title: Promoting tumor penetration of nanoparticles for cancer stem cell therapy by TGF-β signaling pathway inhibition.
abstract: Cancer stem cells (CSCs), which hold a high capacity for self-renewal, play a central role in the development, metastasis, and recurrence of various malignancies. CSCs must be eradicated to cure instances of cancer; however, because they can reside far from tumor vessels, they are not easily targeted by drug agents carried by nanoparticle-based drug delivery systems. We herein demonstrate that promoting tumor penetration of nanoparticles by transforming growth factor β (TGF-β) signaling pathway inhibition facilitates CSC therapy. In our study, we observed that although nanoparticles carrying siRNA targeting the oncogene polo-like kinase 1 (Plk1) efficiently killed breast CSCs derived from MDA-MB-231 cells in vitro, this intervention enriched CSCs in the residual tumor tissue following systemic treatment. However, inhibition of the TGF-β signaling pathway with LY364947, an inhibitor of TGF-β type I receptor, promoted the penetration of nanoparticles in tumor tissue, significantly ameliorating the intratumoral distribution of nanoparticles in MDA-MB-231 xenografts and further leading to enhanced internalization of nanoparticles by CSCs. As a result, synergistic treatment with a nanoparticle drug delivery system and LY364947 inhibited tumor growth and reduced the proportion of CSCs in vivo. This study suggests that enhanced tumor penetration of drug-carrying nanoparticles can enhance CSCs clearance in vivo and consequently provide superior anti-tumor effects.
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, 230027, PR China.
authors.forename: Zu-Qi
authors.initials: ZQ
authors.lastname: Zuo
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, 230027, PR China.
authors.forename: Kai-Ge
authors.initials: KG
authors.lastname: Chen
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, 230027, PR China.
authors.forename: Xiao-Yuan
authors.initials: XY
authors.lastname: Yu
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, 230027, PR China.
authors.forename: Gui
authors.initials: G
authors.lastname: Zhao
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, 230027, PR China.
authors.forename: Song
authors.initials: S
authors.lastname: Shen
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Anhui, 230027, PR China.
authors.forename: Zhi-Ting
authors.initials: ZT
authors.lastname: Cao
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, 230027, PR China.
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Luo
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, 230027, PR China.
authors.forename: Yu-Cai
authors.initials: YC
authors.lastname: Wang
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, 230027, PR China; Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Anhui, 230027, PR China; CAS Center for Excellence in Nanoscience, University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, Anhui, 230027, PR China. Electronic address: jwang699@ustc.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D053769:Nanocapsules / Q000737:chemistry*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016896:Treatment Outcome; D011804:Quinolines
chemical_list: D000970:Antineoplastic Agents; D053769:Nanocapsules; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011758:Pyrroles; D034741:RNA, Small Interfering; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C506615:HTS 466284; D011804:Quinolines
keywords: Cancer stem cell; Nanoparticle drug delivery system; TGF-β signaling pathway inhibition; Tumor penetration; siRNA