42 research outputs found
Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors
The use of chemotherapeutic agents such as docetaxel (DTX) in anticancer therapy is often correlated to side effects and the occurrence of drug resistance, which substantially impair the efficacy of the drug. Here, we demonstrate that self-emulsifying drug delivery systems (SEDDS) coated with enoxaparin (Enox) are a promising strategy to deliver DTX in resistant tumors. DTX partition studies between the SEDDS pre-concentrate and the release medium (water) suggest that the drug is well retained within the SEDDS upon dilution in the release medium. All SEDDS formulations show droplets with a mean diameter between 110 and 145 nm following dilution in saline and negligible hemolytic activity; the droplet size remains unchanged upon sterilization. Enox-coated SEDDS containing DTX exhibit an enhanced inhibition of cell growth compared to the control on cells of different solid tumors characterized by high levels of FGFR, which is due to an increased DTX internalization mediated by Enox. Moreover, only Enox-coated SEDDS are able to restore the sensitivity to DTX in resistant cells expressing MRP1 and BCRP by inhibiting the activity of these two main efflux transporters for DTX. The efficacy and safety of these formulations is also confirmed in vivo in resistant non-small cell lung cancer xenografts
Two Benthic Diatoms, Nanofrustulum shiloi and Striatella unipunctata, Encapsulated in Alginate Beads, Influence the Reproductive Efficiency of Paracentrotus lividus by Modulating the Gene Expression
Physiological effects of algal metabolites is a key step for the isolation of interesting bioactive compounds. Invertebrate grazers may be fed on live diatoms or dried, pelletized, and added to compound feeds. Any method may reveal some shortcomings, due to the leaking of wound-activated compounds in the water prior to ingestion. For this reason, encapsulation may represent an important step of bioassay-guided fractionation, because it may assure timely preservation of the active compounds. Here we test the effects of the inclusion in alginate (biocompatible and non-toxic delivery system) matrices to produce beads containing two benthic diatoms for sea urchin Paracentrotus lividus feeding. In particular, we compared the effects of a diatom whose influence on P. lividus was known (Nanofrustulum shiloi) and those of a diatom suspected to be harmful to marine invertebrates, because it is often present in blooms (Striatella unipunctata). Dried N. shiloi and S. unipunctata were offered for one month after encapsulation in alginate hydrogel beads and the larvae produced by sea urchins were checked for viability and malformations. The results indicated that N. shiloi, already known for its toxigenic effects on sea urchin larvae, fully conserved its activity after inclusion in alginate beads. On the whole, benthic diatoms affected the embryogenesis of P. lividus, altering the expression of several genes involved in stress response, development, skeletogenesis and detoxification processes. Interactomic analysis suggested that both diatoms activated a similar stress response pathway, through the up-regulation of hsp60, hsp70, NF-kappa B, 14-3-3 epsilon and MDR1 genes. This research also demonstrates that the inclusion in alginate beads may represent a feasible technique to isolate diatom-derived bioactive compounds
Dysregulation of NF–Y splicing drives metabolic rewiring and aggressiveness in colon cancer
NF-Y is an evolutionarily conserved transcription factor that binds specifically to the CCAAT
elements of eukaryotic genes, most of which frequently deregulated in cancer. NF-YA, the
regulatory subunit of the NF-Y complex, has two isoforms generated by alternative splicing,
NF-YAl and NF-YAs, which differ in the transactivation domain.
Transcriptomic data from The Cancer Genome Atlas (TCGA) database highlighted a
significant increase in the expression of NF-YAs at the expense of NF-YAl in colorectal cancer
(CRC), compared to healthy tissues. Despite this, high NF-YAl levels predict lower patients’
survival and distinguish the mesenchymal molecular subtype CMS4, which is characterized by
the worst prognosis.
Through the analysis of 3D cellular models, we demonstrated that altered expression of genes
related to extracellular matrix and epithelial-mesenchymal transition sustains enhanced
migratory and invasive behavior of NF-YAl-transduced cells. Moreover, the integration of
metabolomics, bioenergetics and transcriptional analyses demonstrated a direct role for NFYAl
in metabolic flexibility of cancer cells that adjust their metabolism in response to
environmental changes to potentiate migration. The zebrafish xenograft model confirmed the
metastatic potential triggered by NF-YAl in CRC cells.
