RESUMO
Purpose: To validate the therapeutic efficacy of sorafenib-eluting embolic microspheres (SOR-EMs) used in combination with transarterial chemoembolization (TACE) for treatment of hepatocellular carcinoma (HCC) in a preclinical animal model. Materials and Methods: SOR-EMs were prepared with poly(d,l-lactide-co-glycolide), iron oxide nanoparticles, and sorafenib. The morphology of the prepared SOR-EMs was confirmed by using optical microscopy. Drug release from the SOR-EMs was quantified in vitro by using high-performance liquid chromatography. In an orthotopic rat model of HCC, embolic doxorubicin-Lipiodol (ethiodized oil) emulsion (DLE) and SOR-EMs were sequentially injected into the hepatic artery of the rats: The rats in group 1 were injected with DLE; group 2 was injected with DLE plus unloaded embolic microspheres (DLE + EM); group 3, with DLE plus SOR-EMs (DLE + SOR-EM); and group 4, with saline solution. The SOR-EM and tumor size changes in each group (of six rats each) over time were measured by using MRI. Tissues were assessed by using immunohistochemistry, with hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated dUTP (2'-deoxyuridine 5'-triphosphate) nick-end labeling staining used for dead cells and CD34 staining used for new microvessel formation. Results: The SOR-EMs were a mean size of 6.6 µm ± 2.3 (standard deviation) and showed 53.7% ± 8.3 sorafenib loading efficiency with T2-weighted MRI capability. In the HCC rat model, the intra-arterially injected SOR-EMs were successfully monitored by using MRI. The DLE + SOR-EM-treated rats showed a superior tumor growth-inhibitory effect compared with the rats treated with DLE only (P < .05). Immunohistochemical assessment of tissue specimens showed that compared with the other treatment groups, the DLE + SOR-EM treatment group had the lowest number of microvessels, as quantified by using the percentage of CD34-positive stained area (P < .01 for all comparisons). Conclusion: In a preclinical rat HCC model, SOR-EMs used in combination with DLE TACE were effective in treating HCC.Keywords: Chemoembolization, Experimental Investigations, Laboratory Tests, Liver, Technology Assessment Supplemental material is available for this article. © RSNA, 2021See also the commentary by Yamada and Gayed in this issue.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Microesferas , Ratos , SorafenibeRESUMO
INTRODUCTION: We investigated to compare the effect of empirical therapy vs clarithromycin resistance-guided tailored therapy (tailored therapy) for eradication of Helicobacter pylori. METHODS: In this prospective, single center, open-label randomized controlled trial, we enrolled 72 patients with H. pylori infection from January 2019 through June 2019 in Korea. The patients were randomly assigned to both groups received empirical (n = 36) or tailored therapy (n = 36). Empirical therapy was defined as triple therapy with esomeprazole, amoxicillin, and clarithromycin for 10 days irrespective of clarithromycin resistance. Tailored therapy was triple or quadruple therapy with esomeprazole, metronidazole, tetracycline, and bismuth for 10 days based on genotype markers of resistance determined by gastric biopsy. Resistance-associated mutations in 23S rRNA were confirmed by multiplex polymerase chain reaction. Eradication status was assessed by C-urea breath test, and the primary outcome was eradication rates. RESULTS: H. pylori was eradicated in 27 patients (75.0%), given empirical therapy and 32 patients (88.9%) treated with tailored therapy (P = 0.136) in intention-to-treat analysis. In per protocol analysis, the eradication rate was 97.0% and 81.8% in tailoredvs empirical groups (P = 0.046). Although clarithromycin-resistant H. pylori was eradicated in 3/9 (33.3%) with empirical therapy, it was treated in 11/12 (91.7%) with tailored therapy (P = 0.009). There was no difference in compliance between 2 groups. The rate of adverse events of the tailored group was higher than that of the empirical group (P = 0.036) because quadruple therapy had more side effects than those of triple therapy (P = 0.001). DISCUSSION: Tailored therapy based on polymerase chain reaction is a good alternative to increase eradication rates in a region of high prevalence of clarithromycin resistance (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A342).
