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Fang Xie, Luchen Zhang, Jinliang Peng, Chong Li, Jun Pu, Yuhong Xu, Zixiu Du
We rationally formulated a nucleic acid nano-vector platform utilizing endogenous molecules in the following steps: nucleic acids are initially packed by a multifunctional peptide and a cationic liposome to form positively charged ternary complexes through electrostatic interaction; then the ternary complexes were coated with hyaluronic acid (HA) to form negatively charged quaternary nanocomplexes (Q-complexes). Among the components of Q-complexes, the multifunctional peptide was composed of a polysixteen-arginine (R16) and a hepatic tumor-targeted cell penetrating peptide (KRPTMRFRYTWNPMK); the cationic lipid component included DOTAP and fusogenic lipid DOPE; the HA component shielded the cationic ternary complexes and actively targeted the CD44 overexpressed on the surface of tumor cells...
December 30, 2016: Molecular Pharmaceutics
Christina F Calver, Kirk S Schanze, Gonzalo Cosa
Here we report a biomimetic light-harvesting antenna based on negatively charged poly(phenylene ethynylene) conjugated polyelectrolytes assembled within a positively charged lipid membrane scaffold constructed by the lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). Light harvested by the polymers was transferred via through-space mechanisms to a lipophilic energy acceptor (the cyanine dye DiI) whose effective molar absorption was enhanced by up to 18-fold due to the antenna effect. Absorption amplification of DiI was found to be due primarily to direct energy transfer from polymers...
November 22, 2016: ACS Nano
Yousra Ali El-Basyuni, Yuan Li, Madhu B Anand-Srivastava
BACKGROUND: We previously showed that the levels of both Giα-2 and Giα-3 proteins were augmented in spontaneously hypertensive rats (SHRs) before the onset of hypertension. In addition, intraperitoneal injection of pertussis toxin, which inactivates both Giα proteins, prevented the development of hypertension in SHRs. The aim of the present study was to determine the specific contributions of Giα-2 and Giα-3 proteins to the development of hypertension. METHODS AND RESULTS: Antisense oligodeoxynucleotide of Giα-2 and Giα-3 encapsulated in PEG/DOTAP/DOPE cationic liposomes were administrated intravenously into 3-week-old prehypertensive SHRs and Wistar Kyoto rats, whereas the control Wistar Kyoto rats and SHRs received PBS, empty liposomes, or sense...
October 26, 2016: Journal of the American Heart Association
Xinwei Cheng, Qibing Liu, Hong Li, Chen Kang, Yang Liu, Tianqi Guo, Ke Shang, Chengyun Yan, Guang Cheng, Robert J Lee
PURPOSE: Bcl-2 is an anti-apoptotic gene that is frequently overexpressed in human cancers. G3139 is an antisense oligonucleotide against bcl-2 that has shown limited efficacy in clinical trials. Here, we report the synthesis of a new antisense oligonucleotide containing additional chemical modifications and its delivery using nanoparticles. METHODS: An oligonucleotide G3139-GAP was synthesized, which has 2'-O-methyl nucleotides at the 5' and 3' ends based on a "gapmer" design...
November 28, 2016: Pharmaceutical Research
Wen Jen Lin, Wei-Chi Lee, Ming-Jium Shieh
The high- and low-molecular weight hyaluronic acid (HHA and LHA) were used to conjugate with PLGA-PEG copolymers which were applied to encapsulate DOTAP/pDNA (D/P) lipoplex as a CD44-targeted micelle delivery system. The size and zeta potential of DNA loaded micelles were measured. The cytotoxicity and cellular transfection of DNA loaded micelles were performed in CD44-positive MDA-MB-231 and MCF-7 cancer cells and CD44-negative HepG2 cells. The endocytosis mechanism of micelles was investigated further. The DNA loaded HA-conjugated micelles possessed negative-charged character which prevented erythrocytes from agglutination...
January 2, 2017: Carbohydrate Polymers
Panpan Qi, Mei Cao, Liju Song, Chong Chen, Mingdong Liu, Ningzhe Li, Daoyan Wu, Jingshan Peng, Guoku Hu, Jian Zhao
In the study we made use of DOTAP (1,2-dioleoyl-3-trimethylammonium), DOPE (1,2-dioleoyl-snglycero-3-phosphoethanolamine) and PEG-PE (polyethylene glycol- polyethylene) to make cationic PEG-liposomes by ultrasonic dispersion method. The plasmid pGPU6 combined with cationic PEG-liposomes or Liopofectamin 2000 was used to transfect PC3 cells to judge the transfection efficiency. HE staining showed that the pGUP6-shAurora B plasmid/liposomes complex could significantly inhibit tumor growth in mice tumor model...
