RESUMEN
Hepatocellular carcinoma (HCC) is the second-leading cause of cancer related deaths worldwide and new strategies to efficiently treat HCC are critically needed. The aim of this study was to assess the longitudinal treatment effects of two complementary miRNAs (miRNA-122 and antimiR-21) encapsulated in biodegradable poly lactic-co-glycolic acid (PLGA) - poly ethylene glycol (PEG) nanoparticles (PLGA-PEG-NPs), administered by an ultrasound-guided and microbubble-mediated delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Using in vitro assays, we show that repeated miRNA treatments resulted in gradual reduction of HCC cell proliferation and reversal of doxorubicin resistance. Optimized US parameters resulted in a 9-16 fold increase (pâ¯=â¯0.03) in miRNA delivery in vivo in HCC tumors after two US treatments compared to tumors without US treatment. Furthermore, when combined with doxorubicin (10â¯mg/kg), longitudinal miRNA delivery showed a significant inhibition of tumor growth in both resistant and non-resistant tumors compared to non-treated, and doxorubicin treated controls. We also found that ultrasound-guided miRNA therapy was not only effective in inhibiting HCC tumor growth but also allowed lowering the dose of doxorubicin needed to induce apoptosis. In conclusion, the results of this study suggest that ultrasound-guided and MB-mediated delivery of miRNA-122 and antimiR-21, when combined with doxorubicin, is a highly effective approach to treat resistant HCC while reducing doxorubicin doses needed for treating non-resistant HCC in longitudinal treatment experiments. Further refinement of this strategy could potentially lead to better treatment outcomes for patients with HCC.
Asunto(s)
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , MicroARNs/farmacología , Ondas Ultrasónicas , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/diagnóstico por imagen , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Terapia Combinada , Doxorrubicina/farmacología , Portadores de Fármacos , Liberación de Fármacos , Resistencia a Antineoplásicos , Terapia Genética , Humanos , Lactatos/química , Neoplasias Hepáticas/diagnóstico por imagen , Ratones Desnudos , MicroARNs/administración & dosificación , Microburbujas , Polietilenglicoles/química , Resultado del TratamientoRESUMEN
The 18S ribosomal DNA molecular phylogeny and lipid composition of over 120 marine diatoms showed that the capability to biosynthesize highly branched isoprenoid (HBI) alkenes is restricted to two specific phylogenetic clusters, which independently evolved in centric and pennate diatoms. The molecular record of C25 HBI chemical fossils in a large suite of well-dated marine sediments and petroleum revealed that the older cluster, composed of rhizosolenid diatoms, evolved 91.5 +/- 1.5 million years ago (Upper Turonian), enabling an accurate dating of the pace of diatom evolution that is unprecedented. The rapid rise of the rhizosolenid diatoms probably resulted from a major reorganization of the nutrient budget in the mid-Cretaceous oceans, triggered by plate tectonics.