Targeted Gene Delivery Therapies for Cervical Cancer

Despite being largely preventable through early vaccination and screening strategies, cervical cancer is the most common type of gynecological malignancy worldwide and constitutes one of the leading causes of cancer deaths in women. Patients with advanced or recurrent disease have a very poor prognosis; hence, novel therapeutic modalities to improve clinical outcomes in cervical malignancy are needed. In this regard, targeted gene delivery therapy is presented as a promising approach, which leads to the development of multiple strategies focused on different aspects. These range from altered gene restoration, immune system potentiation, and oncolytic virotherapy to the use of nanotechnology and the design of improved and enhanced gene delivery systems, among others. In the present manuscript, we review the current progress made in targeted gene delivery therapy for cervical cancer, the advantages and drawbacks and their clinical application. At present, multiple targeted gene delivery systems have been reported with encouraging preclinical results. However, the translation to humans has not yet shown a significant clinical benefit due principally to the lack of efficient vectors. Real efforts are being made to develop new gene delivery systems, to improve tumor targeting and to minimize toxicity in normal tissues.This research was supported by the Fundación Mutua Madrileña (project FMM-AP16683-2017) and Consejería de Salud Junta de Andalucía (PI-0089-2017)

Cell surface immobilization of GABAARs in cerebellar granule cells depends on the M3/M4 cytoplasmatic loop of the alpha 1 subunit

Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate brain. The localization of GABA receptors type A (GABAARs) at strategically located domains of the neuronal membrane is of vital importance for fast inhibitory synapse transmission efficacy. We have shown before that the lateral mobility of GABAARs depends on subunit composition of the complex. To study the lateral mobility of GABAARs in living, cultured neurons, we transfected cerebellar granule cells with either the complete 1 GABAAR subunit or with a truncation of the 1 subunit that lacks the major intracellular loop (M3/M4). We examined the location and lateral mobility of receptors containing both versions of the 1 subunit in living neurons. From fluorescence recovery after photobleaching experiments we present novel evidences that the intracellular M3/M4 loop of the 1 subunit restricts the lateral mobility of GABAARs when expressed in neurons. In addition, our immunocytochemical studies suggested that receptors containing the truncated subunit seem to be unable to reach synaptic localizations. Here we show for the first time that the 1 intracellular loop (M3/M4) domain has a relevant role in controlling the lateral mobility of GABAARs in neurons, and we believe that this is a novel and important contribution in neurobiology of GABAA receptors

Anti-Cancerous Potential of Polysaccharides Derived from Wheat Cell Culture

There is a global need to discover effective anti-cancerous compounds from natural sources. Cultivated wheat cells can be a valuable source of non-toxic or low toxic plant-derived polysaccharides. In this study, we evaluated the anti-cancer ability of seven fractions of wheat cell culture polysaccharides (WCCPSs) in the HCT-116 colon cancer cell line. Almost all (6/7) fractions had an inhibitory effect on the proliferation of colon cancer cells, and two fractions (A-b and A-f) had considerable therapeutic indexes. The WCCPS fractions induced cell cycle arrest in the G1 phase and induced different rates of apoptosis ( 48%). Transmission and scanning electron microscopy revealed that WCCPS fractions caused apoptotic changes in the nucleus and cytoplasm, including damage to mitochondria and external morphological signs of apoptosis. In addition, the WCCPSs induced an increase in the levels of Bax, cytochrome c, and caspases 8 and 3, indicating that cell death progressed through intrinsic and extrinsic pathways of apoptosis. Furthermore, some fractions caused a significant decrease of c-Myc, b-catenin, NFkB2, and HCAM (CD 44) levels, indicating enhanced cell differentiation. Thus, for the first time, our results provide a proof of concept of the anti-cancer capacity of WCCPS fractions in colorectal cancer.FEDER Operational Program 2020/Junta de AndaluciaConsejeria de Economia y Conocimiento/Project B-CTS-562-UGR20Chair "Doctors GaleraRequena in cancer stem cell research" CMC-CTS963Erasmus+ Mobility ProgramRepublic of KazakhstanScottish Government's Rural and Environment Science and Analytical Services (RESAS) divisio

