Abstract:Purpose
Nano dense-silica (
d
SiO
2
) has many advantages such as adjustable core–shell structure, multiple drug delivery, and controllable release behavior. Improving the gastric tumor-specific targeting efficiency based on the development of various strategies is crucial for anti-cancer drug delivery systems.
Methods
Superparamagnetic iron oxide nanoparticles (SPION) were coated with
d
Si… Show more
“…MCAM is also involved in several cellular processes including cell invasion, migration, angiogenesis, epithelial mesenchymal transition, immune response, and signal transduction (10). Additionally, MCAM has low expression levels in normal tissue, primarily restricted at intracellular junctions of endothelial cells (10,11). Previous studies have shown differential expression of MCAM in primary tumors correlated with metastasis and poor prognosis in several cancers, showing its significant potential in cancer therapy (12–14).…”
Despite favorable responses to initial therapy, SCLC relapse occurs within a year exhibiting a multidrug resistant phenotype. Due to limited accessibility of patient tissues for research purpose, SCLC patient derived xenografts (PDXs) have provided the best opportunity to address this limitation. We sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines that exhibited a mesenchymal phenotype and in chemoresistant PDXs compared to matched treatment-naïve tumors. MCAM is a cell membrane protein whose expression has been implicated in multiple human cancers. MCAM expression is also detected in lung adenocarcinoma; however, its expression and role in SCLC is has not been explored. MCAM knockdown in chemoresistant cells reduced cell proliferation and decreased the IC50 inhibitory concentration of chemotherapeutic drugs. MCAM was found to modulate sensitivity of SCLC cells to chemotherapeutic drugs through up-regulation of MRP1/ABCC1 expression and of the PI3/AKT pathway in a SOX2-dependent manner. Metabolomic profiling revealed that MCAM modulates lactate production in chemoresistant cells that exhibit a distinct metabolic phenotype characterized by low oxidative phosphorylation. MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC.
“…MCAM is also involved in several cellular processes including cell invasion, migration, angiogenesis, epithelial mesenchymal transition, immune response, and signal transduction (10). Additionally, MCAM has low expression levels in normal tissue, primarily restricted at intracellular junctions of endothelial cells (10,11). Previous studies have shown differential expression of MCAM in primary tumors correlated with metastasis and poor prognosis in several cancers, showing its significant potential in cancer therapy (12–14).…”
Despite favorable responses to initial therapy, SCLC relapse occurs within a year exhibiting a multidrug resistant phenotype. Due to limited accessibility of patient tissues for research purpose, SCLC patient derived xenografts (PDXs) have provided the best opportunity to address this limitation. We sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines that exhibited a mesenchymal phenotype and in chemoresistant PDXs compared to matched treatment-naïve tumors. MCAM is a cell membrane protein whose expression has been implicated in multiple human cancers. MCAM expression is also detected in lung adenocarcinoma; however, its expression and role in SCLC is has not been explored. MCAM knockdown in chemoresistant cells reduced cell proliferation and decreased the IC50 inhibitory concentration of chemotherapeutic drugs. MCAM was found to modulate sensitivity of SCLC cells to chemotherapeutic drugs through up-regulation of MRP1/ABCC1 expression and of the PI3/AKT pathway in a SOX2-dependent manner. Metabolomic profiling revealed that MCAM modulates lactate production in chemoresistant cells that exhibit a distinct metabolic phenotype characterized by low oxidative phosphorylation. MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC.
