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Published on: June 13, 2014
Developing Nanoparticle-Based Therapeutics for Targeting the Microenvironment in Obesity-Induced Endometrial Cancer
Laura D Paredes Cuatin1, David Zhang1, Federico Zertuche1
1Department of Biomedical Engineering and Chemical Engineering, The University of Texas at San Antonio, AET 1.328, 1 UTSA Circle, San Antonio, TX 78249 USA.
Background:
The global rise of obesity has contributed to an increase in the incidence of endometrial cancer, the most common gynecologic malignancy. This obesity-driven increase, alongside limited therapeutic options, presents a growing public health concern. Our previous research indicated that adipose stem cells (ASCs), shed from fat depots, infiltrate the endometrium via the circulation in endometrial cancer patients with obesity. Furthermore, ASCs elicited the malignant transformation of endometrial epithelial cells (EECs) and fostered an oncogenic microenvironment driven by the plasminogen activator inhibitor 1 (PAI-1).
Objective:
To develop a nanoparticle-based system to deliver PAI-1 siRNA targeting the microenvironment of obesity-driven endometrial tumors.
Methods:
We developed 2D and 3D spheroid in vitro systems modeling the effects of endometrial microenvironment on ASCs to identify ASC integrin targeting markers. We also analyzed gonadal fat and uterine tissue from obese (ob/ob) mice, validating these ASC integrin markers in vivo. For targeted delivery, we engineered lipid-coated mesoporous silica nanoparticles (LCMSNs) loaded with PAI-1 siRNA. These nanoparticles were administered to ob/ob mice via intraperitoneal injection to evaluate targeting and therapeutic efficiency.
Results:
ASCs exposed to an oncogenic endometrial microenvironment showed increased integrin alpha 7 (ITGA7) and PAI-1 expression in vitro. Analysis of gonadal fat and uterine tissue from obese mice confirmed ITGA7 as a promising ASC targeting marker within the endometrial cancer microenvironment. LCMSNs conjugated with anti-ITGA7 antibody exhibited targeting capability toward ITGA7-positive ASCs. In obese mice, these LCMSNs showed strong uterine retention and effective PAI-1 silencing.
Conclusion:
Our findings demonstrate the potential of ITGA7-targeted LCMSNs as a PAI-1 siRNA delivery system to therapeutically target ASC-mediated oncogenesis in the endometrial tumor microenvironment. Future studies will evaluate the efficacy of PAI-1 silencing in inhibiting obesity-driven endometrial cancer growth, using in vivo models.
