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Mitigation of Blood Borne Cell Attachment to Metal Implants through CD47-Derived Peptide Immobilization
Published on: December 3, 2020
Dual Template Molecularly Imprinted Polymers Targeting Blockade of CD47 for Enhanced Macrophage Phagocytosis and
Yao-Jia Ma1, Lei Shi1, Ya-Ting Qin1
1State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China.
Abstract:
Glycinamide ribonucleotide formyltransferase (GARFT) is an important enzyme in the folate metabolism pathway, and chemical drugs targeting GARFT have been used in tumor treatments over the past few decades. The development of novel antimetabolism drugs that target GARFT with improved performance and superior activity remains an attractive strategy. Herein, we proposed a targeted double-template molecularly imprinted polymer (MIP) for enhancing macrophage phagocytosis and synergistic antimetabolic therapy. The double-template MIP was prepared by imprinting the exposed peptide segment of the extracellular domain of CD47 and the active center of GARFT. Owing to the imprinted cavities on the surface of MIP, it can actively target cancer cells and mask the "do not eat me" signal upon binding to CD47 thereby blocking the CD47-SIRPα pathway and ultimately enhancing phagocytosis by macrophages. In addition, MIP can specifically bind to the active center of GARFT upon entry into the cells, thereby inhibiting its catalytic activity and ultimately interfering with the normal expression of DNA. A series of cell experiments demonstrated that MIP can effectively target CD47 overexpressed 4T1 cancer cells and inhibit the growth of 4T1 cells. The enhanced phagocytosis ability of macrophages-RAW264.7 cells was also clearly observed by confocal imaging experiments. In vivo experiments also showed that the MIP exhibited a satisfactory tumor inhibition effect. Therefore, this study provides a new idea for the application of molecular imprinting technology to antimetabolic therapy in conjunction with macrophage-mediated immunotherapy.
Insights
This study introduces a novel double-template molecularly imprinted polymer (MIP) that targets cancer cells by blocking immune evasion signals and inhibiting DNA synthesis, enhancing macrophage-mediated immunotherapy and antimetabolic therapy for tumor treatment.
Area of Science:
- Biomaterials Science
- Cancer Therapy
- Immunology
Background:
- Glycinamide ribonucleotide formyltransferase (GARFT) is a key enzyme in folate metabolism, targeted by existing cancer drugs.
- Developing novel antimetabolism drugs with improved efficacy for cancer treatment is an ongoing strategy.
Purpose of the Study:
- To develop a targeted double-template molecularly imprinted polymer (MIP) for synergistic antimetabolic therapy and enhanced macrophage phagocytosis.
- To investigate the dual-targeting capability of MIP for CD47 and GARFT in cancer cells.
Main Methods:
- Fabrication of a double-template MIP by imprinting the CD47 extracellular peptide and the GARFT active center.
- Evaluation of MIP's ability to target CD47-overexpressing cancer cells and inhibit the CD47-SIRPα pathway.
- Assessment of MIP's intracellular inhibition of GARFT activity and its effect on DNA synthesis.
- In vitro and in vivo experiments to determine the efficacy of MIP in cancer cell growth inhibition and tumor suppression.
Main Results:
- The MIP effectively targeted CD47-overexpressing 4T1 cancer cells, enhancing macrophage phagocytosis by blocking the 'do not eat me' signal.
- Intracellular binding of MIP to GARFT inhibited its activity, interfering with DNA synthesis and cancer cell growth.
- Confocal imaging confirmed enhanced phagocytosis of RAW264.7 macrophages.
- In vivo studies demonstrated significant tumor inhibition by the MIP.
Conclusions:
- The developed double-template MIP offers a novel strategy for combining antimetabolic therapy with macrophage-mediated immunotherapy.
- Molecular imprinting technology shows promise for developing advanced cancer therapeutics with dual targeting capabilities.
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