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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Selenium nanoparticle-delivered MDM2 inhibitor reactivates p53 and reprograms tumor immune microenvironment in
Weiming You1,2, Jun Feng1,2, Litao Guo3
1Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Background:
Colorectal cancer (CRC) remains a major global health challenge, with limited immunotherapy efficacy in microsatellite stable (MSS) tumors that comprise ~85% of cases. The p53 tumor suppressor pathway, frequently inactivated through the mouse double minute 2 homolog (MDM2) overexpression in wild-type tumor protein 53(TP53) tumors, represents a promising therapeutic target for both direct antitumor effects and immune modulation.
Methods:
We developed selenium nanoparticles loaded with the MDM2-targeting peptide inhibitor MI (Se@MI) using a one-pot synthesis approach. The nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, and UV-Vis spectroscopy. In vitro assays included MTT cytotoxicity evaluation, cellular uptake by flow cytometry, RNA-seq, and Western blotting of p53-pathway/apoptosis markers. Antitumor efficacy was evaluated in CT26 murine colorectal cancer models, with mechanistic studies including transcriptomic analysis, immunohistochemistry, and flow cytometry. Safety profiles were assessed through body weight monitoring, hematological analysis, histopathological examination of major organs, and serum biomarker evaluation.
Results:
Se@MI nanoparticles demonstrated uniform spherical morphology (45-50nm diameter) and displayed a positive zeta potential (+24.69 mV), indicative of favorable colloidal dispersibility. Enhanced cellular uptake (74.3% positive cells) and potent cytotoxicity (IC50 = 1.00 μM) were observed in CT26 cells. Transcriptomic analysis revealed significant activation of p53 signaling pathways (NES = 1.504, P = 0.029) and protein analyses confirmed induction of p21, PUMA, Bax, and cleaved caspase-3. In vivo, Se@MI treatment achieved 72.23% tumor growth inhibition, significantly outperforming controls. Mechanistically, Se@MI restored p53 function by disrupting MDM2-p53 interactions, inducing apoptosis and cell cycle arrest. Importantly, Se@MI reprogrammed the tumor immune milieu through increased infiltration of CD8+ T cell and cytotoxic function while suppressing regulatory T cells. Comprehensive safety evaluation revealed excellent biocompatibility with no adverse effects on body weight, hematological parameters, organ histology, inflammatory cytokines, or hepatic/renal function markers.
Conclusions:
Se@MI represents a novel nanomedicine strategy that combines direct p53 pathway reactivation with immune microenvironment modulation. This dual mechanism of action offers a potential strategy to boost immunotherapeutic outcomes in colorectal carcinoma and may help overcome resistance mechanisms to immune checkpoint blockade.
Insights
Selenium nanoparticles loaded with an MDM2 inhibitor (Se@MI) effectively target colorectal cancer by reactivating the p53 pathway and enhancing anti-tumor immunity. This novel nanomedicine shows promise for overcoming immunotherapy resistance.
Area of Science:
- Nanomedicine
- Oncology
- Immunotherapy
Background:
- Colorectal cancer (CRC) poses a significant global health burden.
- Immunotherapy efficacy is limited in microsatellite stable (MSS) CRC, which accounts for ~85% of cases.
- Inactivating mutations in the p53 pathway, often due to MDM2 overexpression, present a therapeutic target.
Purpose of the Study:
- To develop and evaluate selenium nanoparticles loaded with an MDM2 inhibitor (Se@MI) for colorectal cancer treatment.
- To investigate the mechanisms of action, including p53 pathway reactivation and immune modulation.
- To assess the antitumor efficacy and safety profile of Se@MI in preclinical models.
Main Methods:
- Se@MI nanoparticles were synthesized and characterized.
- In vitro studies assessed cytotoxicity, cellular uptake, and p53 pathway activation.
- In vivo studies in CT26 colorectal cancer models evaluated antitumor efficacy, tumor microenvironment modulation, and safety.
Main Results:
- Se@MI nanoparticles exhibited favorable physicochemical properties and enhanced cellular uptake and cytotoxicity.
- Treatment with Se@MI significantly inhibited tumor growth by 72.23% through p53 pathway reactivation, apoptosis, and cell cycle arrest.
- Se@MI reprogrammed the tumor immune microenvironment, increasing CD8+ T cell infiltration and function while decreasing regulatory T cells.
- Comprehensive safety evaluations indicated excellent biocompatibility with no observed adverse effects.
Conclusions:
- Se@MI is a novel nanomedicine that combines direct p53 pathway reactivation with immune microenvironment modulation.
- This dual mechanism offers a potential strategy to improve immunotherapy outcomes in colorectal cancer.
- Se@MI may help overcome resistance to immune checkpoint blockade in CRC.
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