1-2-dioleoyloxy-3-(trimethylammonium)propane and Neoplasms

1-2-dioleoyloxy-3-(trimethylammonium)propane has been researched along with Neoplasms* in 18 studies

Other Studies

18 other study(ies) available for 1-2-dioleoyloxy-3-(trimethylammonium)propane and Neoplasms

ArticleYear
Lipid nanoparticles of Type-A CpG D35 suppress tumor growth by changing tumor immune-microenvironment and activate CD8 T cells in mice.
    Journal of controlled release : official journal of the Controlled Release Society, 2019, 11-10, Volume: 313

    Type-A CpG oligodeoxynucleotides (ODNs), which have a natural phosphodiester backbone, is one of the highest IFN-α inducer from plasmacytoid dendritic cells (pDC) via Toll-like receptor 9 (TLR9)-dependent signaling. However, the in vivo application of Type-A CpG has been limited because the rapid degradation in vivo results in relatively weak biological effect compared to other Type-B, -C, and -P CpG ODNs, which have nuclease-resistant phosphorothioate backbones. To overcome this limitation, we developed lipid nanoparticles formulation containing a Type-A CpG ODN, D35 (D35LNP). When tested in a mouse tumor model, intratumoral and intravenous D35LNP administration significantly suppressed tumor growth in a CD8 T cell-dependent manner, whereas original D35 showed no efficacy. Tumor suppression was associated with Th1-related gene induction and activation of CD8 T cells in the tumor. The combination of D35LNP and an anti-PD-1 antibody increased the therapeutic efficacy. Importantly, the therapeutic schedule and dose of intravenous D35LNP did not induce apparent liver toxicity. These results suggested that D35LNP is a safe and effective immunostimulatory drug formulation for cancer immunotherapy.

    Topics: Animals; Antineoplastic Agents; Blood Cells; CD8-Positive T-Lymphocytes; Drug Compounding; Drug Stability; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Humans; Immunosuppression Therapy; Immunotherapy; Lipids; Liver; Mice; Nanocapsules; Neoplasms; Neoplasms, Experimental; Oligodeoxyribonucleotides; Phosphatidylethanolamines; Phosphorylcholine; Programmed Cell Death 1 Receptor; Quaternary Ammonium Compounds; Tumor Microenvironment

2019
Cell cytotoxicity, immunostimulatory and antitumor effects of lipid content of liposomal delivery platforms in cancer immunotherapies. A comprehensive in-vivo and in-vitro study.
    International journal of pharmaceutics, 2019, Aug-15, Volume: 567

    Liposome is one of the promising technologies for antigen delivery in cancer immunotherapies. It seems that the phospholipid content of liposomes can act as immunostimulatory molecules in cancer immunotherapy. In the present study, the immunological properties of different phospholipid content of liposomal antigen delivery platforms were investigated. To this aim, F1 to F4 naïve liposomes (without tumor-specific loaded antigens) of positively charged DOTAP/Cholesterol/DOPE (4/4/4 mol ratio), negatively charged DMPC/DMPG/Cholesterol/DOPE (15/2/3/5), negatively charged DSPC/DSPG/Cholesterol/DOPE (15/2/3/5) and PEGylated HSPC/mPEG2000-DSPE/Cholesterol (13/110) liposomal compositions were administered in mice bearing C26 colon carcinoma to assess tumor therapy. Moreover, In-vitro studies were conducted, including cytotoxicity assay, serum cytokines measurements, IFN-γ and IL-4 ELISpot assay, T cells subpopulation frequencies assay. The liposomes containing DOTAP and DOPE (F1 liposomes) were able to stimulate cytotoxic T lymphocytes signals such as IFN-γ secretions. In parallel, the aforementioned phospholipids stimulated secretion of IL-4 and IL-17 cytokines from T helper cells. However, these liposomes did not improve survival indices in mice. As conclusion, DOTAP and DOPE contained liposomes (F1 liposomes) stimulate a mixture of Th1 and Th2 immune responses in a tumor-specific antigens-free manner in mice bearing C26 colon carcinoma. Therefore, phospholipid composition of liposomes merits consideration in designing antigen-containing liposomes for cancer immunotherapy.