Altogether, our data highlight the transcriptional role of NF-YAl in CRC aggressiveness and
suggest splice-switching strategies to hinder NF-YAl-induced metastatic dissemination
ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma
The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor V\u3b39V\u3b42 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of V\u3b39V\u3b42 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and V\u3b39V\u3b42 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor \u3b1 (LXR\u3b1); Ras/ERK1/2/HIF-1\u3b1 axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and V\u3b39V\u3b42 T-cell infiltration. We suggest that the ABCB1 high ABCA1 low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas
Transferrin-Conjugated SNALPs Encapsulating 2 -O-Methylated miR-34a for the Treatment of Multiple Myeloma
Stable nucleic acid lipid vesicles (SNALPs) encapsulating miR-34a to treat multiple myeloma (MM) were developed. Wild type or completely 2 -O-methylated (OMet) MiR-34a was used in this study. Moreover, SNALPs were conjugated with transferrin (Tf) in order to target MM cells overexpressing transferrin receptors (TfRs). The type of miR-34a chemical backbone did not significantly affect the characteristics of SNALPs in terms of mean size, polydispersity index, and zeta potential, while the encapsulation of an OMet miR-34a resulted in a significant increase of miRNA encapsulation into the SNALPs. On the other hand, the chemical conjugation of SNALPs with Tf resulted in a significant decrease of the zeta potential, while size characteristics and miR-34a encapsulation into SNALPs were not significantly affected. In an experimental model of MM, all the animals treated with SNALPs encapsulating miR-34a showed a significant inhibition of the tumor growth. However, the use of SNALPs conjugated with Tf and encapsulating OMet miR-34a resulted in the highest increase of mice survival. These results may represent the proof of concept for the use of SNALPs encapsulating miR-34a for the treatment of MM
Development of innovative formulations for topical administration of vitamin K1
The research activity has been focused on the study of new strategies for the dermal and transdermal administration of pharmacologically active molecules. In particular, the study was aimed to develop formulations based on nanocarriers for the administration of vitamin K1 (phylloquinone) in aerosol form on the skin. Recently, it was found that creams containing vitamin K1 was very useful in the prevention of acneiform reactions affecting the skin in patients receiving cetuximab for the treatment of metastatic colorectal cancer. (Ocvirk Janja et al., 2010, Tomková et al., 2011). Different semisolid formulations containing vitamin K1, namely Rencoval®, VigorSkinK1® and VigorSkinK1 Plus®, are already present on the market. The purpose of this study was therefore to develop alternative strategies for the administration of vitamin K1 on the skin, overcoming the drawbacks associated with the use, for more administration in a day, of fatty formulations. Therefore, innovative aqueous formulations to be administered on the skin by aerosol, thus avoiding the use of semisolid preparations, have been designed and developed in this work. To nebulize the developed formulations, a patented device (Eautè), portable and pocket with battery was used. In the development of vitamin K1-containing formulation alternative to the lipophilic formulations currently on the market, the possibility to increase the accumulation of vitamin in the epidermis and dermis was also taken into account. The formulative strategies used in this work start from previous published findings on lipid-based nanocarriers, such as liposomes, already used to administer different drugs on the skin. Then, the possibility to develop transfersomes and ethosomes to increase, compared to liposome-based formulations, the vitamin accumulation into the skin was investigated. Finally, the possibility to use lipid-free nanoemulsions, to propose formulative approaches less expensive for future commercial development, has been investigated. Thus, during all the experimental work, special attention was paid on the development of formulations suitable to be transferred to the industry (technological transfer). Thus, once designed the different formulations, their optimization has been aimed to combine high encapsulation of active compound, absent o low release of the encapsulated molecule during storage, long shelf-life, as well as increased accumulation into the skin.
