1-2-oleoylphosphatidylcholine and Neoplasms

MicroRNAs (miRNAs) are small RNA molecules that affect cellular processes by controlling gene expression. Recent studies have shown that hypoxia downregulates Drosha and Dicer, key enzymes in miRNA biogenesis, causing a decreased pool of miRNAs in cancer and resulting in increased tumor growth and metastasis. Here we demonstrate a previously unrecognized mechanism by which hypoxia downregulates Dicer. We found that miR-630, which is upregulated under hypoxic conditions, targets and downregulates Dicer expression. In an orthotopic mouse model of ovarian cancer, delivery of miR-630 using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) nanoliposomes resulted in increased tumor growth and metastasis, and decreased Dicer expression. Treatment with the combination of anti-miR-630 and anti-vascular endothelial growth factor antibody in mice resulted in rescue of Dicer expression and significantly decreased tumor growth and metastasis. These results indicate that targeting miR-630 is a promising approach to overcome Dicer deregulation in cancer. As demonstrated in the study, use of DOPC nanoliposomes for anti-miR delivery serves as a better alternative approach to cell line-based overexpression of sense or antisense miRNAs, while avoiding potential in vitro selection effects. Findings from this study provide a new understanding of miRNA biogenesis downregulation observed under hypoxia and suggest therapeutic avenues to target this dysregulation in cancer.

Topics: Animals; Cell Hypoxia; Cell Line, Tumor; DEAD-box RNA Helicases; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Liposomes; Mice; MicroRNAs; Neoplasms; Ovarian Neoplasms; Phosphatidylcholines; Ribonuclease III; Vascular Endothelial Growth Factor A

The protoporphyron (PPIX)-lipid (PL-C17) liposomes were successfully prepared from the corresponding micelles by post-inserted method. Both the PL-C17 micelles and liposomes were distributed in plasma membrane and cytoplasm after incubation of the cells with PL-C17 liposomes for 1h. They translocated from plasma membrane into a certain organelle in the cells after incubation in the photosensitizer-free medium. Higher photo-cytotoxicity was observed in the PL-C17 micelles and liposomes localized in plasma membrane in comparison with those localized in the cytoplasm under light irradiation. The LDH assay revealed that cytopathic damages of the plasma membrane were observed in the PL-C17 micelles and liposomes highly localized in plasma membrane. The fluorescent intensity of the calcein-encapsulating DOPC liposomes post-inserted with PL-C17 increased after light irradiation, suggesting that the membrane disruption is possibly caused by oxidation of membrane lipids with ROS generated from photosensitizers and affects the photo-cytotoxicity in PDT.

Topics: Cell Line; HeLa Cells; Humans; Liposomes; Micelles; Neoplasms; Phosphatidylcholines; Photochemotherapy; Photosensitizing Agents; Protoporphyrins; Reactive Oxygen Species

Zwitterionic phosphotydylcholine lipo-somes stably adsorb a number of metal oxide nanoparticles via its phosphate group. This is different from physisorption and fusion with SiO2. The hybrid materials can be internalized by cancer cells and TiO2 allows light controlled liposome content release.

Topics: Adsorption; Biosensing Techniques; Cell Line, Tumor; Drug Delivery Systems; Humans; Light; Lipid Bilayers; Liposomes; Metal Nanoparticles; Metals; Nanotechnology; Neoplasms; Oxides; Phosphates; Phosphatidylcholines; Silicon Dioxide; Static Electricity

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

We showed that magnetotactic bacteria (MTB) have great potentials to be used as microcarriers for targeted delivery of therapeutic agents. Indeed, magnetotaxis inherent in MTB can be exploited to direct them towards a tumor while being propelled by their own flagellated molecular motors. Nonetheless, although the thrust propelling force above 4 pN of the MC-1 MTB showed to be superior compared to other technologies for displacement in the microvasculature, MTB becomes much less efficient when travelling in larger blood vessels due to higher blood flow. In the latter case, a new technique developed by our group and referred to as Magnetic Resonance Navigation (MRN), has been successfully applied in larger vessels using synthetic microcarriers nut proved to be less efficient in the microvasculature due mainly to technological constraints. These findings called for the need to integrate both approaches by encapsulating MTB in special MRN-compatible microcarriers to be release in the vicinity of microvascular networks where they becomes more effective for targeting purposes in tumoral lesions. In this study Magnetococcus strain MC-1 were encapsulated in giant vesicles. The survival of the encapsulated bacteria was monitored. The release of bacteria from giant vesicles was also studied in different time intervals and conditions.

Topics: Antineoplastic Agents; Bacteria; Bacterial Physiological Phenomena; Drug Carriers; Drug Delivery Systems; Flagella; Humans; Liposomes; Magnetics; Microcirculation; Microfluidics; Molecular Motor Proteins; Neoplasms; Phosphatidylcholines; Software; Time Factors

Liposomal locked-in dendrimers (LLDs), the combination of liposomes and dendrimers in one formulation, represents a relatively new term in the drug carrier technology. LLDs undergone appropriate physicochemical investigation can merge the benefits of liposomal and dendrimeric nanocarriers. In this study generation 1 and 2 hydroxy-terminated dendrimers were synthesized and were then "locked" in liposomes consisting of DOPC/DPPG. The anticancer drug doxorubicin (Dox) was loaded into pure liposomes or LLDs and the final products were subjected to lyophilization. The loading of Dox as well as its in vitro release rate from all systems was determined and the interaction of liposomes with dendrimers was assessed by thermal analysis and fluorescence spectroscopy. The results were very promising in terms of drug encapsulation and release rate, factors that can alter the therapeutic profile of a drug with low therapeutic index such as Dox. Physicochemical methods revealed a strong, generation dependent, interaction between liposomes and dendrimers that probably is the basis for the higher loading and slower drug release from the LLDs comparing to pure liposomes.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Dendrimers; Differential Thermal Analysis; Doxorubicin; Drug Carriers; Drug Compounding; Drug Delivery Systems; Freeze Drying; Indicators and Reagents; Liposomes; Membrane Fluidity; Neoplasms; Phosphatidylcholines; Phosphatidylglycerols; Solubility; Spectrometry, Fluorescence

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

Topics: Antineoplastic Agents; Drug Carriers; Liposomes; Molecular Structure; Neoplasms; Phosphatidylcholines; Phosphatidylethanolamines; Porphyrins; Radiation-Sensitizing Agents; Spectrum Analysis; X-Rays

Topics: Animals; Base Sequence; Breast Neoplasms; Cell Division; Cell Line, Tumor; Chickens; Drug Delivery Systems; Female; Genetic Therapy; Humans; Liposomes; Neoplasms; Oligonucleotides, Antisense; Phosphatidylcholines; Thymidine Kinase