    Topics: Animals; Cell Line, Tumor; Cell Survival; Cytokines; Fatty Acids, Monounsaturated; Immunotherapy; Liposomes; Mice, Inbred BALB C; Neoplasms; Phosphatidylethanolamines; Quaternary Ammonium Compounds; Tumor Burden

2019
Dequalinium-based functional nanosomes show increased mitochondria targeting and anticancer effect.
    European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2018, Volume: 124

    Mitochondria are targets with great potential for therapeutics for many human disorders. However, drug delivery systems for such therapeutics remain in need of more efficient mitochondrial-targeting carriers. In this study, we report that nanosomes composed of Dequalinium/DOTAP (1,2-dioleoyl-3-trimethylammonium-propane)/DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), called DQA80s, can act in the dual role of mitochondrial-targeting carrier and anticancer agent for therapeutic interventions against mitochondrial diseases. In cytotoxicity assays, DQA80s were shown to be more toxic than DQAsomes. The DQA80s showed significantly increased cellular uptake as compared to that of DQAsomes, and DQA80s also showed more efficient escape from the endolysosome to the cytosol. We observed the efficient targeting of DQA80s to mitochondria in living cells using flow cytometry, confocal microscopy, and TEM imaging. We also found evidence of anticancer potential that mitochondrial-targeted DQA80s induced apoptosis by production of reactive oxygen species (ROS) via MAPK signaling pathways, loss of mitochondrial membrane potential, and the caspase-3 activation. The present study demonstrates that DQA80s have excellent dual potential both as a carrier and as an anticancer therapeutic for mitochondria-related disease therapy in vivo.

    Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Cell Cycle; Dequalinium; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Fatty Acids, Monounsaturated; Flow Cytometry; HeLa Cells; Humans; Membrane Potential, Mitochondrial; Microscopy, Confocal; Microscopy, Electron, Transmission; Mitochondria; Nanomedicine; Nanoparticles; Neoplasms; Phosphatidylethanolamines; Quaternary Ammonium Compounds; Reactive Oxygen Species; Technology, Pharmaceutical

2018
Structural Characterization of Self-Assembling Hybrid Nanoparticles for Bisphosphonate Delivery in Tumors.
    Molecular pharmaceutics, 2018, 03-05, Volume: 15, Issue:3

    Hybrid self-assembling nanoparticles (hsaNPs) encapsulating bisphosphonates (BPs) recently showed very promising results in preclinic experiments for the treatment of brain tumor. However, the poor knowledge on the architecture of hybrid nanovectors is certainly one of the main reasons hampering further clinical and industrial development of these technologies. Here we propose to combine different techniques, that is, small angle neutron scattering (SANS) and X-ray Sscattering (SAXS), with cryo-electron transmission microscopy (cryo-TEM) to study the architecture of the final hsaNPs as well as of the four components before the assembling process. Data analysis based on SANS and SAXS experiments suggested a multiple compartment architecture of the final product, consisting of two bilayers sourrounding a core. Structures consisting of two shells surrounding an internal core were also observed in the cryo-TEM analysis. Such high resolution insight, also combined with size distribution and zeta potential of the NPs, provides exhaustive characterization of hsaNPs encapsulating BPs, and it is aimed at supporting further their clinical and industrial development.

    Topics: Antineoplastic Agents; Cryoelectron Microscopy; Drug Compounding; Fatty Acids, Monounsaturated; Humans; Liposomes; Microscopy, Electron, Transmission; Molecular Structure; Nanoparticles; Neoplasms; Neutron Diffraction; Phosphatidylethanolamines; Polyethylene Glycols; Quaternary Ammonium Compounds; Scattering, Small Angle; Transferrin; X-Ray Diffraction; Zoledronic Acid

2018
Polymer-coated pH-responsive high-density lipoproteins.
    Journal of controlled release : official journal of the Controlled Release Society, 2016, Apr-28, Volume: 228

    Intracellular drug delivery by nanoparticles is often hampered by their endosomal entrapment followed by their degradation in the lysosomal compartment and/or exocytosis. Here, we show that internalization and endosomal escape of cargoes in a cationized natural nanocarrier, high-density lipoprotein (HDL), can be controlled in a pH-dependent manner through stable complexation with a membranolytic anionic block polymer. A genetically and chemically cationized form of HDL (catHDL) is prepared for the first time by both genetic fusion with YGRKKRRQRRR peptide and incorporation of 1,2-dioleoyloxy-3-(trimethylammonium)propane. Upon addition of poly(ethylene glycol)-block-poly(propyl methacrylate-co-methacrylic acid) (PA), catHDL yields inhibition of internalization at neutral pH and its subsequent recovery at mildly acidic pH. catHDL forms a stable discoidal-shape complex with PA (catHDL/PA) (ca. 50 nm in diameter), even in the presence of serum. Significant enhancement of endosomal escape of a catHDL component is observed after a 1-h treatment of human cancer cells with catHDL/PA. Doxorubicin and curcumin, fluorescent anti-cancer drugs, encapsulated into catHDL/PA are also translocated outside of endosomes, compared with that into catHDL, and their cytotoxicities are enhanced inside the cells. These data suggest that catHDL/PA may have a potential benefit to improve the cellular delivery and endosomal escape of therapeutics under mildly acidic conditions such as in tumor tissues.

