Peng Guo,Alexander Moses-Gardner,Jing Huang,Edward R. Smith & Marsha A. Moses.
Dessa forskare utgår från Boston Children´s Hospital och Harvard Medical School.
Forskningsrapporten offentliggjordes idag för nån timme sen,och är betitlad
ITGA2 as a potential nanotherapeutic target for glioblastoma
Published:
Abstract
High grade gliomas, including glioblastoma (GBM), are the most common and deadly brain cancers in adults.
Here, we performed a quantitative and unbiased screening of 70 cancer-related antigens using comparative flow cytometry and, for the first time, identified integrin alpha-2 (ITGA2) as a novel molecular target for GBM.
In comparison to epidermal growth factor receptor (EGFR), a well-established GBM target, ITGA2 is significantly more expressed on human GBM cells and significantly less expressed on normal human glial cells.
We also found that ITGA2 antibody blockade significantly impedes GBM cell migration but not GBM cell proliferation.
To investigate the utility of ITGA2 as a therapeutic target in GBM, we designed and engineered an ITGA2 antibody-directed liposome that can selectively deliver doxorubicin, a standard-of-care chemotherapeutic agent, to GBM cells.
This novel approach significantly improved antitumor efficacy.
We also demonstrated that these ITGA2 antibody-directed liposomes can effectively breach the blood-brain tumor barrier (BBTB) in vitro via GBM-induced angiogenesis effects.
These findings support further research into the use of ITGA2 as a novel nanotherapeutic target for GBM.
Conclusion
For the first time, we have identified and characterized ITGA2 as a novel molecular target for GBM that is robustly expressed in multiple representative GBM cell lines while being absent in normal glial cells.
By analyzing R2: Genomics Analysis and Visualization Platform database, we found that ITGA2 is significantly upregulated in human GBM tumor tissues and high ITGA2 expression has a negative impact on GBM patient survival, suggesting ITGA2 as a promising therapeutic target for GBM.
We have developed an ITGA2 antibody-directed, doxorubicin encapsulating liposome (ITGA2-Dox-LP) as a novel GBM-targeted nanomedicine that selectively binds and kills GBM cells in vitro.
We also demonstrated that these GBM-targeted ITGA2-Dox-LP could effectively breach an in vitro BBTB via GBM induced angiogenesis effects, but not a normal intact in vitro BBB.
These findings may have significant clinical potential for GBM therapy and diagnosis and support further research into the use of ITGA2 as a therapeutic target for GBM.
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Materials
Quantitative phase imaging analysis
GBM cell migratory behaviors with ITGA2 antibody or IgG-conjugated liposome treatment was evaluated using an established quantitative phase imaging method as previously described.Briefly, GBM cells were cultured in 6-well plates with a density of 50,000 cells per well.
After allowing for attachment overnight, the six well plate was placed on a motorized stage of HoloMonitor® M4 (Phase Holographic Imaging Phi AB, Lund, Sweden) with a 20× objective lens.
The system was kept in a humidified incubator with 5% CO2.
HstudioM4 software was used to record phase images of the sample within the field of integration (0.5 mm2).
For each well, 4 locations on the plate were selected to scan every 5 minutes to acquire continuous phase images for a period of 48 h.
Cell morphology, migration, and proliferation characteristics were also documented and recorded for statistical analysis with ITGA2 antibody or IgG-conjugated liposome treatments (at equivalent antibody concentration of 2 µg/mL).
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