Cyclodextrin-based host-guest complexes loaded with regorafenib for colorectal cancer treatment

• Published in: Nature communications Vol. 12; no. 1; pp. 759 - 18
• Main Authors: Bai, Hongzhen, Wang, Jianwei, Phan, Chi Uyen, Chen, Qi, Hu, Xiurong, Shao, Guoqiang, Zhou, Jun, Lai, Lihua, Tang, Guping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.02.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 140/131; 140/58; 147/137; 147/3; 38/77; 631/67; 639/301/357; 64/60; 82/1; Animal models; Animals; Anticancer properties; Bioavailability; Biocompatibility; Cancer; Cancer therapies; Cell activation; Cell Line; Cell Line, Tumor; Cell proliferation; Cell Survival - drug effects; Cell Survival - genetics; Colitis; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cyclodextrin; Cyclodextrins; Design modifications; Drug development; Enzyme inhibitors; gamma-Cyclodextrins - administration & dosage; gamma-Cyclodextrins - chemistry; Gene Expression Regulation, Neoplastic - drug effects; HT29 Cells; Humanities and Social Sciences; Humans; Inflammation; Kinases; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Malignancy; Mannose; Mannose - chemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nanotechnology; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Pharmacokinetics; Pharmacology; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - chemistry; Pyridines - administration & dosage; Pyridines - chemistry; Science; Science (multidisciplinary); Supramolecular compounds; Targeted cancer therapy; Therapeutic targets; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Vascularization
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21071-0

The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG’s anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment. Regorafenib is a multi-kinase inhibitor in use for the treatment of colorectal cancer (CRC). To improve drug pharmacokinetics and bioavailability, here the authors design mannose-modified cyclodextrin-based host-guest complexes loaded with Regorafenib, showing anti-tumor responses in preclinical models of CRC.