dioleoyl-phosphatidylethanolamine and Neoplasms

The purpose of this review is to provide an insight into the different aspects of pH-sensitive liposomes. The review consists of 6 parts: the first introduces different types of medications made in liposomal drug delivery to overcome several drawbacks; the second elaborates the development of pH-sensitive liposomes; the third explains diverse mechanisms associated with the endocytosis and the cytosolic delivery of the drugs through pH-sensitive liposomes; the fourth describes the role and importance of pH-sensitive lipid dioleoylphosphatidylethanolamine (DOPE) and research carried on it; the fifth explains successful strategies used so far using the mechanism of pH sensitivity for fusogenic activity; the final part is a compilation of research that has played a significant role in emphasizing the success of pH-sensitive liposomes as an efficient drug delivery system in the treatment of malignant tumours. pH-Sensitive liposomes have been extensively studied in recent years as an amicable alternative to conventional liposomes in effectively targeting and accumulating anti-cancer drugs in tumours. This research suggests that pH-sensitive liposomes are more efficient in delivering anti-cancer drugs than conventional and long-circulating liposomes due to their fusogenic property. Research focused on the clinical and therapeutic side of pH-sensitive liposomes would enable their commercial utility in cancer treatment.

Topics: Antineoplastic Agents; Cytosol; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Drug Design; Endocytosis; Hydrogen-Ion Concentration; Liposomes; Membrane Fusion; Neoplasms; Phosphatidylethanolamines

The acidic microenvironment of cancer can promote tumor metastasis and drug resistance. Acidic tumor microenvironment-targeted therapy is currently an important means for treating tumors, inhibiting metastasis, and overcoming drug resistance. In this study, a dual pH-responsive DOX-encapsulated liposome (DOPE-DVar7-lip@DOX) was designed and fabricated for targeting the acidic tumor microenvironment. On the one hand, the response of acid-sensitive peptide (DVar7) to the acidic tumor microenvironment increased the uptake of liposomes in tumors and prolonged the retention time; on the other hand, the response of acid-sensitive phospholipid (DOPE) to the acidic tumor microenvironment improved the controlled release of DOX in tumors.. The acid-sensitive peptide DVar7 modified liposomes can be obtained by simple incubation of DSPE-DVar7 with DOX-loaded DOPE liposomes (DOPE-lip@DOX). The tumor targeting of the dual pH-responsive liposome was investigated in vitro and in vivo by near-infrared fluorescence imaging. The tumor therapeutic efficacy of DOPE-DVar7-lip@DOX was evaluated in breast cancer mouse model using the traditional liposome as a control. Moreover, we regulated the tumor microenvironment acidity by injecting glucose to further enhance the therapeutic efficacy of cancer.. DVar7 can allosterically insert into the tumor cell membrane in the acidic tumor microenvironment to enhance the tumor uptake of liposomes and prolong the retention time of liposomes in tumor. In addition, the therapeutic efficacy of pH-responsive liposomes can be further enhanced by glucose injection regulating the acidity of tumor microenvironment.. DVar7 modified acid-sensitive nanocarriers combined with acidity regulation have great potential to improve drug resistance in clinical practice, thus improving the response rate and therapeutic effect of chemotherapy.

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Drug Liberation; Endocytosis; Glucose; Humans; Hydrogen-Ion Concentration; Liposomes; Mice, Inbred BALB C; Neoplasms; Optical Imaging; Particle Size; Phosphatidylethanolamines

