title: Retinal-conjugated pH-sensitive micelles induce tumor senescence for boosting breast cancer chemotherapy.
abstract: Evoking tumor cellular senescence, an irreversible status of cell growth quiescence, has been recently proposed as a potential strategy to improve the efficacy of cancer treatment. In the current study, all-trans retinal, the precursor of all-trans retinoic acid, was conjugated to dextran via hydrazone bond to generate amphiphilic dextran-retinal (DR) conjugates, which self-assembled into pH-sensitive DR micelles. Our results showed that DR micelles moderately inhibited MCF-7 breast cancer cell growth through inducing p21-associated cellular senescence, which relied on retinoic acid receptors (RARs) and was accompanied by significant G0/G1 cell cycle arrest. Moreover, DR micelles were capable of encapsulating doxorubicin (DOX) to generate DOX-loaded DD micelles, facilitating the uptake and release of DOX in cancer cells. Compared with free DOX, DD micelles more effectively suppressed tumor growth and prolonged survival time of mouse xenograft model through inducing tumor apoptosis and cellular senescence. However, blocking cellular senescence diminished DD-caused apoptosis in MCF-7 cells by 40-50%. Therefore, pH-sensitive DR micelles not only served as a potent platform for DOX delivery, but also enhanced the anti-tumor effect of DOX by inducing tumor cellular senescence. These data reveal a great potential of evoking tumor senescence with retinal-conjugated micelles for boosting breast cancer chemotherapy.
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Yijuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Manyi
authors.initials: M
authors.lastname: Ji
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Sheng
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Ce
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Lintao
authors.initials: L
authors.lastname: Cai
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China. Electronic address: yf.ma@siat.ac.cn.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D003911:Dextrans / Q000138:chemical synthesis / Q000737:chemistry; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012172:Retinaldehyde / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D008823:Micelles; D018168:Receptors, Retinoic Acid; D004317:Doxorubicin; D012172:Retinaldehyde
keywords: All-trans retinal; Breast cancer; Cellular senescence; Chemotherapy; RAR; pH-sensitive micelle