Anticancer Drugs in Liposomal Nanodevices: A Target Delivery for a Targeted Therapy

International audienceFor many years, nanocarriers have been investigated to modify pharmacokinetics and biodistribution of various active molecules. In the cancer domain, one of the biggest challenges still remains the improvement of the therapeutic index, often too low, for the majority of antitumor drugs. The application of nanotechnologies for the treatment and the diagnosis of cancers are nowadays currently developed, or under development, and liposomes play an important role in the history of nanodevices. Because of their high degree of biocompatibility, lipid nanosystems have been used to improve pharmacological profiles of various anticancer drugs otherwise discarded because of their low water solubility, poor bioavailability or either fragile and subjected to rapid biotransformations. This review aims at introducing an overview of the last 40 years of liposome researches until the last liposomal formulations commercially available or undergoing clinical trials. Liposome properties will be described, with a particular emphasis over the last generation of carriers appreciated for their active targeting characteristics. Researchers foresee a remarkable impact of nanotechnologies in the field of medicine; this review will try to summarize the main concepts over liposome domain, which can count on encouraging results as target therapy associated with targeted delivery

Significance and applications of nanoparticles in siRNA delivery for cancer therapy

International audienceRNAi is a powerful gene silencing process that holds great promise in cancer therapy by the use of siRNA. The aim of this review is to give an outline on different approaches to deliver siRNA and to describe the advantages and disadvantages of these systems. The prospects for siRNA are to be substantially better than other therapies, as they are easily applicable to any therapeutic target. They also promise potent gene inhibition with exquisite selectivity, down to the level of a single nucleotide polymorphism, and can easily identify offending proteins or variants by screening across a gene sequence. The main obstacle of using RNAi technology in cancer treatment is to protect such a fragile and quickly metabolized biological molecule and to efficiently deliver it in vivo to the target cells. Therefore, there is a requirement for new systems, such as nanoparticles, for siRNA delivery to help the siRNAs reach, and improve their biodistribution in, target tissues

Lipid conjugated oligonucleotides: a useful strategy for delivery.

International audienceOligonucleotides, including antisense oligonucleotides and siRNA, are promising therapeutic agents against a variety of diseases. Effective delivery of these molecules is critical in view of their clinical application. Therefore, cation-based nanoplexes have been developed to improve the stability as well as the intracellular penetration of these short fragments of nucleic acids. However, this approach is clearly limited by the strong interaction with proteins after administration and by the inherent toxicity of these positively charged transfection materials. Neutral lipid-oligonucleotide conjugates have become a subject of considerable interest to improve the safe delivery of oligonucleotides. These molecules have been chemically conjugated to hydrophobic moieties such as cholesterol, squalene, or fatty acids to enhance their pharmacokinetic behavior and trans-membrane delivery. The present review gives an account of the main synthetic methods available to conjugate lipids to oligonucleotides and will discuss the pharmacological efficacy of this approach

Induction of TTF-1 or PAX-8 expression on proliferation and tumorigenicity in thyroid carcinomas

International audienceTTF-1 and PAX-8 are responsible for thyroid organogenesis and for maintenance of differentiation in thyrocytes. Thus, we hypothesized that the induction of these two transcription factors could affect proliferation and tumorigenicity. Moreover, the ability of various pharmacological agents to modulate expression of the TTF-1 and PAX-8 and their effects on apoptosis were also analysed. For this purpose, cell lines derived from papillary (TPC-1 and BHP 10-3) and anaplastic (ARO) thyroid carcinomas were stably transfected with expression vectors containing TTF-1 or PAX-8 genes. Subsequently, the effects on expression at gene and protein levels, as well as on cell growth, cell cycle, migration and in vivo tumorigenicity were studied. Our results showed that: i) TTF-1 reciprocally induces PAX-8 expression; ii) the basal state of TTF-1 or PAX-8 influences proliferation, migration and tumorigenicity; iii) the induction of TTF-1 acts on cell proliferation more than PAX-8 and mainly affects tumorigenicity; and iv) TTF-1 was found to be more sensitive to epigenetic modulators than PAX-8. Therefore, we postulated that both TTF-1 and PAX-8 when co-expressed have anti-proliferative and anti-tumorigenic properties up to a threshold expression level and beyond that, are able to induce pro-tumorigenic effects. Hence in future, it will be quite interesting to systematically take into account the basal state of expression of TTF-1 and PAX-8. It will also be important to study the two thyroid transcription factors as part of a duo. This could open in the long-term, new therapeutic perspectives for thyroid carcinomas

Relevance of Fusion Genes in Pediatric Cancers: Toward Precision Medicine

International audiencePediatric cancers differ from adult tumors, especially by their very low mutational rate. Therefore, their etiology could be explained in part by other oncogenic mechanisms such as chromosomal rearrangements, supporting the possible implication of fusion genes in the development of pediatric cancers. Fusion genes result from chromosomal rearrangements leading to the juxtaposition of two genes. Consequently, an abnormal activation of one or both genes is observed. The detection of fusion genes has generated great interest in basic cancer research and in the clinical setting, since these genes can lead to better comprehension of the biological mechanisms of tumorigenesis and they can also be used as therapeutic targets and diagnostic or prognostic biomarkers. In this review, we discuss the molecular mechanisms of fusion genes and their particularities in pediatric cancers, as well as their relevance in murine models and in the clinical setting. We also point out the difficulties encountered in the discovery of fusion genes. Finally, we discuss future perspectives and priorities for finding new innovative therapies in childhood cancer

