1,721,039 research outputs found
A New Anticancer Agent for the Hedgehog-dependent tumors: from Drug Discovery to Drug Delivery
No full textThis Ph.D. thesis focuses on two main topics:
Part A. Identification of a natural compound capable of inhibiting the Hedgehog signalling pathway
Hedgehog (Hh) signaling is essential for tissue development and stemness and its deregulation has been observed in many tumors. For this reason, the understanding of the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, which represents a crucial goal in cancer therapy. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify the natural isoflavone Glabrescione B (GlaB) as the first small molecule binding to Gli1 zinc-finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, GlaB inhibited the growth of Hedgehog-dependent tumor cells such as medulloblastoma (MB) and basal cell carcinoma (BCC) both in vitro and in orthotopic xenograft mice and in allograft mice models, as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. Moreover, since extraction methods developed allow to get very limited amounts of pure isoflavone, we provided the total synthesis of Glabrescione B which foresees just three steps route with a overall yield 15%. This synthetic strategy allowed us the preparation of five derivatives with the aim to elucidate the structure-activity relationships and to clarify the molecular mechanism behind the Hedgehog signalling modulation.Part B. Drug Delivery Strategies
Nanoparticles are submicrometer-sized carriers designed to improve the biodistribution of systemically administered (chemo)therapeutic agents. By delivering pharmacologically active agents more effectively and more selectively to the target site, nanocarriers aim to improve the balance between the efficacy and the toxicity of systemic (chemo)therapeutic administrations.
Indeed, nanomaterials with an intrinsic ability to be used for imaging purposes, such as iron oxide–based magnetic nanoparticles (MNPs), are increasingly being loaded with drugs or alone for combining disease diagnosis and therapy. In this study, non-ionic surfactant vesicles (niosomes) loaded with lipophilic and hydrophilic MNPs have been prepared. Vesicles have been characterized in terms of dimensions, ζ-potential, time stability, bilayer characteristics and overall iron content. The quantification of the effective diameter of the MNPs entrapped in some niosomes was deduced from magnetic force microscopy. The encouraging obtained results proved that such vesicles could be promising carriers for the delivery of hydrophilic and lipophilic MNPs, thereby prompting various opportunities for the development of suitable strategies of both diagnosis and therapy (“theranostics”).
In part A it has been showed that GlaB is a drug able to inhibit Hh-dependent tumors. However, the major drawbacks in its clinical translation for cancer therapy are its poor water solubility, poor pharmacokinetics and limited bioavailability at the tumor site.
In order to, on the one hand, enhance the bioavailability of GlaB and, on the other one, to target selectively the MB cancer cells, different niosomal formulations have been designed that could pass through the blood-brain barrier. The novelty of the performed study lies in the use of two different polisorbates (namely Tween 20 and Tween 80) as surfactants in the formulation. They have been used in vesicles preparation, to act as an anchor for apolipoprotein E (apo E) from blood plasma. The particles seem to mimic LDL and interact with the LDL receptor leading to their uptake by the endothelial cells. In an attempt to formulate niosomal vesicles of smallest size and narrow polydispersity index, different ratio of Tween 20 and Tween 80 were studied in combination with two different purification techniques.
With the purpose of delivering high doses of the natural compound GlaB, to solid tumors after systemic administration, for therapeutic applications in vivo, long-circulating GlaB loaded oil- cored polymeric nanocapsules (NC-GlaB) were designed and formulated. Furthermore, we showed that NC-GlaB is effective at inhibiting the proliferation of different Hedgehog-dependent cell lines in vitro. Notably, however, both GlaB and NC-GlaB are remarkably more effectively against pure cancer stem cells lines than cancer cells (composed by normal cancer cells and a subpopulation of cancer stem cells). These studies provide early evidence of a nanoparticle-encapsulated agent that might be useful for chemotherapy in patients affected by a Hedgehog-dependent tumor
The plant-derived triterpenoid tingenin B is a potent anticancer agent due to its cytotoxic activity on cancer stem cells of breast cancer in vitro
No full textDespite the rapid advances in chemotherapy regimens, the outcome of patients with breast cancer is not satisfactory. One of the reasons of this dissatisfaction is that subsets of cells in tumors which referred as cancer stem cells (CSCs) show and/or gain resistance to therapies. Thus, compounds that target CSCs are urgently needed. Since some are already used in the clinic, natural products have great potential for further development as anti cancer drugs. The aim of this study is to investigate the cytotoxic activity of tingenin b (or 22β-hydroxytingenone) which is a quinone-methide triterpenoid structurally related to tingenone, against breast CSCs (stem-cell enriched population from MCF-7 cell line, MCF-7s). It has been found that tingenin b was cytotoxic against MCF-7s (IC50 value for 48 h was found to be 2.38 μM) by inducing apoptosis. It was evident by Annexin V staining positivity, decreased mitochondrial membrane potential and Bcl-2 dephosphorylation with a concomitant increase in Bax protein expression. In addition, endoplasmic reticulum stress was also found to be involved in tingenin b-induced cell death. In conclusion, the results warrant further studies aimed at elucidating and corroborating its possible use in the treatment of breast cancer
