title: Supramolecular self-assembly forming a multifunctional synergistic system for targeted co-delivery of gene and drug.
abstract: For developing a multifunctional bioreducible targeted and synergistic co-delivery system for anticancer drug paclitaxel (PTX) and p53 gene for potential cancer therapy, supramolecular self-assembled inclusion complex was prepared from PTX and star-shaped cationic polymer containing γ-cyclodextrin (γ-CD) and multiple oligoethylenimine (OEI) arms with folic acid (FA) conjugated via a disulfide linker. The inclusion complex, termed as γ-CD-OEI-SS-FA/PTX, was formed between PTX and the hydrophobic cavity of γ-CD core of the star polymer. The γ-CD-OEI-SS-FA/PTX complex further formed polyplexes with pDNA to give positively charged nanoparticles, becoming multifunctional supramolecular self-assembled co-delivery system for PTX and pDNA targeting to cancer cells that overexpress folate receptors (FRs). The results showed that the FA-targeted function induced higher gene transfection efficiency in the FR-positive KB cells. The redox-sensitive disulfide linker in the self-assembly system led to the detachment of the FA groups from the carrier after the FR-mediated endocytosis, which resulted in the release of the bound FRs followed by the recycling of the FRs from the cytosol onto the cell membrane surface, facilitating continuous FR-mediated endocytosis to achieve enhanced gene transfection. In addition, the complexed PTX was co-delivered to the cells with pDNA, which further enhanced the gene transfection even at low N/P ratios in the FR-positive KB cells. Further, the efficient delivery of wild-type p53 gene resulted in large cell population at sub G1 and G2/M phases, inducing significant cell apoptosis. Therefore, the multifunctional γ-CD-OEI-SS-FA/PTX self-assembly system with the synergistic effects of redox-sensitive FA-targeted and PTX-enhanced p53 gene delivery may be promising for cancer therapeutic application.
authors.affiliation: Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, 7 Engineering Drive 1, Singapore 117574, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Hui
authors.initials: H
authors.lastname: Yin
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D017239:Paclitaxel / Q000008:administration & dosage*; D014162:Transfection / Q000379:methods*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D047408:gamma-Cyclodextrins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016159:Tumor Suppressor Protein p53; D047408:gamma-Cyclodextrins; D004247:DNA; D005492:Folic Acid; C023792:gamma-cyclodextrin; D017239:Paclitaxel
keywords: Cationic polymer; Cyclodextrin; Folate-targeted delivery; Paclitaxel; Redox-sensitive; p53 Gene transfection