October 2016: Environmental Toxicology and Pharmacology
George R Dakwar, Kevin Braeckmans, Wim Ceelen, Stefaan C De Smedt, Katrien Remaut
Delivery of small interfering RNA (siRNA) is recently gaining tremendous attention for the treatment of ovarian cancer. The present study investigated the potential of different liposomal formulations composed of (2,3-dioleoyloxy-propyl)-trimethylammonium (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) encapsulating siRNA (hydration method) for their ability to knockdown luciferase (Luc) activity in human ovarian cancer SKOV-3 cells. Fluorescence single particle tracking (fSPT) and fluorescence correlation spectroscopy (FCS) in human-undiluted ascites fluid obtained from a peritoneal carcinomatosis patient revealed that cationic hydra-lipoplexes (HYDRA-LPXs) and HYDRA-LPXs decorated with stable DSPE-PEG (DSPE HYDRA-LPXs) showed high stability during at least 24 h...
September 8, 2016: Drug Delivery and Translational Research
Matthew Tiffany, Francis C Szoka
We utilized quantitative high-resolution single particle tracking to study the internalization and endosomal sorting of lipid nanoparticles (LNPs) by HeLa cells in vitro to gain a better understanding of how cells process LNPs that are used for siRNA delivery. We compared the trafficking of three formulations that have been demonstrated to deliver siRNA into cells. They were composed of either a tritratable anionic lipid, formulation of cholesterol hemisuccinate (CHEMS), or a titratatable cationic lipid formulation of 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA) or a non-titratable cationic formulation lipid formulation of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)...
November 2016: Journal of Drug Targeting
Anna Lechanteur, Tania Furst, Brigitte Evrard, Philippe Delvenne, Pascale Hubert, Géraldine Piel
The delivery of small interfering RNA (siRNA) is an attractive therapeutic approach to treat several pathologies, such as viral infections or cancers. However, the stability and the efficacy of these biotherapies are still a major obstacle to their use. Cationic liposomes (DOTAP/Chol/DOPE 1/0.75/0.5M ratio) have been complexed to siRNA (lipoplexes) in order to be administrated by the vaginal route, in the context of HPV16 induced cervical preneoplastic lesions. To overcome the constraint of the cervico-vaginal mucus, PEGylation is required to allow the diffusion of lipoplexes through it...
October 10, 2016: European Journal of Pharmaceutical Sciences
Mihael Lazebnik, Rahul K Keswani, Daniel W Pack
PURPOSE: siRNA may be delivered as electrostatic complexes with cationic lipids (lipoplexes) or polycations (polyplexes). The purpose of this project was to determine the effect of cellular internalization mechanism(s) on siRNA-mediated gene silencing efficiency. METHODS: Lipoplexes were formed comprising siRNA and N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol and dioleoyl phosphatidylethanolamine (DOPE), and polyplexes comprised siRNA with polyethylenimine (PEI)...
September 1, 2016: Pharmaceutical Research
Chul-Ho Yun, Chun-Sik Bae, Taeho Ahn
Nanoparticles (NPs) containing cationic monovalent lipids such as 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and N-(1-[2,3-dioleyloxy]propyl)-N,N,N-trimethylammonium chloride (DOTMA), have been widely used for the delivery of nucleic acid such as small-interfering RNA and polypeptide to cells as cancer therapies and vaccine development. Several previous reports have suggested that cationic liposomes induce reactive oxygen species (ROS) and ROS-mediated toxicity in cells. Here, we systematically investigated the effects of DOTAP- or DOTMA-containing NPs without any cargo on the human carcinoma cells, HepG2...
2016: Biological & Pharmaceutical Bulletin
Sara Falsini, Sandra Ristori
This chapter describes the topic of gene therapy based on colloidal drug delivery, as an alternative to the use of viral carriers. Non-viral vectors are promising transfection agents and do not suffer from limitations related to toxicity and immunogenic effects. In particular, lipid-based aggregates are generally considered biocompatible and versatile nanocarriers whose composition can be designed to include a cationic molecule which ensures strong interaction with nucleic acid. Herein the main issues related to complex formation and in vitro administration are illustrated with key examples, such as liposome-DNA plasmid (pDNA) association and micelles-siRNA complexes...
2016: Methods in Molecular Biology
Ichiki Fukuda, Shinichi Mochizuki, Kazuo Sakurai
Cell specific ligand molecules are attached to polyethylene glycol (PEG) modified nanoparticles to enhance the drug delivery efficiency. The tethered PEG would interfere in ligand recognition as well as providing biocompatibility to the nanoparticles. The denser PEG can give the greater biocompatibility, while should more hamper the ligand recognition. Therefor it is important to tune PEG density at an appropriate amount to compensate these two factors. In this study, we prepared a series of nanoparticles composed of α-mannose-bearing lipid, dioleoyltrimethyl ammoniumpropane (DOTAP) and 1,2-distearoyl-sn-glycero -3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000)...