Liposomal trichostatin A: therapeutic potential in hormone-dependent and -independent breast cancer xenograft models

International audienceTrichostatin A (TSA) is one of the most potent histone deacetylase inhibitors (HDACi) in vitro but it lacks biological activity in vivo when injected intravenously owing to its fast metabolism

Liposomes loaded with histone deacetylase inhibitors for breast cancer therapy

International audienceHistone deacetylase (HDAC) inhibitors (HDACi) of the class I trichostatin A (TSA), CG1521 (CG), and PXD101 (PXD) were incorporated at a high rate (approximately 1mM) in liposomes made of egg phosphatidylcholine/cholesterol/distearoylphosphoethanolamine-polyethylenglycol(2000) (64:30:6). Physicochemical parameters (size, zeta potential, loading, stability, release kinetics) of these HDACi-loaded pegylated liposomes were optimized and their cytotoxicity (MTT test) was measured in MCF-7, T47-D, MDA-MB-231 and SkBr3 breast cancer cell lines. In MCF-7 cells, TSA and PXD were efficient inducers of proteasome-mediated estradiol receptor alpha degradation and they both affected estradiol-induced transcription (TSA>PXD) contrary to CG. Moreover, TSA most efficiently altered breast cancer cell viability as compared to the free drug, CG-liposomes being the weakest, while unloaded liposomes had nearly no cytotoxicity. Pegylated liposomes loaded with TSA or PXD remained stable in size, charge and biological activity for one month when stored at 4 degrees C. All HDACi-loaded liposomes released slowly the encapsulated drug in vitro, CG-loaded liposomes showed the slowest release kinetic. These formulations could improve the efficacy of HDACi not only in breast cancers but also in other solid tumors because most of these drugs are poor water soluble and unstable in vivo, and their administration remains a challenge

Congiuntivite da Chlamydia trachomatis in un adolescente maschio: descrizione di un caso

Made available in DSpace on 2015-06-01T19:34:26Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) anna_carvalhoet_IOC_2014.pdf: 85721 bytes, checksum: 3217f27d2edbd74aae8515b7bf57ae49 (MD5) Previous issue date: 2014University of Brescia.University Division of Infectious and Tropical Diseases. Brescia. Italy.University of Brescia.University Division of Infectious and Tropical Diseases. Brescia. Italy.University of Brescia. Department of Neurological Sciences and Vision. Eye Clinic. Brescia, Italy.University of Brescia.University Division of Infectious and Tropical Diseases. Brescia. Italy / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos (LITEB). Rio de Janeiro, RJ, Brasil.University of Brescia.University Division of Infectious and Tropical Diseases. Brescia. Italy.An 18-year-old man was seen at a Sexually Transmitted Infections (STIs) clinic for counselling and treatment of Chlamydia trachomatis genital infection which had been diagnosed during a screening survey of high-school students. For two months he had reported conjunctival hyperaemia, increased tearing, itching, and mucopurulent secretions, predominantly on the left eye. His ophthalmologist had made a diagnosis of follicular conjunctivitis and lower superficial punctate keratitis (left eye > right eye), irresponsive to topical treatment. Chlamydial conjunctivitis was suspected and confirmed by a positive nucleic acid amplification test (NAAT) performed on conjunctival scraping. The patient was treated with azithromycin 1 g single dose orally and tetracycline/ betamethasone eye ointment for one month. A complete resolution of symptoms was observed three months after aetiological treatment. This case highlights the need to include C. trachomatis infection in the differential diagnosis of acute or chronic follicular conjunctivitis among sexually active young individuals

Antineoplastic Effects of siRNA against TMPRSS2-ERG Junction Oncogene in Prostate Cancer

International audienceTMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis. Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and then to assess the biological consequences of this inhibition. First, we designed siRNAs against the two TMPRSS2-ERG fusion variants (III and IV), most frequently identified in patients' biopsies. Two of the five siRNAs tested were found to efficiently inhibit mRNA of both TMPRSS2-ERG variants and to decrease ERG protein expression. Microarray analysis further confirmed ERG inhibition by both siRNAs TMPRSS2-ERG and revealed one common down-regulated gene, ADRA2A, involved in cell proliferation and migration. The siRNA against TMPRSS2-ERG fusion variant IV showed the highest anti-proliferative effects: Significantly decreased cell viability, increased cleaved caspase-3 and inhibited a cluster of anti-apoptotic proteins. To propose a concrete therapeutic approach, siRNA TMPRSS2-ERG IV was conjugated to squalene, which can self-organize as nanoparticles in water. The nanoparticles of siRNA TMPRSS2-ERG-squalene injected intravenously in SCID mice reduced growth of VCaP xenografted tumours, inhibited oncoprotein expression and partially restored differentiation (decrease in Ki67). In conclusion, this study offers a new prospect of treatment for prostate cancer based on siRNA-squalene nanoparticles targeting TMPRSS2-ERG junction oncogene