Smart Drug-Delivery Systems for Cancer Nanotherapy

Despite all the advances achieved in the field of tumor-biology research, in most cases conventional therapies including chemotherapy are still the leading choices. The main disadvantage of these treatments, in addition to the low solubility of many antitumor drugs, is their lack of specificity, which explains the frequent occurrence of serious side effects due to nonspecific drug uptake by healthy cells. Progress in nanotechnology and its application in medicine have provided new opportunities and different smart systems. Such systems can improve the intracellular delivery of the drugs due to their multifunctionality and targeting potential. The purpose of this manuscript is to review and analyze the recent progress made in nanotherapy applied to cancer treatment. First, we provide a global overview of cancer and different smart nanoparticles currently used in oncology. Then, we analyze in detail the development of drug-delivery strategies in cancer therapy, focusing mainly on the intravenously administered smart nanoparticles with protein corona to avoid immune-system clearance. Finally, we discuss the challenges, clinical trials, and future directions of the nanoparticle-based therapy in cancer.Comment: Preprint version, 25 pages, 7 figures, 3 tables. Authors thank to Bentham Science the posibility of deposit the ACCEPTED VERSION of the peer-reviewed article after 12 months of publication on journal web site on arXiv repository. The published manuscript is available at EurekaSelect via https://www.eurekaselect.com/openurl/content.php?genre=article&doi=10.2174/138945011766616052714254

Smart drug-delivery systems for cancer nanotherapy

Authors thanks Bentham Sciencew for allow the deposit of the ACCEPTED VERSION of this peer-reviewed article in this institutional repository. Commons License CC BY-NC-ND 4.0 - Attribution-NonCommercial-NoDerivatives 4.0 International. The published manuscript is available at EurekaSelect via https://www.eurekaselect.com/openurl/content.php? genre=article&doi=10.2174/1389450117666160527142544Despite all the advances achieved in the field of tumor-biology research, in most cases conventional therapies including chemotherapy are still the leading choices. The main disadvantage of these treatments, in addition to the low solubility of many antitumor drugs, is their lack of specificity, which leads to the occurrence of severe side effects due to nonspecific drug uptake by healthy cells. Progress in nanotechnology and its application in medicine have provided new opportunities and different smart systems. Such systems can improve the intracellular delivery of the drugs due to their multifunctionality and targeting potential. The purpose of this manuscript is to review and analyze the recent progress made in cancer nanotherapy. First, we provide a global overview of cancer and different smart nanoparticles currently used in oncology. Then, we analyze in detail the development of drug-delivery strategies in cancer therapy, focusing mainly on the intravenously administered smart nanoparticles with protein corona to avoid immune-system clearance. Finally, we discuss the challenges, clinical trials, marketed nanomedicines and future directions of the nanotherapy applied to cancer treatment.This work was supported by the projects MAT2013-43922-R, MAT2015-63644-C2-2-R, (European FEDER support included, MINECO Spain), PI-0533-2014 (Fundación Progreso y Salud/Janssen Cilag, Junta de Andalucía, Spain) and P07-FQM2496, P10-CTS-6270 and P07- FQM3099 (Junta de Andalucía, Spain)

Thermo-Sensitive Nanomaterials: Recent Advance in Synthesis and Biomedical Applications

Progress in nanotechnology has enabled us to open many new fronts in biomedical research by exploiting the peculiar properties of materials at the nanoscale. The thermal sensitivity of certain materials is a highly valuable property because it can be exploited in many promising applications, such as thermo-sensitive drug or gene delivery systems, thermotherapy, thermal biosensors, imaging, and diagnosis. This review focuses on recent advances in thermo-sensitive nanomaterials of interest in biomedical applications. We provide an overview of the different kinds of thermoresponsive nanomaterials, discussing their potential and the physical mechanisms behind their thermal response. We thoroughly review their applications in biomedicine and finally discuss the current challenges and future perspectives of thermal therapies.This research was supported by the Fundación Mutua Madrileña (project FMM-AP16683-2017), Consejería de Salud Junta de Andalucía (PI-0089-2017), Instituto de Salud Carlos III (FEDER funds PIE16/00045), MINECO MAT2015-63644-C2-R, MAT 2016-78778-R, PCIN-2015-051 projects (Spain), European Regional Development Fund (ERDF) and from the Chair “Doctors Galera-Requena in cancer stem cell research”

Ldrb toxin with in vitro and in vivo antitumor activity as a potential tool for cancer gene therapy