“…CD146 expression is primarily constrained to the intracellular junctions of endothelial cells and is actively involved in several cellular processes including cell-matrix adhesion, cell migration, signal transduction, stem cell differentiation, immune response, and angiogenesis [12]. Additionally, CD146 has low background levels in normal tissue as well as differential expression in metastases and advanced primary tumors, showing its significant potential in cancer therapy [12, 13]. We have previously shown that persistent and specific targeting of CD146 in vivo may be accomplished with the monoclonal antibody known as YY146 [14].…”
Section: Introductionmentioning
confidence: 99%
“…Subsequently, the most immunoreactive antibody clones were determined by ELISA and further evaluated with YY146 showing optimal properties for continued investigation [14]. To date, the use of YY146 has been limited to brain and gastric cancer with both diseases showing high levels of CD146 expression and high uptake of YY146 [13]. PET imaging of YY146 allowed for visualization of small tumor nodules with high specificity in glioblastoma multiforme [14].…”
Section: Introductionmentioning
confidence: 99%
“…PET imaging of YY146 allowed for visualization of small tumor nodules with high specificity in glioblastoma multiforme [14]. To target gastric cancer, superparamagnetic iron oxide nanoparticles (SPIONs) were coated with d SiO 2 , labeled with near-infrared fluorescence (NIRF) dye 800 ZW, and YY146 ( 800 ZW-SPION@ d SiO 2 -YY146) for targeting CD146-expressing gastric cancer [13]. Uptake of 800 ZW-SPION@ d SiO 2 -YY146 was rapid and specific allowing for clear delineation of the tumor at 30 min post-injection with the tumor uptake peaking at 24 h post-injection.…”
Purpose
Overexpression of CD146 in solid tumors has been linked to disease progression, invasion, and metastasis. In this study, we describe the generation of a 64Cu-labeled CD146-specific antibody for quantitative immunoPET imaging of CD146 expression in six lung cancer models.
Methods
The anti-CD146 antibody (YY146) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with 64Cu. CD146 expression was evaluated in six human lung cancer cell lines (A549, NCI-H358, NCI-H522, HCC4006, H23, and NCI-H460) by flow cytometry and quantitative Western blot studies. The biodistribution and tumor uptake of 64Cu-NOTA-YY146 was assessed by sequential PET imaging in athymic nude mice bearing subcutaneous lung cancer xenografts. The correlation between CD146 expression and tumor uptake of 64Cu-NOTA-YY146 was evaluated by graphical software while ex vivo biodistribution and immunohistochemistry studies were performed to validate the accuracy of PET data and spatial expression of CD146.
Results
Flow cytometry and Western blot studies showed similar findings with H460 and H23 cells highly expressing CD146. Small differences in CD146 expression levels were found between A549, H4006, H522, and H358 cells. Tumor uptake of 64Cu-NOTA-YY146 was highest in CD146-expressing H460 and H23 tumors, peaking at 20.1 ± 2.86 and 11.6 ± 2.34 %ID/g at 48 h post-injection (n=4). Tumor uptake was lowest in the H522 model (4.1 ± 0.98 %ID/g at 48 h post-injection; n=4), while H4006, A549 and H358 exhibited similar uptake of 64Cu-NOTA-YY146. A positive correlation was found between tumor uptake of 64Cu-NOTA-YY146 (%ID/g) and relative CD146 expression (r2=0.98, p<0.01). Ex vivo biodistribution corroborated the accuracy of PET data.
Conclusions
The strong correlation between tumor uptake of 64Cu-NOTA-YY146 and CD146 expression demonstrates the potential use of this radiotracer for imaging tumors that elicit varying levels of CD146. In the future, this tool may promote enhanced monitoring of therapeutic response and improved patient stratification.
“…Besides, the silica shell can ensure an enough distance between the Fe 3 O 4 core and fluorescent tracers to prevent the fluorescence quenching effect. For example, the fluorescent signals of fluorescent dyes modified on the surface of silica shell or encapsulated with silica could track the process of targeted drug delivery by fluorescence microscopy . In addition, silica exhibits a negative surface charge under physiological condition, and the silanol groups make the particle surfaces lyophilic, thus, enhancing the stability of their suspensions, even when the pH or electrolyte concentrations are changed …”
Section: Anticancer Drug Delivery Systems Based On Inorganic Nanocarrmentioning
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