title: A chitosan-graft-PEI-candesartan conjugate for targeted co-delivery of drug and gene in anti-angiogenesis cancer therapy.
abstract: A multifunctional copolymer-anticancer conjugate chitosan-graft-polyethyleneimine-candesartan (CPC) containing low molecular weight chitosan (CS) backbone and polyethyleneimine (PEI) arms with candesartan (CD) conjugated via an amide bond was fabricated as a targeted co-delivery nanovector of drug and gene for potential cancer therapy. Here, CD was utilized to specifically bind to overexpressed angiotensin II type 1 receptor (AT1R) of tumor cells, strengthen endosomal buffering capacity of CPC and suppress tumor angiogenesis. The self-assembled CPC/pDNA complexes exhibited desirable and homogenous particle size, moderate positive charges, superior stability, and efficient release of drug and gene in vitro. Flow cytometry and confocal laser scanning microscopy analyses confirmed that CD-targeted function and CD-enhanced buffering capacity induced high transfection, specific cellular uptake and efficient intracellular delivery of CPC/pDNA complexes in AT1R-overexpressed PANC-1 cells. In addition, CPC/wt-p53 complexes co-delivering CD and wild type p53 (wt-p53) gene achieved synergistic angiogenesis suppression by more effectively downregulating the expression of vascular endothelial growth factor (VEGF) mRNA and protein via different pathways in vitro, as compared to mono-delivery and mixed-delivery systems. In vivo investigation on nude mice bearing PANC-1 tumor xenografts revealed that CPC/wt-p53 complexes possessed high tumor-targeting capacity and strong anti-tumor activity. Additional analysis of microvessel density (MVD) demonstrated that CPC/wt-p53 complexes significantly inhibited tumor-associated angiogenesis. These findings suggested that CPC could be an ideal tumor-targeting nanovector for simultaneous transfer of drug and gene, and a multifunctional CPC/wt-p53 co-delivery system with tumor-specific targetability, enhanced endosomal buffering capacity and synergistic anti-angiogenesis efficacy might be a new promising strategy for effective tumor therapy.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China. Electronic address: wangyucpu206@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: zhoujp60@163.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Jin
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D016158:Genes, p53; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy*; D011094:Polyethyleneimine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C551320:chitosan-graft-polyethylenimine; D011094:Polyethyleneimine; D004247:DNA; D048271:Chitosan; C081643:candesartan
keywords: Angiotensin II type 1 receptor targeting; Candesartan; Co-delivery; Multifunctional copolymer–anticancer conjugate; Tumor anti-angiogenesis therapy; Wild type p53