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Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/genética , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Idoso , Amoxicilina/farmacologia , Amoxicilina/uso terapêutico , Antibacterianos/farmacologia , Biópsia , Bismuto/uso terapêutico , Claritromicina/farmacologia , DNA Bacteriano/isolamento & purificação , Farmacorresistência Bacteriana/genética , Quimioterapia Combinada/métodos , Esomeprazol/uso terapêutico , Feminino , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/isolamento & purificação , Humanos , Linfoma não Hodgkin/microbiologia , Linfoma não Hodgkin/patologia , Masculino , Metronidazol/farmacologia , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , RNA Ribossômico 23S/genética , República da Coreia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Tetraciclina/farmacologia , Tetraciclina/uso terapêutico , Resultado do TratamentoRESUMO
Colorectal cancer (CRC) is diagnosed with colonoscopy and treated with focal therapies. CRC is a good candidate for nanoparticle-mediated photothermal ablation (PTA) therapy. Herein, we developed a near-infrared fluorescent (NIRF) endoscopic image-guided PTA approach using a nanoparticle capable of simultaneously diagnosing and treating CRC. Dual-modal NIR heating and fluorescent gold nanorods (dual-modal GNRs) were synthesized by conjugation of GNRs to an NIRF probe. To validate the translational potential of our approach, a well-characterized transgenic TS4 CRE/APC loxΔ468 colon cancer mouse model was used to carry out NIRF image-guided PTA using our dual-modal GNRs under clinically relevant conditions. Intravenously infused dual-modal GNRs were effectively targeted at colon polyps by immunogenic capturing of the GNRs within tumor-infiltrating innate immune cells. NIRF endoscopic image-guided PTA using the GNRs permitted successful detection and ablation of inflammatory colon polyps. NIRF endoscopy image-guided PTA using dual-modal GNRs can be utilized for diagnosis and treatment of CRC and various inflammatory diseases.
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Técnicas de Ablação/métodos , Neoplasias Colorretais/terapia , Ouro/química , Nanotubos/química , Fototerapia/métodos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Imunidade Inata/fisiologia , Camundongos , Camundongos Transgênicos , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
PURPOSE: To label Clostridium novyi-NT spores (C. novyi-NT) with iron oxide nanoclusters and track distribution of bacteria during magnetic resonance (MR) imaging-monitored locoregional delivery to liver tumors using intratumoral injection or intra-arterial transcatheter infusion. MATERIALS AND METHODS: Vegetative state C. novyi-NT were labeled with iron oxide particles followed by induction of sporulation. Labeling was confirmed with fluorescence microscopy and transmission electron microscopy (TEM). T2 and T2* relaxation times for magnetic clusters and magnetic microspheres were determined using 7T and 1.5T MR imaging scanners. In vitro assays compared labeled bacteria viability and oncolytic potential to unlabeled controls. Labeled spores were either directly injected into N1-S1 rodent liver tumors (n = 24) or selectively infused via the hepatic artery in rabbits with VX2 liver tumors (n = 3). Hematoxylin-eosin, Prussian blue, and gram staining were performed. Statistical comparison methods included paired t-test and ANOVA. RESULTS: Both fluorescence microscopy and TEM studies confirmed presence of iron oxide labels within the bacterial spores. Phantom studies demonstrated that the synthesized nanoclusters produce R2 relaxivities comparable to clinical agents. Labeling had no significant impact on overall growth or oncolytic properties (P >.05). Tumor signal-to-noise ratio (SNR) decreased significantly following intratumoral injection and intra-arterial infusion of labeled spores (P <.05). Prussian blue and gram staining confirmed spore delivery. CONCLUSIONS: C. novyi-NT spores can be internally labeled with iron oxide nanoparticles to visualize distribution with MR imaging during locoregional bacteriolytic therapy involving direct injection or intra-arterial transcatheter infusion.
