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Evaluation of the In vivo Antitumor Activity of Polyanhydride IL-1α Nanoparticles
Published on: June 28, 2021
Lymphocyte infiltration and antitumoral effect promoted by cytotoxic inflammatory proteins formulated as
Carlos Martínez-Torró1, Lorena Alba-Castellón2, Luis Miguel Carrasco-Díaz3
1Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
Abstract:
Two human proteins involved in the inflammatory cell death, namely Gasdermin D (GSDMD) and the Mixed Lineage Kinase Domain-Like (MLKL) protein have been engineered to accommodate an efficient ligand of the tumoral cell marker CXCR4, and a set of additional peptide agents that allow their spontaneous self-assembling. Upon production in bacterial cells and further purification, both proteins organized as stable nanoparticles of 46 and 54 nm respectively, that show, in this form, a moderate but dose-dependent cytotoxicity in cell culture. In vivo, and when administered in mouse models of colorectal cancer through repeated doses, the nanoscale forms of tumor-targeted GSDMD and, at a lesser extent, of MLKL promoted CD8+ and CD20+ lymphocyte infiltration in the tumor and an important reduction of tumor size, in absence of systemic toxicity. The potential of these novel pharmacological agents as anticancer drugs is discussed in the context of synergistic approaches to more effective cancer treatments.
Insights
Engineered Gasdermin D (GSDMD) and Mixed Lineage Kinase Domain-Like (MLKL) proteins form nanoparticles that target tumors. These novel agents reduce colorectal cancer size in mice by recruiting immune cells, without systemic toxicity.
Area of Science:
- Biochemistry
- Immunology
- Nanotechnology
Background:
- Gasdermin D (GSDMD) and Mixed Lineage Kinase Domain-Like (MLKL) are key proteins in inflammatory cell death.
- Targeting tumor cells and recruiting immune cells are crucial strategies in cancer therapy.
Purpose of the Study:
- To engineer GSDMD and MLKL proteins into tumor-targeted nanoparticles for cancer treatment.
- To evaluate the in vitro and in vivo efficacy and toxicity of these engineered proteins.
Main Methods:
- Proteins GSDMD and MLKL were engineered with a CXCR4 ligand and self-assembling peptides.
- Purified proteins formed stable nanoparticles (46-54 nm) and were tested for cytotoxicity in cell culture.
- Nanoparticles were administered to mouse models of colorectal cancer to assess in vivo effects.
Main Results:
- Engineered GSDMD and MLKL proteins self-assembled into nanoparticles with moderate, dose-dependent cytotoxicity in vitro.
- In vivo administration in colorectal cancer models promoted CD8+ and CD20+ lymphocyte infiltration into tumors.
- Significant tumor size reduction was observed without systemic toxicity.
Conclusions:
- Tumor-targeted GSDMD and MLKL nanoparticles show potential as novel anticancer agents.
- These nanoparticles can stimulate anti-tumor immune responses and reduce tumor growth.
- Further investigation into synergistic approaches with these agents is warranted for enhanced cancer treatment.
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