October 1, 2016: Colloids and Surfaces. B, Biointerfaces
Nikaïa Smith, Pierre-Olivier Vidalain, Sébastien Nisole, Jean-Philippe Herbeuval
Plasmacytoid dendritic cells (pDC) are specialized immune cells that produce massive levels of type I interferon in response to pathogens. Unfortunately, pDC are fragile and extremely rare, rendering their functional study a tough challenge. However, because of their central role in numerous pathologies, there is a considerable need for an efficient and reproducible protocol for gene silencing in these cells. In this report, we tested six different methods for siRNA delivery into primary human pDC including viral-based, lipid-based, electroporation, and poly-ethylenimine (PEI) technologies...
2016: Scientific Reports
Micaela Tamara Vitor, Patrícia Cruz Bergami-Santos, Rafael Henrique Freitas Zômpero, Karen Steponavicius Piedade Cruz, Mariana Pereira Pinho, José Alexandre Marzagão Barbuto, Lucimara Gaziola de la Torre
Cationic liposomes can be designed and developed in order to be an efficient gene delivery system for mammalian cells. Dendritic cell (DC) vaccines can be used to treat cancer, as cationic liposomes can deliver tumor antigens to cells while cells remain active. However, most methods used for liposome production are not able to reproduce in large scale the physicochemical and biological properties of liposomes produced in laboratory scale. In this context, ethanol injection method achieved promising results, although requiring post-treatment for size reduction and/or to remove residual ethanol...
July 7, 2016: Journal of Liposome Research
Joydeep Das, Jae Woong Han, Yun-Jung Choi, Hyuk Song, Ssang-Goo Cho, Chankyu Park, Han Geuk Seo, Jin-Hoi Kim
Gene therapy is a promising technique for the treatment of various diseases. The development of minimally toxic and highly efficient non-viral gene delivery vectors is the most challenging undertaking in the field of gene therapy. Here, we developed dimethyldioctadecylammonium bromide (DODAB)-nanoceria (CeO2) hybrids as a new class of non-viral gene delivery vectors. These DODAB-modified CeO2 nanoparticles (CeO2/DODAB) could effectively compact the pDNA, allowing for highly efficient gene transfection into the selected cell lines...
2016: Scientific Reports
Jing Lin, Kai Xu, Jun Wei, Amy B Heimberger, Jack A Roth, Lin Ji
MicroRNAs play critical roles in regulating gene expression and various cellular processes in human cancer malignant progression. Down-regulated expression of miR-124 gene has been shown to be significantly associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC) but its biological function and regulatory roles in lung cancer tumorigenesis are largely unknown. In this study, we aimed to determine effects of ectopic expression of miR-124 on tumor cell proliferation, invasion, and induction of apoptosis by DOTAP:Cholesterol nanoparticle-mediated gene transfer and identify its endogenous targets under physiological conditions in NSCLC cells...
February 2016: Journal of Gene Therapy
Cong Luo, Lei Miao, Yi Zhao, Sara Musetti, Yuhua Wang, Kai Shi, Leaf Huang
Metformin (dimethylbiguanide) has been found to be effective for the treatment of a wide range of cancer. Herein, a novel lipid (1,2-di-(9Z-octadecenoyl)-3-biguanide-propane (DOBP)) was elaborately designed by utilizing biguanide as the cationic head group. This novel cationic lipid was intended to act as a gene carrier with intrinsic antitumor activity. When compared with 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP), a commercially available cationic lipid with a similar structure, the blank liposomes consisting of DOBP showed much more potent antitumor effects than DOTAP in human lung tumor xenografts, following an antitumor mechanism similar to metformin...
September 2016: Biomaterials
Ranganayaki Muralidharan, Anish Babu, Narsireddy Amreddy, Kanthesh Basalingappa, Meghna Mehta, Allshine Chen, Yan Daniel Zhao, Uday B Kompella, Anupama Munshi, Rajagopal Ramesh
BACKGROUND: Human antigen R (HuR) is an RNA binding protein that is overexpressed in many human cancers, including lung cancer, and has been shown to regulate the expression of several oncoproteins. Further, HuR overexpression in cancer cells has been associated with poor-prognosis and therapy resistance. Therefore, we hypothesized that targeted inhibition of HuR in cancer cells should suppress several HuR-regulated oncoproteins resulting in an effective anticancer efficacy. To test our hypothesis, in the present study we investigated the efficacy of folate receptor-α (FRA)-targeted DOTAP:Cholesterol lipid nanoparticles carrying HuR siRNA (HuR-FNP) against human lung cancer cells...
June 21, 2016: Journal of Nanobiotechnology
Lu Zhang, Jiashu Sun, Yilian Wang, Jiancheng Wang, Xinghua Shi, Guoqing Hu
We report a nonspecific organelle-targeting strategy through one-step microfluidic fabrication and screening of a library of surface charge- and lipid components/ratios-varied lipid shell-polymer core nanoparticles. Different from the common strategy relying on the use of organelle-targeted moieties conjugated onto the surface of nanoparticles, here, we program the distribution of hybrid nanoparticles in lysosomes or mitochondria by tuning the lipid components/ratios in shell. Hybrid nanoparticles with 60% 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 20% 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) can intracellularly target mitochondria in both in vitro and in vivo models...
July 19, 2016: Analytical Chemistry
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