A nanotherapeutic strategy to overcome chemotherapeutic resistance of cancer stem-like cells

• Published in: Nature nanotechnology Vol. 16; no. 1; pp. 104 - 113
• Main Authors: Shen, Shiyang, Xu, Xiao, Lin, Shiqi, Zhang, Ying, Liu, Huayu, Zhang, Can, Mo, Ran
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2021; Nature Publishing Group
• Subjects: 140/131; 631/61/54; 639/166/985; 639/925/352/152; Animal models; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Breast Neoplasms - surgery; Camptothecin; Camptothecin - administration & dosage; Cancer; Cancer therapies; Cell death; Cell Differentiation - drug effects; Chemistry and Materials Science; Chemoresistance; Chemotherapy; Differentiation; Drug Delivery Systems - methods; Drug Liberation; Drug resistance; Drug Resistance, Neoplasm; Female; Heterogeneity; Humans; Hypoxia; Materials Science; Metastases; Mice; Mice, Inbred BALB C; Nanomedicine - methods; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nanotechnology; Nanotechnology and Microengineering; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Rats; Rats, Wistar; Reactive oxygen species; Retinoic acid; Solid tumors; Stems; Strategy; Tissue Distribution; Tretinoin - administration & dosage; Tretinoin - pharmacokinetics; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1748-3387; 1748-3395
• DOI: 10.1038/s41565-020-00793-0

Tumour heterogeneity remains a major challenge in cancer therapy owing to the different susceptibility of cells to chemotherapy within a solid tumour. Cancer stem-like cells (CSCs), which reside in hypoxic tumour regions, are characterized by high tumourigenicity and chemoresistance and are often responsible for tumour progression and recurrence. Here we report a nanotherapeutic strategy to kill CSCs in tumours using nanoparticles that are co-loaded with the differentiation-inducing agent, all- trans retinoic acid, and the chemotherapeutic drug, camptothecin. All- trans retinoic acid is released under hypoxic conditions, leading to CSC differentiation in the hypoxic niche. In differentiating CSC, the reactive oxygen species levels increase, which then causes the release of camptothecin and subsequent cell death. This dual strategy enables controlled drug release in CSCs and reduces stemness-related drug resistance, enhancing the chemotherapeutic response. In breast tumour mouse models, treatment with the nanoparticles suppresses tumour growth and prevents post-surgical tumour relapse and metastasis. Chemoresistant cancer stem-like cells (CSCs) can be selectively killed by a nanoparticle, which releases an agent under hypoxic conditions that induces CSC differentiation, and a chemotherapeutic drug in response to reactive oxygen species in differentiating CSCs.