This PhD work has been carried out in collaboration with the Xenus s.r.l. in the respect of a confidential agreement between the PhD student, the University Tutor prof. Giuseppe De Rosa and the scientific responsible of the company dr. Michele Pitaro, some experimental details of this work have been omitted in this thesis
Os programas de formação de professores da Universidade Estadual Vale do Acaraú (UVA): aportes para refletir sobre A interiorização do ensino Superior
Although the interiorization of Higher Education is often spoken as a synonym for its expansion, we understand that it deserves a more accurate analysis in view of its developments. In this sense, we aim in this article to problematize the idea of interiorization of higher education defended by the decentralization policy of the Vale do Acaraú State University (UVA) started with the offer of special teacher training programs based on the National Education Guidelines and Bases Law (BRAZIL, nº 9394/1996). Our studies were anchored in the analysis of official documents issued by the State Council of Education of Ceará, the regulatory body of UVA, in the analysis of institutional documents, in the analysis of the content of the speeches given by the President of the institution and in interviews with co-managing partners. who participated in the operationalization of the programs. Based on these sources, it was possible to identify the driving elements of the institutional decentralization policy and its operational dynamics. We understand that the teacher training programs offered by UVA did not contribute to the strengthening of the interiorization of Higher Education due to the absence of a contextualized, regionalized teacher training policy based on pedagogical principles beyond the demand for certification and the absence of planning institutional strategic that would make it possible to monitor and evaluate experimental training processes.Embora a interiorização do Ensino Superior seja, muitas vezes, discursada como sinônimo de expansão do mesmo, entendemos que ela mereça uma análise mais acurada frente aos seus desdobramentos. Nesse sentido, objetivamos nesse artigo problematizar a ideia de interiorização do ensino superior defendida pela política de descentralização da Universidade Estadual Vale do Acaraú (UVA) iniciada com a oferta de programas especiais de formação de professores a partir da Lei de Diretrizes e Bases da Educação Nacional (BRASIL, nº 9394/1996). Nossos estudos ancoraram-se na análise de documentos oficiais emitidos pelo Conselho Estadual de Educação do Ceará, órgão regulador da UVA, na análise de documentos institucionais, na análise de conteúdo dos discursos proferidos pelo Reitor da instituição e em entrevistas realizadas com parceiros co-gestores que participaram da operacionalização dos programas. Com base nessas fontes foi possível identificar os elementos impulsionadores da política institucional de descentralização e sua dinâmica de operacionalização. Compreendemos que os programas de formação de professores ofertados pela UVA não contribuíram com o fortalecimento da interiorização do Ensino Superior pela ausência de uma política de formação contextualizada, regionalizada e fundamentada em princípios pedagógicos para além da demanda da certificação e pela ausência de um planejamento estratégico institucional que viabilizasse acompanhamento e avaliação dos processos formativos experimentais
Lipid-based core-shell nanoparticles: Evolution and potentialities in drug delivery
Over the last decade, impressive progress in the field of nanomedicine has led to the development of novel biomaterials and nanotechnology platforms. However, lipid-based nanovectors, i.e. liposomes, combining safety, versatility and delivery efficiency, remain the most “popular” approach. Lipids, especially charged lipids, have been used to design nanoparticles characterized by a core-shell structure. In these nanoparticles a lipid shell interacts with a core based on different biomaterials. Drugs characterized by a net charge can be condensed in the core, which is then covered by the lipid shell. This approach has been investigated in relation to the delivery of different active molecules, among them macromolecular drug, e.g. nucleic acids, and small molecules, e.g. bisphosphonates. This review reports the progress that has been made in the development of this technology and its potential applications in drug delivery. Keywords: Core-shell nanoparticles, Hybrid nanoparticles, Cationic lipids, RNA delivery, DNA delivery, Bisphosphonate deliver
Lipid Nanovectors to Deliver RNA Oligonucleotides in Cancer
The growing knowledge on the mechanisms of gene silencing and gene regulation by non-coding RNAs (ncRNA), mainly small interfering RNA (siRNA) and microRNA (miRNA), is providing a significant boost to the development of new therapeutic strategies for the treatment of cancer. However, the design of RNA-based therapeutics is hampered by biopharmaceutical issues, thus requiring the use of suitable delivery strategies. In this regards, lipid nanovectors have been successfully investigated to deliver RNA in different forms of cancer. Compared to other biomaterials, lipids offer advantages such as biocompatibility, biodegradability, easy production, low cost, limited toxicity and immunogenicity. The possibility to formulate these materials in the form of nanovectors allows overcoming biopharmaceutical issues associated to the therapeutic use of RNA, with the possibility to target tumors. This review takes stock of the main lipid nanovectors proposed to deliver ncRNA. For each considered delivery strategy, the rational design and the most meaningful in vitro and in vivo results are reported and discussed