemotherapy demonstrates only limited efficacy in the treatment of advanced melanoma. Clinical application of widely used chemotherapeutic drug cisplatin, is hampered by the intrinsic resistance of this type of tumor, indicating the urgent need for the development of more effective chemotherapies for melanoma. The rapid progress in medicinal organometallic chemistry in the past few years allows rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. Poor solubility and toxicity of organotin compounds, however, restrains more complex studies and further development in the preclinical and subsequently clinical setting. Nanotechnology now becomes an important part of pharmaceutical research and development, for improving the solubility and selective toxicity of cancer therapeutics. Encapsulating hydrophobic antitumor agents in ordered mesoporous silica nanomaterials is an emerging strategy to enhance drug dissolution. Due to its high drug loading capacity, SBA-15 is the most interesting mesoporous silicate for targeted drug delivery. Antitumor potential of organotin(IV) compound [Ph3Sn(CH2)6OH] grafted on nanostructured material SBA-15 (SBA-15pSn) in vitro and in vivo in the mouse model of melanoma, was tested for the first time in this study. Considering the enormous heterogeneity of this type of tumor, it was of interest to test these experimental therapeutics in a highly invasive human A375 melanoma cell line. Given the fact that SBA-15pSn nanoparticles are relatively large, the mechanism of cellular uptake was defined. At the molecular level, main intracellular events triggered by the treatment, as well as the expression of key signaling pathways mediating tumor cell response, were analyzed...