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

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

Folate receptors (FR) are cellular markers highly expressed in various cancer cells. Here, we report on the synthesis of a novel folate-containing lipoconjugate (FC) built of 1,2-di-O-ditetradecyl-rac-glycerol and folic acid connected via a PEG spacer, and the evaluation of the FC as a targeting component of liposomal formulations for nucleic acid (NA) delivery into FR expressing tumor cells. FR-targeting liposomes, based on polycationic lipid 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride (2X3), lipid helper dioleoylphosphatidylethanolamine (DOPE) and novel FC, formed small compact particles in solution with diameters of 60 ± 22 nm, and were not toxic to cells. Complexes of NAs with the liposomes were prepared at various nitrogen to phosphate ratios (N/P) to optimize liposome/cell interactions. We showed that FR-mediated delivery of different nucleic acids mediated by 2X3-DOPE/FC liposomes occurs in vitro at low N/P (1/1 and 2/1); under these conditions FC-containing liposomes display 3-4-fold higher transfection efficiency in comparison with conventional formulation. Lipoplexes formed at N/P 1/1 by targeted liposomes and cargo (Cy7-labeled siRNA targeting MDR1 mRNA) in vivo efficiently accumulate in tumor (∼15-18% of total amount), and kidneys (71%), and were retained there for more than 24 h, causing efficient downregulation of p-glycoprotein expression (to 40% of control) in tumors. Thus, FC containing liposomes provide effective targeted delivery of nucleic acids into tumor cells in vitro and in xenograft tumors in vivo.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line; Down-Regulation; Female; Folic Acid; Folic Acid Transporters; HEK293 Cells; Heterografts; Humans; Kidney; Liposomes; Mice; Mice, SCID; Neoplasms; Nucleic Acids; Particle Size; Phosphatidylethanolamines; Transfection

Lipid-based nanoparticles as gene vectors have attracted considerable attention for their high gene transfection efficiency and low cytotoxicity. In our previous work, we synthesized gold nanoparticles/dimethyldioctadecylammonium bromide (DODAB)/dioleoylphosphatidylethanolamine (DOPE) (GDD) as anionic lipid- and pH-sensitive gene vectors. To further realize targeted gene transfection, a series of gold nanoparticles/DODAB/DOPE/DOPE-folic acid (DOPE-FA) with various ratios of DOPE-FA were prepared and termed as GFn (for which n=1.0, 2.5, 5.0, 7.5, or 10.0 %). The gene transfection efficiency mediated by GF2.5 can reach about 85 % for MCF-7 (FA-receptor-positive cells), higher than those of the negative control (GDD, 35 %) and positive control (Lipofectamine 2000, 65 %). However, GF2.5 does not further promote gene transfection into A549 (FA-receptor-negative cells). The higher gene transfection efficiency for MCF-7 cells can be attributed to enhanced cellular uptake efficiency mediated by the FA targeting ability. Furthermore, GF2.5 was also found to accumulate at the specific tumor site and showed enhanced in vivo gene delivery ability. In addition, no significant harm was observed for the main tissues of the mice after treatment with GF2.5. Therefore, GF2.5, with the targeting ability and improved transfection efficiency, shows promise for its utility in gene therapy for tumor cells that overexpress FA receptors. We believe the results of this study will find more broad applications in gene therapy.

Topics: A549 Cells; Animals; Cell Survival; Folic Acid; Genetic Vectors; Gold; Humans; MCF-7 Cells; Metal Nanoparticles; Mice; Microscopy, Confocal; Neoplasms; Phosphatidylethanolamines; Rhodamines; Spectrophotometry, Ultraviolet; Transfection

The sterically polymer-based liposomal complexes (SPLexes) were formed by cationic polymeric liposomes and pH-sensitive diblock copolymer were studied for their capabilities in improving the stability with high efficiency of siRNA delivery. The SPLexes were formed a dual-shelled structure and uniform size distribution. The PEGylated outer shell could mitigate the phagocytosis and reduce the cytotoxicity. Moreover, the folated SPLexes improved 42.9× accumulation in vitro and 1.7× tumor uptake in vivo in contrast with nonfolated SPLexes. The protonated copolymer at low pH would improve the siRNA released into cytoplasm following SPLexes fusion with the endo/lysosome membrane and inhibited the protein expression to 75.6 ± 4.5% efficiently. Results of this study significantly contribute to efforts to develop lipoplexes based siRNA delivery systems.

Topics: Animals; Apoptosis; Blotting, Western; Cations; Cell Line, Tumor; Cell Proliferation; Cholesterol; Cytoplasm; Drug Delivery Systems; Humans; Liposomes; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Transmission; Neoplasms; Phagocytosis; Phosphatidylethanolamines; Polymers; RNA, Small Interfering; Vascular Endothelial Growth Factor A

