1,721,080 research outputs found
Peptide chemistry encounters nanomedicine: Recent applications and upcoming scenarios in cancer
No full textCancer is the second worldwide cause of death [1]. The considerable efforts to develop cancer treatments have produced only limited results; in fact, the term cancer does not refer to a single disease but rather to a pool of unique diseases with some common features such as the uncontrolled cell proliferation and absence of cell death. The primary tumor exploits the new vascularization to invade other tissues, leading to metastasis and eventually death [1]. Unfortunately, angiogenesis, a key step in the transition from a dormant to a malignant tumor, is also a vital process in growth and development. Surgery and radiotherapy are the primary treatments for local and nonmetastatic cancers, while chemotherapy is the main choice in metastatic cancers. Chemotherapy consists in delivering drugs to the cancer; the bad news is that although many anticancer drugs are highly active in vitro, when transferred in vivo, they also affect healthy tissues and suffer from poor pharmacokinetics and dynamics, which obviously limits their use in a clinical setting [1]. Even when the initial therapy is successful, the risk of cancer recurrence remains a problem. The indiscriminate damages to normal cells, together with the development of multidrug resistance, reinforce the need of an ideal therapy foreseeing effective and targeted treatments: this is still the visionary concept of the ‘magic bullet’ proposed at the very start of the 20th century by the Nobel Prize winner, Paul Ehrlich [2]
Hydrophobicity: The door to drug delivery
No full text: The engineering of intracellular delivery systems with the goal of achieving personalized medicine has been encouraged by advances in nanomaterial science as well as a greater understanding of diseases and of the biochemical pathways implicated in many disorders. The development of vectors able to transport the drug to a target location and release it only on demand is undoubtedly the primary issue. From a molecular perspective, the topography of drug carrier surfaces is directly related to the design of an effective drug carrier because it provides a physical hint to modifying its interactions with biological systems. For instance, the initial ratio of hydrophilic to hydrophobic surfaces and the changes brought about by external factors enable the release or encapsulation of a therapeutic molecule and the ability of the nanosystem to cross biological barriers and reach its target without causing systemic toxicity. The first step in creating new materials with enhanced functionality is to comprehend and characterize the interplay between hydrophilic and hydrophobic molecules at the molecular level. Therefore, the focus of this review is on the function of hydrophobicity, which is essential for matching the complexity of biological environments with the intended functionality
Membranotropic Cell Penetrating Peptides: The Outstanding Journey
No full textThe membrane bilayer delimits the interior of individual cells and provides them with the ability to survive and function properly. However, the crossing of cellular membranes constitutes the principal impediment to gaining entry into cells, and the potential therapeutic application of many drugs is predominantly dependent on the development of delivery tools that should take the drug to target cells selectively and efficiently with only minimal toxicity. Cell-penetrating peptides are short and basic peptides are widely used due to their ability to deliver a cargo across the membrane both in vitro and in vivo. It is widely accepted that their uptake mechanism involves mainly the endocytic pathway, the drug is catched inside endosomes and lysosomes, and only a small quantity is able to reach the intracellular target. In this wide-ranging scenario, a fascinating novel hypothesis is that membranotropic peptides that efficiently cross biological membranes, promote lipid-membrane reorganizing processes and cause a local and temporary destabilization and reorganization of the membrane bilayer, may also be able to enter cells circumventing the endosomal entrapment; in particular, by either favoring the escape from the endosome or by direct translocation. This review summarizes current data on membranotropic peptides for drug delivery
beta-barrel membrane bacterial proteins: structure, function, assembly and interaction with lipids
No full textMembrane proteins, although constituting about one-third of all proteins encoded by the genomes of living organisms, are still strongly underrepresented in the database of 3D protein structures, which reflects the big challenge posed by this class of proteins. Novel and fundamental insights into the structure, function, assembly and interaction with lipids of membrane proteins are continuously revealed by structural biologists employing electron and x-ray approaches. To date, two structural motifs, -helices and -sheets, have been found in membrane proteins and interestingly these two structural motives correlate with the location: while -helical bundles are most often found in the receptors and ion channels of plasma and endoplasmic reticulum membranes, -barrels are restricted to the outer membrane of Gram-negative bacteria, the mitochondrial membrane and chloroplasts and represent the structural motif used by several microbial toxins to form cytotoxic transmembrane channels. The -barrel, while being a rigid and stable motif is a versatile scaffold, having a wide variation in the size of the barrel, in the mechanism to open or close the gate and to impose selectivity on substrates. The difficulty in obtaining crystals suitable for high-resolution studies of outer membrane proteins has resulted in their under-representation in the Protein data Bank [1]. Even if the number of x-ray structures of integral membrane proteins has greatly increased in recent years, only a few of them provide information at a molecular level on how proteins interact with lipids that surround them in the membrane. The detailed mechanism of protein lipid interactions is of fundamental importance for understanding membrane protein folding, membrane adsorption, insertion and function in lipid bilayers. Both specific and aspecific interactions with lipids may participate in protein folding and assembly
