Lipid nanocarriers targeting breast cancers to delivery modulators of estrogens receptors

International audienceDespite the efficiency of antiestrogens and aromatase inhibitors on hormone-dependent breast cancer (BC) growth, resistance occurrence and detrimental side effects are still registered. In order to improve the efficacy of these drugs, as well as other anticancer agents, their targeted delivery must be envisaged. Since clinical management of cancer is increasingly guided by assessment of tumour phenotypic parameters, the development of a delivery system depends first on the precise knowledge of the disease at both physical and molecular level, secondly, on the target to be attained, and finally on the physico-chemical parameters of the drug/molecule chosen as therapeutic agent. Then, the device containing the anticancer agent can be developed and further evaluated. In hormone-dependent BC, antiestrogens and/or aromatase inhibitors modulate the estrogenic response by targeting two types of estrogen receptors (ER) with opposite activities: ER alpha (ERα) is responsible for the proliferative effects of estrogenic compounds in the mammary gland, whereas ER beta (ERβ) favours differentiation and has a putative tumour suppressor function. Estradiol induces ER-mediated transcription but also triggers rapid non genomic effects in BC cells, mostly by “cross-talk” with growth factor signalling. In addition, several ER-associated proteins have been identified as co-modulators of ER activities. All constitute potent targets for the treatment of hormone-dependent BCs. In hormone-independent BC, there is an inverse relationship between ER expression and that of the growth factor membrane receptor Erb-B2 (HER2/NEU), rendering hormone therapy inefficient and necessitating the use of more aggressive treatments based on immunotherapy and chemotherapies. Many agents targeting growth factor receptor signalling, heat shock protein 90 (Hsp90), histone deacetylase (HDAC) and other ER-associated factors and targets involved in pathways affecting cell survival are currently being assessed in clinical trials. However, most of these cofactors are present in both healthy tissue and tumors, and specific targeting is required to prevent adverse secondary effects. We review here the recent innovative strategies for abolishing ERα integrity and function in BCs tumours and other strategies for the re-expression of both ER isotypes in order to re-sensitize to hormone therapy. These strategies are based on the engineering of nanoparticles, mainlly lipid nanocarriers targeting passively or actively breast tumour cells. To be efficient they must be able to deliver highly active compounds inhibiting cell cycle progression, angiogenesis and/or enhancing apoptosis in a specific manner. Special emphasis will be made on engineering new liposomal nanomedicines targeting specifically BC tumor cells

Lipid nanocarriers targeting breast cancers to delivery modulators of estrogens receptors

International audienceDespite the efficiency of antiestrogens and aromatase inhibitors on hormone-dependent breast cancer (BC) growth, resistance occurrence and detrimental side effects are still registered. In order to improve the efficacy of these drugs, as well as other anticancer agents, their targeted delivery must be envisaged. Since clinical management of cancer is increasingly guided by assessment of tumour phenotypic parameters, the development of a delivery system depends first on the precise knowledge of the disease at both physical and molecular level, secondly, on the target to be attained, and finally on the physico-chemical parameters of the drug/molecule chosen as therapeutic agent. Then, the device containing the anticancer agent can be developed and further evaluated. In hormone-dependent BC, antiestrogens and/or aromatase inhibitors modulate the estrogenic response by targeting two types of estrogen receptors (ER) with opposite activities: ER alpha (ERα) is responsible for the proliferative effects of estrogenic compounds in the mammary gland, whereas ER beta (ERβ) favours differentiation and has a putative tumour suppressor function. Estradiol induces ER-mediated transcription but also triggers rapid non genomic effects in BC cells, mostly by “cross-talk” with growth factor signalling. In addition, several ER-associated proteins have been identified as co-modulators of ER activities. All constitute potent targets for the treatment of hormone-dependent BCs. In hormone-independent BC, there is an inverse relationship between ER expression and that of the growth factor membrane receptor Erb-B2 (HER2/NEU), rendering hormone therapy inefficient and necessitating the use of more aggressive treatments based on immunotherapy and chemotherapies. Many agents targeting growth factor receptor signalling, heat shock protein 90 (Hsp90), histone deacetylase (HDAC) and other ER-associated factors and targets involved in pathways affecting cell survival are currently being assessed in clinical trials. However, most of these cofactors are present in both healthy tissue and tumors, and specific targeting is required to prevent adverse secondary effects. We review here the recent innovative strategies for abolishing ERα integrity and function in BCs tumours and other strategies for the re-expression of both ER isotypes in order to re-sensitize to hormone therapy. These strategies are based on the engineering of nanoparticles, mainlly lipid nanocarriers targeting passively or actively breast tumour cells. To be efficient they must be able to deliver highly active compounds inhibiting cell cycle progression, angiogenesis and/or enhancing apoptosis in a specific manner. Special emphasis will be made on engineering new liposomal nanomedicines targeting specifically BC tumor cells

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

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

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

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