Caspase-cleavable peptide-doxorubicin conjugate in combination with CD47-antagonizing nanocage therapeutics for immune-mediated elimination of colorectal cancer. (October 2021)

• Record Type: Journal Article
• Authors: Lee, Na Kyeong; Choi, Jeong Uk; Kim, Ha Rin; Chung, Seung Woo; Ko, Yoon Gun; Cho, Young Seok; Park, Seong Jin; Lee, Eun Jung; Kim, Sang Yoon; Kim, In-San; Byun, Youngro
• Is Part Of: Biomaterials. Volume 277(2021)
• Publication Date: 2021-10
• Subjects: Caspase-cleavable peptide-doxorubicin conjugate -- Nanocage therapeutics -- CD47 antagonist -- Immunotherapy combination -- MSS colorectal Cancer; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2021.121105
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Here we report a novel combination of a caspase-cleavable peptide-doxorubicin conjugate (MPD-1) with CD47-antagonizing nanocage therapeutics for the treatment of microsatellite-stable (MSS) colorectal cancer (CRC). MPD-1 (i) upregulated markers of immunogenic cell death (ICD) in tumor, and increased co-stimulatory markers on dendritic cells (DCs), (ii) enhanced CD8 + T cell infiltration and antigen presenting cell (APC) activation, and (iii) showed negligible off-target immune-related toxicity compared to free dox. Then, the CD47 antagonist FS nanocage, a SIRPα-expressing ferritin nanocage, was co-administered with MPD-1 that resulted in 95.2% (p < 0.001) tumor growth inhibition in an established CRC model. T cell-mediated elimination of tumors was also confirmed by the tumor-specific activation of T cells detected by IFNγ and tumor-free mice were observed (95%) that bared a memory response when re-challenged. The strategically developed MPD-1 is an ideal adjuvant to immunotherapy and the combination with FS nanocage triggers potent immunity against MSS CRC. In summary, we present an approach to initiate and stimulate immune-mediated eradication of cancer cells using synergistic immunogenic agents targeting the MSS CRC. Graphical abstract: Caspase-cleavable peptide-doxorubicin conjugate is combined with CD47-antagonizing nanocage therapeutics, targeting both innate and adaptive immunity for eliciting a potent anti-cancer immune response. Image 1 Highlights: Caspase-cleavable peptide-doxorubicin conjugate for combination with immunotherapy. Immunogenic doxorubicin conjugate shows negligible immune toxicity compared to free doxorubicin. FS nanocage, SIRPα-expressing ferritin nanocage for innate immune checkpoint blockade. Synergistic combination of immunogenic agents for microsatellite-stable colorectal cancer.