    Topics: Amino Acid Sequence; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Delayed-Action Preparations; Doxorubicin; Endosomes; Fatty Acids, Monounsaturated; Humans; Hydrogen-Ion Concentration; Lipoproteins, HDL; Neoplasms; Polyethylene Glycols; Polymethacrylic Acids; Quaternary Ammonium Compounds; Recombinant Fusion Proteins

2016
A novel liposomal recombinant lipoimmunogen enhances anti-tumor immunity.
    Journal of controlled release : official journal of the Controlled Release Society, 2016, 07-10, Volume: 233

    Synthetic liposomes provide a biocompatible and biodegradable approach for delivering drugs and antigens. In addition, self-adjuvanting recombinant lipoproteins (rlipoproteins) can enhance Th1 anti-tumor immune responses via the TLR2 signaling pathway. To generate a liposomal rlipoprotein for a cancer immunotherapeutic vaccine, we assessed 3 types of synthetic liposomes for use with the rlipoproteins rlipoE7m and rlipoOVA. We determined that the cationic liposome DOTAP could stabilize anionic rlipoproteins and delay rlipoprotein release. Surprisingly, rlipoproteins and DOTAP could synergistically up-regulate CD83 expression in bone marrow-derived dendritic cells (BMDCs). Compared with other liposome formulations, the rlipoprotein/DOTAP formulation elicited higher cytotoxic T-lymphocyte (CTL) responses. To explore the mechanism of BMDC activation by rlipoprotein/DOTAP, we assessed the production of reactive oxygen species (ROS) and the TNF-α secretion of BMDCs. We observed that rlipoprotein/DOTAP induced ROS to the same extent as DOTAP did. In addition, TLR2 signaling was also required for the TNF-α secretion of rlipoprotein/DOTAP-treated BMDCs. Moreover, compared with rlipoOVA-treated BMDCs, rlipoOVA/DOTAP-treated BMDCs increased the levels of IFN-γ produced by OVA-specific T cells. We also observed that rlipoE7m/DOTAP treatment but not rlipoE7m treatment delayed tumor growth. These results indicate that the rlipoprotein/DOTAP formulation can synergistically activate BMDCs via ROS and the TLR2 signaling pathway. In summary, rlipoprotein/DOTAP is a novel and stable formulation for cancer immunotherapy.

    Topics: Allergens; Animals; Cancer Vaccines; Cell Line, Tumor; Cell Survival; Dendritic Cells; Fatty Acids, Monounsaturated; Lipoproteins; Liposomes; Mice, Inbred C57BL; Neoplasms; Ovalbumin; Papillomavirus E7 Proteins; Quaternary Ammonium Compounds; Reactive Oxygen Species; Recombinant Proteins; Tumor Burden

2016
Predicting diffusive transport of cationic liposomes in 3-dimensional tumor spheroids.
    Journal of controlled release : official journal of the Controlled Release Society, 2014, Oct-28, Volume: 192