Due to the high prevalence of cancer in recent years, it is necessary to develop new and more effective therapies that produce fewer side effects. Development of gene therapy for cancer based on the use of suicide genes that can damage the tumor cell, without requiring a prodrug for its lethal effect, is one of the recent foci of gene therapy strategies. We evaluated the cytotoxic impact of the LdrB toxin from Escherichia coli k12 as a possible tool for cancer gene therapy. For that, colorectal and breast cancer cells were transfected under the control of a TRE3G promoter inducible by doxycycline. Our results showed that ldrB gene expression induced a drastic inhibition of proliferation in vitro, in both 2D and 3D experimental models. Moreover, unlike conventional chemotherapy, the ldrB gene induced a severe loss of proliferation in vivo without any side effects in our animal model. This antitumor outcome was modulated by cell cycle arrest in the G0/G1 phase and apoptotic death. Scanning electronic microscopy demonstrates that the LdrB toxin conserves its pore-forming ability in HCT-116 cells as in E. coli k12. Taken together, our results provide, for the first time, a proof of concept of the antitumor capacity of the ldrB gene in colorectal and breast cancer.This research was supported by the Fundación Mutua Madrileña (project FMM-AP16683-2017), Consejería de Salud Junta de Andalucía (PI-0089-2017), the MNat Scientitc Unit of Excellence (UCE.PP2017.0f), and from the Chair “Doctors Galera-Requena in cancer stem cell research”

Clinical Trials of Thermosensitive Nanomaterials: An Overview

Currently, we are facing increasing demand to develop efficient systems for the detection and treatment of diseases that can realistically improve distinct aspects of healthcare in our society. Sensitive nanomaterials that respond to environmental stimuli can play an important role in this task. In this manuscript, we review the clinical trials carried out to date on thermosensitive nanomaterials, including all those clinical trials in hybrid nanomaterials that respond to other stimuli (e.g., magnetic, infrared radiation, and ultrasound). Specifically, we discuss their use in diagnosis and treatment of different diseases. At present, none of the existing trials focused on diagnosis take advantage of the thermosensitive characteristics of these nanoparticles. Indeed, almost all clinical trials consulted explore the use of Ferumoxytol as a current imaging test enhancer. However, the thermal property is being further exploited in the field of disease treatment, especially for the delivery of antitumor drugs. In this regard, ThermoDox®, based on lysolipid thermally sensitive liposome technology to encapsulate doxorubicin (DOX), is the flagship drug. In this review, we have evidenced the discrepancy existing between the number of published papers in thermosensitive nanomaterials and their clinical use, which could be due to the relative novelty of this area of research; more time is needed to validate it through clinical trials. We have no doubt that in the coming years there will be an explosion of clinical trials related to thermosensitive nanomaterials that will surely help to improve current treatments and, above all, will impact on patients’ quality of life and life expectancy.This research was supported by the Fundación Mutua Madrileña by the project FMM-AP16683-2017, Consejería de Salud Junta de Andalucía (PI-0089-2017), MINECO MAT 2016-78778-R, PCIN-2015-051 projects (Spain), European Regional Development Fund (ERDF) and from the Chair “Doctors Galera-Requena in cancer stem cell research”

Silver Nanoparticles from Annona muricata Peel and Leaf Extracts as a Potential Potent, Biocompatible and Low Cost Antitumor Tool

Cancer is one of the most prevalent diseases in the world and requires new therapies for its treatment. In this context, the biosynthesis of silver nanoparticles (AgNPs) has been developed to treat different types of tumors. The Annona muricata plant is known for having anticancer activity. Its main compounds present in the leaves, stems and skin, allowing for its use as reducing agents. In this manuscript, AgNPs with leaf extract (AgNPs-LE) and fruit peel extract (AgNPs-PE) of A. muricata were biosynthesized obtaining an average nanoparticle diameter sizes smaller than 50 nm, being 19.63 ± 3.7 nm and 16.56 ± 4.1 nm, and with a surface plasmonic resonance (SPR) at 447 and 448 nm, respectively. The lactone functional group present in the LE and PE extracts was identified by the FTIR technique. The behavior and antiproliferation activity of AgNPs-LE and AgNPs-PE were evaluated in breast, colon and melanoma cancer cell lines. Our results showed that Annona muricata fruit peel, which is a waste product, has an antitumor effect more potent than leaf extract. This difference is maintained with AgNPs where the destruction of cancer cells was, for the first time, achieved using concentrations that do not exceed 3 μg/mL with a better therapeutic index in the different tumor strains. In conclusion, we present a low-cost one-step experimental setup to generate AgNPs-PE whose in-vitro biocompatibility and powerful therapeutic effect make it a very attractive tool worth exploiting.Fundacion Empresa Universidad de Granada (Project PR/18/001)Fundación Mutua Madrileña (Project FMM-AP16683-2017)Consejería de Salud Junta de Andalucía (PI-0089-2017)Instituto de Salud Carlos III (RTI2018-101309-B-C22