title: PEGylated liposomes with NGR ligand and heat-activable cell-penetrating peptide-doxorubicin conjugate for tumor-specific therapy.
abstract: Cell-penetrating peptides (CPPs) mediated tumor-oriented nanocarriers have been widely studied by researchers recently. However, applications of CPPs in vivo were usually hampered by their loss in untargeted tissues and enzymatic degradation. These shortfalls required strategies to camouflage CPPs before their arrival at the targeted site. In this work, we constructed a thermosensitive liposome (TSL) containing Asparagines-Glycine-Arginine (NGR) peptide as the targeting moiety and heat-activable cell-penetrating peptide-doxorubicin conjugate for enhancing specific cancer therapy. Different to the masking strategies of CPPs reported, CPPs existing in conjugation form of CPPs and doxorubicin (CPP-Dox) were hidden in TSL to cloak and protect CPPs. Meanwhile, NGR moiety and local tumor hyperthermia were utilized to achieve specific targeting of CPPs to the tumor. The nanocarrier (CPP-Dox/NGR-TSL) prepared in this work possessed suitable physiochemical properties such as small particle size of about 90 nm, high drug encapsulation efficiency of approximately 95%, good stability in the medium containing 10% fetal bovine serum (FBS) and so on. In vitro experiments on Human fibrosarcoma cells (HT-1080) and human breast adenocarcinoma cells (MCF-7) verified the specific targeting ability and enhanced intracellular drug delivery of the liposomes to HT-1080 cells. Furthermore, comparing with NGR-targeted TSL containing Dox (Dox/NGR-TSL), the results of intravenous administration showed CPP-Dox/NGR-TSL significantly inhibited tumor growth in nude mice xenografted HT-1080 tumors and excellent body safety. In conclusion, the nanocarrier constructed in this study would be a safe and efficiently drug delivery system for specific cancer treatment.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China; Wuhan General Hospital of Guangzhou Military Command, Wuhan 430070, PR China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Xie
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Xingshi
authors.initials: X
authors.lastname: Cai
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China. Electronic address: newddsbj@163.com.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Mei
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D008024:Ligands; C526428:NGR peptide; D009842:Oligopeptides; D010714:Phosphatidylethanolamines; C506643:liposomal doxorubicin; C038089:1,2-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Cell-penetrating peptides; Conjugates of cell-penetrating peptides and doxorubicin; Heat activation; NGR-targeted; Thermosensitive liposomes; Tumor-oriented therapy