    Nanotechnology is widely used in cancer research. Models that predict nanoparticle transport and delivery in tumors (including subcellular compartments) would be useful tools. This study tested the hypothesis that diffusive transport of cationic liposomes in 3-dimensional (3D) systems can be predicted based on liposome-cell biointerface parameters (binding, uptake, retention) and liposome diffusivity. Liposomes comprising different amounts of cationic and fusogenic lipids (10-30mol% DOTAP or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1-20mol% DOPE or 1,2-dioleoyl-3-trimethylammonium-propane, +25 to +44mV zeta potential) were studied. We (a) measured liposome-cell biointerface parameters in monolayer cultures, and (b) calculated effective diffusivity based on liposome size and spheroid composition. The resulting parameters were used to simulate the liposome concentration-depth profiles in 3D spheroids. The simulated results agreed with the experimental results for liposomes comprising 10-30mol% DOTAP and ≤10mol% DOPE, but not for liposomes with higher DOPE content. For the latter, model modifications to account for time-dependent extracellular concentration decrease and liposome size increase did not improve the predictions. The difference among low- and high-DOPE liposomes suggests concentration-dependent DOPE properties in 3D systems that were not captured in monolayers. Taken together, our earlier and present studies indicate the diffusive transport of neutral, anionic and cationic nanoparticles (polystyrene beads and liposomes, 20-135nm diameter, -49 to +44mV) in 3D spheroids, with the exception of liposomes comprising >10mol% DOPE, can be predicted based on the nanoparticle-cell biointerface and nanoparticle diffusivity. Applying the model to low-DOPE liposomes showed that changes in surface charge affected the liposome localization in intratumoral subcompartments within spheroids.

    Topics: Biological Transport; Computer Simulation; Diffusion; Fatty Acids, Monounsaturated; Humans; Liposomes; Neoplasms; Phosphatidylethanolamines; Quaternary Ammonium Compounds; Spheroids, Cellular; Tumor Cells, Cultured

2014
Effective induction of anti-tumor immunity using p5 HER-2/neu derived peptide encapsulated in fusogenic DOTAP cationic liposomes co-administrated with CpG-ODN.
    Immunology letters, 2014, Volume: 162, Issue:1 Pt A

    Cationic liposomes have been used as efficient antigen delivery systems for cancer vaccination. The current study has investigated whether the incorporation of the helper-fusogenic lipid dioleoylphosphatidylethanolamine (DOPE) in cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-cholesterol enhances the cytosolic delivery of p5 HER-2/neu derived peptide (p5) and promotes cytotoxic T lymphocytes (CTL) response. The p5, which is a very hydrophobic peptide, was encapsulated into liposomes by using three different methods and characterized for their colloidal properties. A chaotropic loading method using 7 M urea provided the highest encapsulation yields. Mice were first immunized with encapsulated p5 in liposomes composed of either DOTAP-cholesterol or DOTAP-cholesterol-DOPE, alone or co-administered with CpG-ODN, as an immunoadjuvant, then, inoculated with a subcutaneous injection of TUBO tumor cells. Results obtained from enzyme-linked immunospot, cytotoxicity and intracellular cytokine assays as well as tumor sizes and animal survival analysis demonstrated that p5 encapsulated in DOTAP-cholesterol-DOPE liposomes co-administered with CpG-ODN greatly enhanced the cytotoxic T lymphocytes response and highly inhibited the tumor progression. The outperformance of DOTAP-cholesterol-DOPE liposomes+CpG-ODN was found to be attributed to its capability in induction of both CD8+ and CD4+ responses. This formulation could be a suitable vaccine candidate against Her2 positive cancers and merits further investigations.

    Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Cell Line, Tumor; Cytokines; Cytotoxicity, Immunologic; Disease Models, Animal; Fatty Acids, Monounsaturated; Female; Humans; Immunization; Liposomes; Mice; Neoplasms; Oligodeoxyribonucleotides; Peptide Fragments; Quaternary Ammonium Compounds; Receptor, ErbB-2; Spleen; T-Lymphocyte Subsets; Tumor Burden

2014
A new design for nucleolipid-based Ru(III) complexes as anticancer agents.
    Dalton transactions (Cambridge, England : 2003), 2013, Dec-28, Volume: 42, Issue:48

    In continuation with our studies concerning the synthesis, characterization and biological evaluation of nucleolipidic Ru(III) complexes, a novel design for this family of potential anticancer agents is presented here. As a model compound, a new uridine-based nucleolipid has been prepared, named HoUrRu, following a simple and versatile synthetic procedure, and converted into a Ru(III) salt. Stable formulations of this highly functionalized Ru(III) complex have been obtained by co-aggregation with either the zwitterionic lipid POPC or the cationic DOTAP, which have been subjected to an in-depth microstructural characterization, including DLS, SANS and EPR measurements. The in vitro bioactivity profile of HoUrRu, as a pure compound or in formulation with POPC or DOTAP, reveals high antiproliferative activity against MCF-7 and WiDr human cancer cell lines.

    Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Coordination Complexes; Drug Design; Fatty Acids, Monounsaturated; Humans; Neoplasms; Phosphatidylcholines; Quaternary Ammonium Compounds; Ruthenium; Uridine

2013
Calcium phosphate nanoparticles with an asymmetric lipid bilayer coating for siRNA delivery to the tumor.
    Journal of controlled release : official journal of the Controlled Release Society, 2012, Feb-28, Volume: 158, Issue:1

    Calcium phosphate (CaP) nanoparticles (NP) with an asymmetric lipid bilayer coating have been designed for targeted delivery of siRNA to the tumor. An anionic lipid, dioleoylphosphatydic acid (DOPA), was employed as the inner leaflet lipid to coat the nano-size CaP cores, which entrap the siRNA, such that the coated cores were soluble in organic solvent. A suitable neutral or cationic lipid was used as the outer leaflet lipid to form an asymmetric lipid bilayer structure verified by the measurement of NP zeta potential. The resulting NP was named LCP-II with a size of about 25 to 30nm in diameter and contained a hollow core as revealed by TEM imaging. PEGylation of NP was done by including a PEG-phospholipid conjugate, with or without a targeting ligand anisamide, in the outer leaflet lipid mixture. The sub-cellular distribution studied in the sigma receptor positive human H460 lung cancer cells indicated that LCP-II could release more cargo to the cytoplasm than our previous lipid/protamine/DNA (LPD) formulation, leading to a significant (~40 fold in vitro and ~4 fold in vivo) improvement in siRNA delivery. Bio-distribution study showed that LCP-II required more PEGylation for MPS evasion than the previous LPD, probably due to increased surface curvature in LCP-II.

    Topics: Animals; Calcium Phosphates; Cell Line, Tumor; Fatty Acids, Monounsaturated; Female; Gene Silencing; Gene Transfer Techniques; Humans; Lipid Bilayers; Mice; Mice, Nude; Nanoparticles; Neoplasms; Phosphatidic Acids; Phosphatidylcholines; Quaternary Ammonium Compounds; RNA, Small Interfering

2012
Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution.
    Nanomedicine (London, England), 2010, Volume: 5, Issue:8

    The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment.. MCLs (with incorporated high SPION cargo) were administered to a severe combined immunodeficiency mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre- and post-injection magnetic resonance (MR) images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by ¹¹¹In-labeled MCLs and the amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations.. We have shown that tumor signal intensities in T₂-weighted MR images decreased by an average of 20 ± 5% and T₂* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T₂* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance.. MR and biodistribution analysis clearly show the efficacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.

    Topics: Animals; Contrast Media; Drug Carriers; Fatty Acids, Monounsaturated; Ferric Compounds; Fluorescent Dyes; Humans; Injections, Intravenous; Kinetics; Liposomes; Magnetic Resonance Imaging; Magnetics; Melanoma; Mice; Mice, SCID; Nanoparticles; Neoplasm Metastasis; Neoplasms; Quaternary Ammonium Compounds; Tissue Distribution

2010
Saporin suicide gene therapy.
    Methods in molecular biology (Clifton, N.J.), 2009, Volume: 542

    New genes useful in suicide gene therapy are those encoding toxins such as plant ribosome-inactivating proteins (RIPs), which can irreversibly block protein synthesis, triggering apoptotic cell death. Plasmids expressing a cytosolic saporin (SAP) gene from common soapwort (Saponaria officinalis) are generated by placing the region encoding the mature plant toxin under the control of strong viral promoters and may be placed under tumor-specific promoters. The ability of the resulting constructs to inhibit protein synthesis is tested in cultured tumor cells co-transfected with a luciferase reporter gene. SAP expression driven by the cytomegalovirus (CMV) promoter (pCI-SAP) demonstrates that only 10 ng ofplasmid DNA per 1.6 x 10(4) B16 melanoma cells drastically reduces luciferase reporter activity to 18% of that in control cells (1). Direct intratumoral injections are performed in an aggressive melanoma model. B16 melanoma-bearing mice injected with pCI-SAP complexed with lipofectamine or N-(2,3-dioleoyloxy-1-propyl) trimethylammonium methyl sulfate (DOTAP) show a noteworthy attenuation in tumor growth, and this effect is significantly augmented by repeated administrations of the DNA complexes. Here, we describe in detail this cost-effective and safe suicide gene approach.

