Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer

Figure 1 Schematic illustration of mechanisms of colorectal cancer cell resistance to chemotherapy, radiotherapy, immunotherapy, targeted therapy, and metastasis. ABC: ATP binding cassette; B2M: β2-microglobulin; CAFs: Cancer associated fibroblasts; CIMP: CpG island methylator phenotype; CIN: Chromosomal instability; CTC: Circulating tumor cell; CYP3A4: Cytochrome P450 3A4; DPD: Dihydropyrimidine dehydrogenase; EGFR: Epidermal growth factor receptor; EMT: Epithelial-mesenchymal transition; ERBB2: Erb-b2 receptor tyrosine kinase 2; ERK2: Extracellular regulated protein kinases; HGF: Hepatocyte growth factor; hMLH1: Human MutL homolog 1; HSP27: Heat shock protein 27; IGF-1R: Insulin-like growth factor 1 receptor; ILC3s: Group 3 innate lymphoid cells; MAPKAPK2: Mitogen-activated protein; MDSCs: Myeloid-derived suppressive cells; MSI: Microsatellite instability; NETs: Neutrophil extracellular traps; NF1: Neurofibromin 1; p38MAPK: p38 mitogen-activated protein kinase; PP2A: Protein phosphatase 2A; SLC: Solute carrier; TAP1: Transporter 1; TAP2: Transporter 2; TAMs: Tumor associated macrophages; TME: Tumor microenvironment; TOP-1: Topoisomerase 1; TP: Thymine phosphorylase; TRAP1: TNF receptor associated protein 1; TS: Thymidylate synthase; UGT1A: Uridine diphosphate glucuronosyltransferase 1A.

Figure 2 Intraoperative implant of biopolymer exhibited therapeutic effect on colorectal cancer growth. A: Schematic illustration of the implant preparation process; B: Immunoimplant inhibited tumor growth post-surgery; C: Immunoimplant showed survival benefit after tumor re-challenge. Citation: Ji G, Zhang Y, Si X, Yao H, Ma S, Xu Y, Zhao J, Ma C, He C, Tang Z, Fang X, Song W, Chen X. Biopolymer Immune Implants’ Sequential Activation of Innate and Adaptive Immunity for Colorectal Cancer Postoperative Immunotherapy. Adv Mater 2021; 33: e2004559[20]. Copyright ©The Author(s) 2021. Published by Wiley-VCH GmbH Publications. The authors have obtained the permission for figure using from the Wiley-VCH GmbH Publications (Supplementary material).

Figure 3 Nanoemulsioned Paclitaxel and BEZ235 reduced multidrug resistance of colorectal cancer. A: Morphological changes of cells treated with nanoemulsioned Paclitaxel and BEZ235; B: Downregulated expression of P-gp after NE-PTX and BEZ235 treatment; C: Synergistic inhibition of CRC growth in vivo. Citation: Hu Y, Zhang K, Zhu X, Zheng X, Wang C, Niu X, Jiang T, Ji X, Zhao W, Pang L, Qi Y, Li F, Li L, Xu Z, Gu W, Zou H. Synergistic Inhibition of Drug-Resistant Colon Cancer Growth with PI3K/mTOR Dual Inhibitor BEZ235 and Nano-Emulsioned Paclitaxel via Reducing Multidrug Resistance and Promoting Apoptosis. Int J Nanomedicine 2021; 16: 2173-2186[214]. Copyright ©The Author(s) 2021. Published by Dove Medical Press Ltd. The authors have obtained the permission for figure using from the Dove Medical Press Ltd. (Supplementary material).

Figure 4 Organosilica-based O₂ nanoeconomizer improved radiotherapy efficacy. A: Design and synthesis of nanoeconomizer; B: pHPFON-NO reduced oxygen consumption (left), and broadened oxygenation (right); C: Multi-modal imaging by pHPFON-NO/O₂, and inhibited tumor growth after pHPFON-NO/O₂ administration. Citation: Tang W, Yang Z, He L, Deng L, Fathi P, Zhu S, Li L, Shen B, Wang Z, Jacobson O, Song J, Zou J, Hu P, Wang M, Mu J, Cheng Y, Ma Y, Tang L, Fan W, Chen X. A hybrid semiconducting organosilica-based O(2) nanoeconomizer for on-demand synergistic photothermally boosted radiotherapy. Nat Commun 2021; 12: 523[245]. Copyright ©The Author(s) 2021. Published by Springer Nature Ltd. The authors have obtained the permission for figure using from the Springer Nature Ltd. (Supplementary material).

Figure 5 Duplex CRISPR/Cas9 ribonucleoprotein nanomedicine disrupted antigen-presentation cells and KRAS expression to treat colorectal cancer. A: Schematic illustration of preparation of nanoformulations; B: Disruption of antigen-presentation cells and KRAS expression after duplex HAPD/RNP treatment; C: In vivo luciferase expression of orthotopic CRC (left), and representative intestine images and H&E staining of intestine sections after nanomedicine treatment. Citation: Wan T, Pan Q, Liu C, Guo J, Li B, Yan X, Cheng Y, Ping Y. A Duplex CRISPR-Cas9 Ribonucleoprotein Nanomedicine for Colorectal Cancer Gene Therapy. Nano Lett 2021; 21: 9761-9771[270]. Copyright ©The Author(s) 2021. Reprinted permission from ACS Publications. The authors have obtained the permission for figure using from the ACS Publications (Supplementary material).

Figure 6 Nanomedicine targeted myeloid-derived suppressive cells exhibited synergistic inhibitory effect on colorectal cancer growth with radiotherapy and PD-L1 blockade. A: Schematic illustration of synthesis of HMP nanoparticles and drug loading; B: IPI549@HMP treatment improved hypoxia environment (left), and augmented radiotherapy efficacy; C: Kaplan-Meier survival curves and tumor growth curves of each groups. Citation: Guan X, Sun L, Shen Y, Jin F, Bo X, Zhu C, Han X, Li X, Chen Y, Xu H, Yue W. Nanoparticle-enhanced radiotherapy synergizes with PD-L1 blockade to limit post-surgical cancer recurrence and metastasis. Nat Commun 2022; 13: 2834[16]. Copyright ©The Author(s) 2022. Reprinted permission from Springer Nature Publications. The authors have obtained the permission for figure using from the Springer Nature Publications (Supplementary material).