Biomedical applications of nanodiamonds: an overview
No full textNanodiamonds are a novel class of nanomaterials which have raised much attention for application
in biomedical field, as they combine the possibility of being produced on large scale using relatively
inexpensive synthetic processes, of being fluorescent as a consequence of the presence of nitrogen
vacancies, of having their surfaces functionalized, and of having good biocompatibility. Among other
applications, we mainly focus on drug delivery, including cell interaction, targeting, cancer therapy,
gene and protein delivery. In addition, nanodiamonds for bone and dental implants and for antibacterial
use is discussed. Techniques for detection and imaging of nanodiamonds in biological tissues
are also reviewed, including electron microscopy, fluorescence microscopy, Raman mapping, atomic
force microscopy, thermal imaging, magnetic resonance imaging, and positron emission tomography,
either in vitro, in vivo, or ex vivo. Toxicological aspects related to the use of nanodiamonds are
also discussed. Finally, patents, preclinical and clinical trials based on the use of nanodiamonds for
biomedical applications are reviewed
Molecular recognition of natural products by resorc[4]arene receptors
No full textThis review is aimed at providing an overview of the up-to-now published literature on resorc[4]arene macrocycles exploited as artificial receptors for the molecular recognition of some classes of natural products. A concise illustration of the main synthetic strategies developed to afford the resorc[4]arene scaffold is followed by a report on the principles of the gas-phase investigation of recognition phenomena by mass spectrometry (MS). Emphasis is placed on gas-phase studies of diastereoisomeric complexes generated inside a Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometer by resorc[4]arene receptors towards a series of natural products, namely amino acids, amphetamine, ethanolamine neurotransmitters, dipeptides, vinca alkaloids and nucleosides. The literature outcomes discussed here, taken largely from our own revisited work, have been completed by references to other studies, in order to draw a broader picture of this rapidly evolving field of research
Flavonoids from Sorocea bonplandii as antiproliferative agents towards breast cancer and leukemia
No full textSmart magnetic nanovesicles for theranostic application: Preparation and characterization
No full textNanomedicines are submicrometer-sized carrier materials designed to improve the biodistribution of systemically administered (chemo)therapeutic agents. By delivering pharmacologically active agents more effectively and more selectively to the pathological site nanomedicines aim to improve the balance between the efficacy and the toxicity of systemic (chemo)therapeutic administrations. Nanomedicine formulations have also been used for imaging applications and, in recent years, for theranostic approaches, that is, for systems and strategies in which disease diagnosis and therapy are combined. On the one hand, "classical" drug delivery systems are being co-loaded with both drugs and contrast agents. Actually, nanomaterials with an intrinsic ability to be used for imaging purposes, such as iron-oxide-based magnetic nanoparticles (MNPs), are increasingly being loaded with drugs or alone for combining disease diagnosis and therapy. In this study, non-ionic surfactant vesicles loaded with lipophilic and hydrophilic MNPs have been prepared. Vesicles have been characterized in terms of dimensions, β-potential, time stability, bilayer characteristics and overall iron content. The encouraging obtained results confirm that Tween 20 and Span 20 vesicles could be promising carriers for the delivery of hydrophilic and lipophilic MNPs, respectively, thereby prompting various opportunities for the development of suitable theranostic strategies. The analyzed formulations confirm the importance of surfactant chemical-physical characteristics in entrapping the MNPs of different polarity, highlighting the high versatility of niosomal bilayer and structure; property that make them so appealing among drug delivery nanocarriers. © Società Italiana di Fisica
Vesicular systems in dairy products: an up to date overview
No full textFood nanotechnology involves the utilization of nanocarrier system to stabilize the
bioactive materials against a range of environmental and chemical changes as well as to
improve their bioavailability. Liposomes and non-phospholipid vesicles represent exciting
opportunities for food technologists in different areas.
In several studies the potential of vesicles has been shown for the improvement of the
flavor of cheese which has been ripened using accelerated methods, the targeted delivery
of functional food ingredients, the synergistic delivery of vitamins for enhancing antioxidant
activity and the stability of functional substances in dairy products. Furthermore, liposomes
have been investigated for their ability to incorporate antimicrobials that could aid the
protection of dairy products. Vesicular structures and systems not strictly fitting the
definition of liposomes (e.g. multiple phase emulsions) will continue to find more
applications in foods.
In this paper, a summary of the application of vesicles in the production of dairy products is
provided and some of the industrially applicable methods for their manufacture are also
reviewed
- …