    Topics: Animals; Cell Death; Cell Line, Tumor; Cell Proliferation; DNA; Fatty Acids, Monounsaturated; Gene Transfer Techniques; Genes, Transgenic, Suicide; Genetic Therapy; Genetic Vectors; Mice; Neoplasms; Plasmids; Polyethyleneimine; Quaternary Ammonium Compounds; Ribosome Inactivating Proteins, Type 1; Saporins

2009
Reactive oxygen species play a central role in the activity of cationic liposome based cancer vaccine.
    Journal of controlled release : official journal of the Controlled Release Society, 2008, Aug-25, Volume: 130, Issue:1

    Recently, we developed a simple and potent therapeutic liposome cancer vaccine consisting of a peptide antigen and a cationic lipid. The molecular mechanism of the adjuvanticity of cationic liposome was studied and described in the current report. First, cationic DOTAP liposome, but not the neutral liposome DOPC, was shown to generate reactive oxygen species (ROS) in mouse bone marrow-derived dendritic cells (BMDC). ROS generation by DOTAP was required for ERK and p38 activation and downstream chemokine/cytokine induction. Furthermore, ROS were shown to be involved in the expression of the co-stimulatory molecules CD86/CD80 induced by DOTAP. However, as the DOTAP concentration increased from 50 to 800 microM, the apoptotic marker Annexin V and ROS double positive cells increased, suggesting that high dose of DOTAP-generated ROS causes cell apoptosis. In vivo, optimal amount of ROS in the draining lymph nodes (DLN) and anti-tumor (HPV positive TC-1 tumor) activity induced by E7 peptide (antigen derived from E7 oncoprotein of human papillomavirus (HPV) type 16) formulated in 100 nmol DOTAP were attenuated by incorporating DOPC in the formulation, suggesting that ROS are essential for the vaccine induced anti-tumor activity. Moreover, 600 nmol DOTAP/E7 generated huge amount of ROS in the DLN and showed no activity of tumor regression. Interestingly, 600 nmol DOTAP/E7-induced ROS were tuned down to the same level induced by 100 nmol DOTAP/E7 by adding DOPC in the formulation and this formulation showed tumor regression activity. In conclusion, DOTAP is an active DC stimulator resulting in the activation of ERK and p38 and induction of chemokines, cytokines and co-stimulatory molecules mediated by appropriate amount of ROS. Our data elucidated an important mechanism of adjuvant activity of cationic liposome and could facilitate rational design of synthetic lipid based adjuvants and vaccine formulation.

    Topics: Adjuvants, Immunologic; Animals; Annexin A5; Blotting, Western; Cancer Vaccines; Cations; Cytokines; Extracellular Signal-Regulated MAP Kinases; Fatty Acids, Monounsaturated; Female; Flow Cytometry; Liposomes; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms; Oncogene Proteins, Viral; p38 Mitogen-Activated Protein Kinases; Papillomavirus E7 Proteins; Phosphatidylcholines; Quaternary Ammonium Compounds; Reactive Oxygen Species

2008
Vesicular stomatitis virus matrix protein gene enhances the antitumor effects of radiation via induction of apoptosis.
    Apoptosis : an international journal on programmed cell death, 2008, Volume: 13, Issue:10

    Vesicular stomatitis virus (VSV) matrix (M) protein can directly induce apoptosis by inhibiting host gene expression when it is expressed in the absence of other viral components. Previously, we found that the M protein gene complexed to DOTAP-cholesterol liposome (Lip-MP) can suppress malignant tumor growth in vitro and in vivo; however, little is known regarding the biological effect of Lip-MP combined with radiation. The present study was designed to determine whether Lip-MP could enhance the antitumor activity of radiation. LLC cells treated with a combination of Lip-MP and radiation displayed apparently increased apoptosis compared with those treated with Lip-MP or radiation alone. Mice bearing LLC or Meth A tumors were treated with intratumoral or intravenous injections of Lip-MP and radiation. The combined treatment significantly reduced mean tumor volumes compared with either treatment alone in both tumor models and prolonged the survival time in Meth A tumor models and the intravenous injection group of LLC tumor models. Moreover, the antitumor effects of Lip-MP combined with radiation were greater than their additive effects when compared with the expected effects of the combined treatment in vivo. This study suggests that Lip-MP enhanced the antitumor activity of radiation by increasing the induction of apoptosis.

    Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Fatty Acids, Monounsaturated; Gamma Rays; Genetic Therapy; Liposomes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms; Quaternary Ammonium Compounds; Tumor Stem Cell Assay; Viral Matrix Proteins

2008
In vivo comparative study of lipid/DNA complexes with different in vitro serum stability: effects on biodistribution and tumor accumulation.
    Journal of pharmaceutical sciences, 2008, Volume: 97, Issue:1

    To evaluate the in vivo biodistribution and expression of DOTAP-Chol/DNA complexes (lipoplexes) with different in vitro serum stability, quantitative real-time PCR, in vitro luciferase expression and whole body luminescence imaging were used. In general, less tissue biodistribution, lower luciferase expression and whole body luminescence were observed for DOTAP:Chol (mol/mol 1:4)/DNA lipoplexes which had higher in vitro serum stability as compared to DOTAP:Chol (mol/mol 1:1)/DNA lipoplexes. Plasmid DNA biodistribution and expression were mainly confined to the lungs, and the results suggest that in vitro serum stability may serve as a predictor of transfection in the lung. No correlation between plasmid DNA tissue biodistribution and gene expression was observed by simultaneous determination of the level of plasmid DNA tissue biodistribution and gene expression. While high doses of the formulation possessing increased in vitro serum stability did exhibit reduced entrapment in the lung, no corresponding increase in the plasmid levels of other tissues was observed. However, this formulation did show increased accumulation in tumors that was not further enhanced by PEGylation.

    Topics: Animals; Cell Line, Tumor; Chemistry, Pharmaceutical; Cholesterol; DNA; Excipients; Fatty Acids, Monounsaturated; Female; Humans; Lipids; Liposomes; Luciferases; Luminescence; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Plasmids; Quaternary Ammonium Compounds; Reverse Transcriptase Polymerase Chain Reaction; Serum; Tissue Distribution

2008
siRNA delivery by a transferrin-associated lipid-based vector: a non-viral strategy to mediate gene silencing.
    The journal of gene medicine, 2007, Volume: 9, Issue:3

    RNA interference provides a powerful technology for specific gene silencing. Therapeutic applications of small interfering RNA (siRNA) however require efficient vehicles for stable complexation, protection, and extra- and intracellular delivery of these nucleic acids. Here, we evaluated the potential of transferrin (Tf)-associated liposomes for siRNA complexation and gene silencing.. Cationic liposomes composed of DOTAP : Cholesterol associated with or without transferrin (Tf) were complexed with siRNA at different lipid/siRNA charge ratios. Complexation and protection of siRNA from enzymatic degradation was assessed with the PicoGreen intercalation assay and gel electrophoresis. Cellular internalization of these siRNA Tf-lipoplexes was detected by confocal microscopy. Luciferase assay, immunoblot and fluorescence-activated cell sorting (FACS) analysis were used to evaluate reporter gene silencing in Huh-7 hepatocarcinoma and U-373 glioma cells. c-Jun knockdown in HT-22 cells was evaluated by quantitative real-time polymerase chain reaction (RT-PCR). Cytotoxicity of the siRNA complexes was assessed by Alamar blue, lactate dehydrogenase and MTT assays.. Complexation of siRNA with the cationic liposomes in the presence of Tf results in the formation of stable particles and prevents serum-mediated degradation. Confocal microscopy showed fast cellular internalization of the Tf-lipoplexes via endocytosis. In the GFP glioma cells Tf-lipoplexes showed enhanced gene silencing at minimum toxicity in comparison to Tf-free lipoplexes. Targeting luciferase in the hepatocarcinoma cell line resulted in more than 70% reduction of luciferase activity, while in HT-22 cells 50% knockdown of endogenous c-Jun resulted in a significant protection from glutamate-mediated toxicity.. Cationic liposomes associated with Tf form stable siRNA lipoplexes with reduced toxicity and enhanced specific gene knockdown activity compared to conventional lipoplexes. Thus, such formulations may constitute efficient delivery systems for therapeutic siRNA applications.