Staudinger ligation was evaluated as a strategy for synthesizing receptor targeted liposomes. First, an activated lipid derivative was synthesized by reacting dioleoyl phosphatidylethanolamine (DOPE) and 2-(diphenylphosphino) terephthalic acid 1-methyl 4-penta-fluorophenyldiester. Second, transferrin (Tf) was activated with p-azidophenyl isothiocyanate. Third, liposomes containing the activated lipid were prepared and then coupled to the activated Tf via the Staudinger reaction. These liposomes were evaluated in KB cells for cellular uptake and cytotoxicity, and in mice for pharmacokinetic properties. Tf-derivatized liposomes encapsulating calcein prepared by this conjugation method effectively targeted Tf receptor expressing KB cells. In addition, the Tf-targeted liposomes entrapping doxorubicin showed greatly enhanced in vitro cytotoxicity relative to non-targeted control liposomes. Pharmacokinetic parameters indicated that these liposomes retained long circulating properties relative to the free drug. In summary, Staudinger ligation is an effective method for the synthesis of receptor targeted liposomes.

Topics: Animals; Antibiotics, Antineoplastic; Azides; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Doxorubicin; Drug Carriers; Drug Compounding; Endocytosis; Female; Humans; Inhibitory Concentration 50; Injections, Intravenous; Isothiocyanates; Liposomes; Mice; Mice, Inbred ICR; Nanotechnology; Neoplasms; Organothiophosphorus Compounds; Phosphatidylethanolamines; Receptors, Transferrin; Technology, Pharmaceutical; Transferrin

In this study, a novel nonviral gene delivery system, which could enhance the inhibition effect of antisense oligonucleotides (ASODN) against the tumor cells, was developed. The polycation liposomes (PCLs) were prepared using the film hydration method with dioleoylphosphatidylethanolamine (DOPE) and amphipathic compound polyethylenimine-cholesterol (PEI 800-Chol), synthesized by low-molecular-weight polyethylenimine (PEI, MW 800) covalent conjugation with cholesterol. The formation of PEI 800-Chol was confirmed by IR and critical micelle concentration detection. The transfection efficiency of PCLs mediating Green Fluorescence Protein plasmid (pEGFP) in HeLa cells was evaluated and the highest gene expression was obtained by PCLs containing DOPE, which was 1.6-fold of that induced by commercial Lipofectamine 2000, and the gene expression efficiency was influenced in the present of serum. Subsequently, human telomerase reverse transcriptase gene antisense oligonucleotides (hTERT-ASODN) were used as therapeutic gene, and the results showed that PCLs, which demonstrated very low cytotoxicity itself, could significantly enhance the inhibition efficiency of hTERT-ASODN in the growth of tumor cells. These results suggested that the PCLs could be widely applied for ASODN delivery.

Topics: Cholesterol; Gene Transfer Techniques; Green Fluorescent Proteins; HeLa Cells; Humans; Liposomes; Materials Testing; Molecular Structure; Neoplasms; Oligonucleotides, Antisense; Particle Size; Phosphatidylethanolamines; Polyamines; Polyelectrolytes; Polyethyleneimine; Telomerase

In this study, we developed a nonviral, cationic, targeted DNA-carrier system by coupling SAINT/DOPE lipids to monoclonal antibodies. The two monoclonal antibodies used were both tumor specific, that is, MOC31 recognizes the epithelial glycoprotein EGP-2 present in carcinomas and Herceptin recognizes the HER-2/neu protein in breast and ovarian cancers. Coupling was performed under nonreducing conditions by covalent attachment. The coupling procedure appeared to be reproducible and the binding capacity of the antibody was not affected by linking them to the cationic lipid. Binding and transfection efficiency was assayed with target cells and nontarget cells. SAINT/DOPE lipoplexes as such appeared to be an effective transfection reagent for various cell lines. After coupling SAINT/DOPE to the monoclonal antibodies or F(ab)2 fragments, it was shown that the targeted MoAb-SAINT/DOPE lipoplexes preferably bound to target cells, compared to binding to the nontarget cells, especially for the Herceptin-SAINT/DOPE lipoplexes. More importantly, transfection of the target cells could also be improved with these targeted lipoplexes. In conclusion, we have shown that by using monoclonal antibody-coupled SAINT/DOPE lipoplexes cells targeted gene delivery can be achieved, and also a higher number of transfected target cells was seen.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cations; Cell Line, Tumor; DNA; Gene Targeting; Genetic Therapy; Humans; Immunoglobulin Fab Fragments; Lipid Metabolism; Liposomes; Melanoma; Mice; Neoplasms; Phosphatidylethanolamines; Plasmids; Skin Neoplasms; Transfection; Trastuzumab