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Published on: December 1, 2016
Antitumor Activity of Death Receptor 5-Targeted Camptothecin-Loaded Nanoparticles in Murine Syngeneic Models
Anna J Boland1, Michelle K Greene1,2, Úna M Herron1,2
1The Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, United Kingdom.
Abstract:
Death receptor 5 (DR5) is a key mediator of the extrinsic apoptotic pathway that is often upregulated in tumors, rendering it an attractive target for cancer therapy. Activation of DR5 requires oligomerization, which can be achieved through multivalent presentation of DR5 ligands on nanoparticles. DR5-targeted nanoparticles can efficiently agonize DR5 to inhibit the growth of human xenografts, although it remains unclear whether these effects would translate to a syngeneic tumor model with an immunocompetent microenvironment. Here, we develop camptothecin-loaded polymeric nanoparticles coated with the murine DR5 antibody MD5-1 and demonstrate their pro-apoptotic effects in murine cell lines in vitro. Moreover, we show that these nanoparticles inhibit the growth of MC38 colorectal allografts in vivo by >90% relative to control nanoparticles. Collectively, our work confirms that the antitumor efficacy of DR5-targeted nanoparticles extends to syngeneic models, paving the way for future studies to explore their impact on tumor immunity and the surrounding microenvironment.
Insights
Targeting cancer cells with nanoparticles that activate death receptor 5 (DR5) effectively inhibits tumor growth in immunocompetent mice. This approach shows promise for cancer therapy by leveraging the extrinsic apoptotic pathway.
Area of Science:
- Oncology
- Nanomedicine
- Immunology
Background:
- Death receptor 5 (DR5) is crucial for extrinsic apoptosis and is upregulated in tumors, making it a therapeutic target.
- Nanoparticle-based DR5 agonists can induce tumor cell death, but efficacy in immunocompetent models is not well-established.
Purpose of the Study:
- To develop and evaluate camptothecin-loaded polymeric nanoparticles coated with a murine DR5 antibody (MD5-1) for cancer therapy.
- To assess the *in vitro* and *in vivo* antitumor efficacy of these DR5-targeted nanoparticles in syngeneic murine models.
Main Methods:
- Polymeric nanoparticles loaded with camptothecin and coated with the MD5-1 antibody were synthesized.
- Pro-apoptotic effects were evaluated *in vitro* in murine cell lines.
- Antitumor efficacy was assessed *in vivo* using MC38 colorectal allografts in mice, comparing targeted nanoparticles to controls.
Main Results:
- The DR5-targeted nanoparticles demonstrated significant pro-apoptotic effects *in vitro*.
- These nanoparticles inhibited MC38 colorectal allograft growth by over 90% compared to control nanoparticles *in vivo*.
Conclusions:
- DR5-targeted nanoparticles exhibit potent antitumor activity in syngeneic models, confirming their therapeutic potential.
- This study validates the use of DR5-targeted nanoparticles in immunocompetent hosts and suggests further investigation into their effects on tumor immunity.
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