    Topics: Cations; Cell Line, Tumor; Fatty Acids, Monounsaturated; Fluorescence; Gene Transfer Techniques; Genes, Reporter; Genetic Therapy; Genetic Vectors; Green Fluorescent Proteins; Humans; JNK Mitogen-Activated Protein Kinases; Lipids; Liposomes; Neoplasms; Quaternary Ammonium Compounds; RNA Interference; RNA, Small Interfering; Transferrin

2007
Pyridinium cationic lipids in gene delivery: an in vitro and in vivo comparison of transfection efficiency versus a tetraalkylammonium congener.
    Archives of biochemistry and biophysics, 2005, Mar-01, Volume: 435, Issue:1

    Cationic lipids provide a promising alternative to the use of viruses for delivering genes therapeutically. Among the several classes of lipidic vectors, those bearing a heterocyclic cationic head have shown important advantages, such as low cytotoxicity and improved efficiency across different cell lines. We recently reported a simple and efficient strategy for obtaining pyridinium cationic lipids, starting from pyrylium salts and primary amines. The present study is aimed to compare the cellular toxicity and transfection efficiency generated by the pyridinium polar head versus the tetramethylammonium one on several tumor cell lines and also in experimental animals, delivered via intratumor injections. Thus, the lead compound 1-(2,3-dioleoyloxypropyl)-2,4,6-trimethylpyridinium lipid (2Oc), coformulated with different helper lipids in various molar ratios, was tested against its ammonium congener DOTAP-a standard transfection reagent. The results revealed that when formulated with cholesterol at 1:1 molar ratio, the pyridinium lipid 2Oc was able to transfect several cancer cell lines with similar or better efficiency than its tetraalkylammonium congener DOTAP, while producing lower cytotoxicity. The NCI-H23 lung cancer cell line was found to be the most susceptible to be transfected. Therefore, we designed an in vivo assay based on this type of carcinoma in nude mice, which were injected intratumoral with 2Oc- and DOTAP-based lipoplexes. The red fluorescent protein reporter revealed that the pyridinium cationic lipid was superior to its tetraalkylammonium congener, transfecting the tissue on a higher area and with higher efficiency. These encouraging findings, together with the simple and efficient synthetic strategy, lay the foundation for further development of pyridinium lipids for gene therapy with improved transfection efficiency in vivo and even further reduced cytotoxicity.

    Topics: Animals; Cations; Cell Line, Tumor; Coated Materials, Biocompatible; DNA; Drug Delivery Systems; Fatty Acids, Monounsaturated; Gene Targeting; Gene Transfer Techniques; Genetic Therapy; Humans; Lipids; Liposomes; Neoplasms; Pyridinium Compounds; Quaternary Ammonium Compounds; Transfection

2005
Persistent transgene expression following intravenous administration of a liposomal complex: role of interleukin-10-mediated immune suppression.
    Molecular therapy : the journal of the American Society of Gene Therapy, 2004, Volume: 9, Issue:3

    Studies conducted in non-tumor-bearing, immunocompetent mice have shown that intravenous administration of liposome-DNA complex elicits an inflammatory response that results in a failure to sustain adequate transgene expression. In the present study, however, we investigated the effects of a cationic liposomal DOTAP:cholesterol (DOTAP:Chol)-DNA complex on cytokine production and transgene expression in both experimental lung tumor-bearing (TB) mice and non-tumor-bearing (NTB) syngeneic mice and nude mice. Intravenous injection of DOTAP:Chol-luciferase (luc) DNA complex resulted in tumor necrosis factor-alpha levels that were 50% lower and interleukin-10 levels that were 50-60% higher in TB mice than in NTB mice. Furthermore, a significant increase in luc expression (P = 0.001) that persisted for 7 days was observed in TB mice. In contrast, luc expression decreased significantly from day 1 to day 2 in NTB mice. Also, luc expression was two- to threefold higher in TB mice that were given multiple injections of DOTAP:Chol-luc complex than in mice who received a single injection. In contrast, luc expression was significantly suppressed following multiple injections in NTB mice (P = 0.01). Further analysis revealed IL-10 protein expression by the tumor cells in TB mice. Injection of anti-IL-10 antibody in TB mice resulted in a significant decrease in luc expression (P = 0.01) compared with that in mice injected with a control antibody. Based on these findings, we conclude that transgene expression persists in TB mice and is partly mediated by IL-10. Additionally, multiple injections of liposome-DNA complex can increase transgene expression in TB mice. These findings have clinical applications in the treatment of cancer.

    Topics: Animals; Cholesterol; Cytokines; DNA; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Monounsaturated; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Immunohistochemistry; Inflammation; Interleukin-10; Liposomes; Luciferases; Lung; Lung Neoplasms; Macrophages, Alveolar; Mice; Mice, Inbred C3H; Mice, Nude; Models, Biological; Neoplasms; Plasmids; Quaternary Ammonium Compounds; Time Factors; Transgenes

2004