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Terapia Biológica/métodos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Clostridium/metabolismo , Meios de Contraste/administração & dosagem , Compostos Férricos/administração & dosagem , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/terapia , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/administração & dosagem , Imagem Molecular/métodos , Esporos Bacterianos , Animais , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Clostridium/genética , Clostridium/patogenicidade , Meios de Contraste/metabolismo , Compostos Férricos/metabolismo , Neoplasias Hepáticas Experimentais/microbiologia , Neoplasias Hepáticas Experimentais/patologia , Valor Preditivo dos Testes , Coelhos , Ratos Sprague-DawleyRESUMO
Current therapeutic strategies are insufficient for suppressing stent-induced restenosis. Here, branched gold nanoparticles (BGNP)-coated self-expandable metallic stents (SEMSs) were developed for a local heat-induced suppression of stent-related tissue hyperplasia. Our polydopamine (PDA) coating on SEMS allowed BGNP crystal growth on the surface of SEMSs. The prepared BGNP-coated SEMS showed effective local heating under near-infrared laser irradiation. The effectiveness of BGNP-coated SEMSs for suppressing stent-related tissue hyperplasia was demonstrated in a rat esophageal model ( n = 52). BGNP-coated SEMS placement under fluoroscopic guidance was technically successful in all rats. The placed BGNP-coated SEMS in rat esophagus achieved three different local heat dose ranges (50, 65, and 80 °C) under fluoroscopic image-guided local irradiation. Follow-up endoscopic examination readily monitored the local heating and observed significantly decreased tissue hyperplasia at 4 weeks of local heat treatments (50 and 65 °C). Finally, Western blot, histology, immunohistochemistry (HSP70, αSMA, and TUNEL), and immunofluorescence (Ki67 and BrdU) analyses along with the statistical analysis confirmed that optimized BGNP-coated SEMS-mediated local heat treatments inducing the expression of anti-inflammatory HSP70 effectively suppresses tissue hyperplasia after stent placement in the esophagus. Our local heating with nanofunctionalized stents represents a promising new approach for suppressing stent-related tissue hyperplasia.
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Temperatura Alta , Hiperplasia/terapia , Nanopartículas Metálicas/uso terapêutico , Stents , Animais , Modelos Animais de Doenças , Ouro/química , Indóis/química , Indóis/uso terapêutico , Nanopartículas Metálicas/química , Polímeros/química , Polímeros/uso terapêutico , Ratos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Nanoparticle-mediated photothermal therapy for treatment of different types of tumors has attracted tremendous attention in recent years. One major factor that drives this therapy is the ability to carefully control and prevent inadvertent damage to local tissues, while focusing therapeutic heating to specific regions of the tumor tissues. To this end, it is critical to generate efficient heating in the targeted tumors while monitoring the extent and distribution of heating. In our study, we demonstrated the photothermal heating properties of our synthesized branched Au nanoparticles (b-AuNPs) using non-invasive MR thermometry (MRT) techniques to assess its effects both in vitro and in vivo. 75 nm b-AuNPs were synthesized; these b-AuNPs demonstrated strong near infrared (NIR) absorption and high heat transducing efficiency. Proton resonance frequency MRT approaches for monitoring b-AuNPs mediated heating were validated using in vitro agar phantoms and further evaluated during in vivo animal model tumor ablation studies. In vitro phantom studies demonstrated a strong linear correlation between MRT and reference-standard thermocouple measurements of b-AuNPs-mediated heating upon NIR laser irradiation; temperatures increased with both an increase in laser power and increased exposure duration. Localized photothermal heating in regions containing the b-AuNPs was confirmed through MRT generated temperature maps acquired serially at increasing depths during both phantom and in vivo studies. Our results suggested that b-AuNPs exposed to NIR radiation produced highly efficient localized heating that can be accurately monitored dynamically using non-invasive MRT measurements. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2352-2359, 2017.