title: Combined Delivery of Let-7b MicroRNA and Paclitaxel via Biodegradable Nanoassemblies for the Treatment of KRAS Mutant Cancer.
abstract: In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG5K-VE4-DET20 copolymer formed nanoassemblies when mixed with the neutral PEG5K-VE4 copolymer at 1:8 weight ratio, which were investigated as the nanocarriers for combined delivery of paclitaxel and let-7b mimic. We found that the PEG5K-VE4-DET20 nanoassemblies could entrap paclitaxel for an extended period and burst release the drug in the presence of cathepsin B, demonstrating the biodegradability of the copolymers. At N/P ratio of 12:1, the PEG5K-VE4-DET20 nanoassemblies formed stable polyplexes with let-7b mimic, which were efficiently taken up by tumor cells and underwent endosomal escape. In non-small cell lung cancer A549 cells that harbor mutant KRAS, paclitaxel and let-7b mimic-loaded nanoassemblies (N-PTX/let-7b) markedly potentiated the cytotoxicity of paclitaxel, induced apoptosis, and diminished the invasiveness of tumor cells. In mice bearing subcutaneous A549 xenografts, intravenous administration of N-PTX/let-7b retarded tumor growth more efficaciously than Taxol. Our study demonstrates the promise of the PEG5K-VE4-DET20 nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics.
authors.affiliation: Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Mercer University College of Pharmacy , Atlanta, Georgia 30341, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Mercer University College of Pharmacy , Atlanta, Georgia 30341, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Mercer University College of Pharmacy , Atlanta, Georgia 30341, United States.
authors.forename: Yingzhe
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pre-incubator for Innovative Drugs and Medicine, School of Bioscience and Bioengineering Center, South China University of Technology , 382 Waihuan Road, Guangzhou, Guangdong 510006, China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Huang
authors.affiliation: Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Mercer University College of Pharmacy , Atlanta, Georgia 30341, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: School of Life Sciences, Nanjing University , 22 Hankou Road, Nanjing, Jiangsu 210093, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Mercer University College of Pharmacy , Atlanta, Georgia 30341, United States.
authors.forename: DeAngelo
authors.initials: D
authors.lastname: Mckinley
authors.affiliation: Pre-incubator for Innovative Drugs and Medicine, School of Bioscience and Bioengineering Center, South China University of Technology , 382 Waihuan Road, Guangzhou, Guangdong 510006, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.affiliation: Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Mercer University College of Pharmacy , Atlanta, Georgia 30341, United States.
authors.forename: Chalet
authors.initials: C
authors.lastname: Tan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002465:Cell Movement; D049109:Cell Proliferation; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D053761:Nanocomposites / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; C117307:KRAS protein, human; D008823:Micelles; D035683:MicroRNAs; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; D011092:Polyethylene Glycols; D016283:Proto-Oncogene Proteins p21(ras); D017239:Paclitaxel
keywords: chemosensitizer; drug delivery; let-7; microRNA replacement; nanoassembly; paclitaxel