Indoleamine 2,3-dioxygenase (IDO): Only an enzyme or a checkpoint controller?

Tryptophan (Trp) is one of the important essential amino acids and Kynurenine pathway (KP) is the first and rate limiting step of degrading Trp to active metabolites. Recent studies showed that KP metabolites have antimicrobial and immunosuppressive roles. The main controller enzyme of this pathway is indoleamine-2,3-dioxygenase (IDO). IDO is an intracellular monomeric, heme-containing enzyme that controls the Trp breakdown in the KP. In this review, we discuss IDO functions on cancer progression and prognosis, and possible therapeutic aspects of inhibition of IDO on cancer immunotherapy

Bioadhesive coated poly-epsilon-caprolactone nanoparticles loaded with Mitomycin C for the treatment of superficial bladder tumors

2nd BBBB Conference on Pharmaceutical Sciences -- SEP 13-15, 2007 -- Tartu, ESTONIAWOS: 00024901800006

Long-Circulating Peg-Pe Micelles Co-Loaded with Paclitaxel and Elacridar (Gg918) Overcome Multidrug Resistance

Overexpression of drug efflux pump P-gp is one of the major reasons to cause multidrug resistance (MDR). To overcome P-gp mediated MDR, modulators, so called P-gp inhibitors, can be used to block efflux pump activity. Elacridar is one of the most potent P-gp inhibitors, which can cause irreversible and total P-gp blockage. Elacridar, among with other P-gp inhibitors, can be used in combination with anticancer drugs to enhance the effectiveness of chemotherapy against resistant tumor cells. On the other hand, P-gp is presented in normal tissues, thus nonselective blockage of P-gp can cause undesired side effects. Therefore, it is important to deliver P-gp inhibitor only to the tumor cells (along with anticancer drug) and limit its distribution in the body. In this study, we have developed PEG-PE-based long-circulating ca. 15 nm micelles co-loaded with elacridar and paclitaxel, and investigated their ability to overcome paclitaxel resistance in two cancer cell lines. Vitamin E, a common solubility enhancer for PEG-PE micelles, was found to have a negative effect on both particle size and encapsulation efficiencies. The human MDR1 gene-transfected and thus paclitaxel-resistant MDCKII-MDR1 P-gp overexpressing cells were used for cytotoxicity evaluation. Even though PEG-PE based micelles itself have a potential to enhance the cytotoxicity of paclitaxel, elacridar/paclitaxel-co-loaded micelles demonstrated the highest cytotoxicity compared to both free and micellar paclitaxel. The obtained results suggest that co-loading of paclitaxel and elacridar into micellar drug carriers results in promising preparations capable of overcoming paclitaxel resistance.WoSScopu

Surface-engineered polyethyleneimine-modified liposomes as novel carrier of siRNA and chemotherapeutics for combination treatment of drug-resistant cancers

Modification of nanoparticle surfaces with PEG has been widely considered the gold standard for many years. However, PEGylation presents controversial and serious challenges including lack of functionality, hindered cellular interaction, allergic reactions, and stimulation of IgM production after repetitive dosing that accelerates blood clearance of the nanoparticles. We report the development of novel liposomal formulations surface-modified with a low molecular weight, branched polyethyleneimine (bPEI)–lipid conjugate for use as an alternative to PEG. The formulations had very good stability characteristics in ion- and protein-rich mediums. Protein adsorption onto the liposomal surface did not interfere with the cellular interaction. bPEI-modified liposomes (PEIPOS) showed enhanced association with three different cell lines by up to 75 times compared to plain or PEGylated liposomes and were without carrier toxicity. They also penetrated the deeper layers of 3D spheroids. Encapsulating paclitaxel (PTX) into PEIPOS did not change its main mechanism of action. PEIPOS complexed and intracellularly delivered siRNAs and downregulated resistance-associated proteins. Finally, tumor growth inhibition was observed in a mouse ovarian xenograft tumor model, without signs of toxicity, in animals treated with the siRNA/PTX co-loaded formulation. These complex-in-nature but simple-in-design novel liposomal formulations constitute viable and promising alternatives with added functionality to their PEGylated counterparts

Optimization of prednisolone acetate-loaded chitosan microspheres using a 2(3) factorial design for preventing restenosis

WOS: 000275655800011PubMed ID: 20196705Prednisolone acetate (PA)-loaded microspheres were prepared by the spray-drying technique using different polymer (1% and 2%) and drug concentrations (10% and 20%). To obtain the optimum formulation, a three-factor two-level (2<SU3</SU) design was employed. The independent variables were polymer molecular weight, polymer concentration, and theoretical drug loading. Responses were the particle size, percentage of encapsulation efficiency, and the t(50%) release. The best formulation was prepared with 20% of PA and 1% of chitosan with medium molecular weight showing relative good yield of production (48.0 +/- 6.7%) and encapsulation efficiency (45.7 +/- 0.3%), and released the drug at a constant rate in 11 days.</.Hacettepe University Research FundHacettepe University [0302301007]This study was supported by Hacettepe University Research Fund (Project No: 0302301007). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper

A Triple Co-Delivery Liposomal Carrier That Enhances Apoptosis via an Intrinsic Pathway in Melanoma Cells

The effectiveness of existing anti-cancer therapies is based mainly on the stimulation of apoptosis of cancer cells. Most of the existing therapies are somewhat toxic to normal cells. Therefore, the quest for nontoxic, cancer-specific therapies remains. We have demonstrated the ability of liposomes containing anacardic acid, mitoxantrone and ammonium ascorbate to induce the mitochondrial pathway of apoptosis via reactive oxygen species (ROS) production by the killing of cancer cells in monolayer culture and shown its specificity towards melanoma cells. Liposomes were prepared by a lipid hydration, freeze-and-thaw (FAT) procedure and extrusion through polycarbonate filters, a remote loading method was used for dug encapsulation. Following characterization, hemolytic activity, cytotoxicity and apoptosis inducing effects of loaded nanoparticles were investigated. To identify the anticancer activity mechanism of these liposomes, ROS level and caspase 9 activity were measured by fluorescence and by chemiluminescence respectively. We have demonstrated that the developed liposomal formulations produced a high ROS level, enhanced apoptosis and cell death in melanoma cells, but not in normal cells. The proposed mechanism of the cytotoxic action of these liposomes involved specific generation of free radicals by the iron ions mechanism

MDM2 antagonist-loaded targeted micelles in combination with doxorubicin: effective synergism against human glioblastoma via p53 re-activation

PMID = 3065697