An Overview of Supramolecular Platforms Boosting Drug Delivery
No full textNumerous supramolecular platforms inspired by natural self-assembly are exploited as drug delivery systems. The spontaneous arrangement of single building blocks into inorganic and organic structures is determined and controlled by noncovalent forces such as electrostatic interactions, π-π interactions, hydrogen bonds, and van der Waals interactions. This review describes the main structures and characteristics of several building blocks used to obtain stable, self-assembling nanostructures tailored for numerous biological applications. Owing to their versatility, biocompatibility, and controllability, these nanostructures find application in diverse fields ranging from drug/gene delivery, theranostics, tissue engineering, and nanoelectronics. Herein, we described the different approaches used to design and functionalize these nanomaterials to obtain selective drug delivery in a specific disease. In particular, the review highlights the efficiency of these supramolecular structures in applications related to infectious diseases and cancer
Membranotropic peptides mediating viral entry
No full textThe means used by enveloped viruses to bypass cellular membranes are well characterized; how-
ever, the mechanisms used by non-enveloped viruses to deliver their genome inside the cell
remain unresolved and poorly defined. The discovery of short, membrane interacting, amphipathic
or hydrophobic sequences (known as membranotropic peptides) in both enveloped and non-
enveloped viruses suggests that these small peptides are strongly involved in breaching the host
membrane and in the delivery of the viral genome into the host cell. Thus, in spite of noticeable
differences in entry, this short stretches of membranotropic peptides are probably associated with
similar entry-related events. This review will uncover the intrinsic features of viral membranotropic
peptides involved in viral entry of both naked viruses and the ones encircled with a biological
membrane with the objective to better elucidate their different functional properties and possible
applications in the biomedical field
A cell-penetrating peptide as a tool for delivery to blood brain barrier (BBB)
No full textThe high impermeability and selectivity of the BBB prevent the transport of many drugs into
the brain, making them ineffective for the treatment of central nervous system diseases. The
cell-penetrating peptides (CPPs) represent a new strategy to functionalize carriers in order to
deliver therapeutic molecules to the brain. Several studies have demonstrated that gH625, a
peptide derived from the glycoprotein H of herpes simplex virus 1, is able to cross the
membrane bilayer and represents an ideal CPP for the delivery BBB, because of its ability to
escape from the endocytic pathways1. In this study we evaluated the internalization of gH625
in human neuroblastoma (SH-SY5Y) and astrocytoma (U87-MG) cells and in rat brain.
Fluorescence and spectrofluorimetric in vitro analyses show a good rate of uptake in both cell
lines after 2h of treatment with gH625 labeled with 4-chloro-7-nitrobenz-2-oxa-1,3-diazole
(gH625-NBD) (Fig.1). The internalization is almost complete if higher concentration was used
(5μM) and the signal is prevalently found within the cytoplasm. Immunofluorescence studies,
using anti-GFAP and anti-BBB antibodies, were performed after intravenous administration (3h)
of gH625-NBD (160μg/100 g bw) in rats. Five images for each experimental class were
analyzed with ImageJ 1.48 software; the deconvolutionlab plugin was used to deconvolve
image channels through the Tikhonov-Miller’s algorithm; the Co-localization Colormap plugin
was then used to evaluate the degree of correlation between pair of pixels in the red and
green channels, resulting in the distribution of the values of the normalized mean deviation
product (nMDP) and the index of correlation as the fraction of positively correlated pixels in the
image2. Co-localization studies produced a color scale map (from -1 to 1) where negative
indexes (cold colors) represent no co-localization and indexes above 0 (hot colors) represent
co-localization. The study reveals a high co-localization score with BBB and low co-localization
score with GFAP protein of astrocytes; interestingly few neurons were labeled for gH625-NBD,
indicating the passage through the BBB (Fig.2). The index of correlation shows poor positive
correlation in gH625/anti-GFAP and high positive correlation in the gH625/anti-BBB. These data
show that gH625 is up taken by neuronal cells and reaches the rat brain. Taken together, our
results can be considered as a preliminary data to develop a liposome-based systems which
involves the use of gH625 as an efficient drugs delivery through the BBB.
1Guarnieri D et al. 2013 Drug delivery: shuttle-mediated nanoparticle delivery to the BBB.
Small 9(6): 806
2Jaskolski F et al. 2005 An automated method to quantify and visualize colocalized fluorescent
signals. J of Neur Meth 146(1):42-4
Viral Fusion Peptides Induce Several Signal Transduction Pathways Activation That Are Essential For Il-10 and -Interferon Production.
No full textThe deciphering of intracellular signaling pathways
that are activated by the interaction between viral fusion
peptides and cellular membranes are important for the
understanding of both viral replication strategies and host
defense mechanisms
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