2-Hydroxypropyl-β-Cyclodextrin Acts as a Novel Anticancer Agent

2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. HP-β-CyD has recently been approved for the treatment of Niemann-Pick Type C disease, a lysosomal lipid storage disorder, and is used in clinical practice. Since cholesterol accumulation and/or dysregulated cholesterol metabolism has been described in various malignancies, including leukemia, we hypothesized that HP-β-CyD itself might have anticancer effects. This study provides evidence that HP-β-CyD inhibits leukemic cell proliferation at physiologically available doses. First, we identified the potency of HP-β-CyD in vitro against various leukemic cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia (CML). HP-β-CyD treatment reduced intracellular cholesterol resulting in significant leukemic cell growth inhibition through G₂/M cell-cycle arrest and apoptosis. Intraperitoneal injection of HP-β-CyD significantly improved survival in leukemia mouse models. Importantly, HP-β-CyD also showed anticancer effects against CML cells expressing a T315I BCR-ABL mutation (that confers resistance to most ABL tyrosine kinase inhibitors), and hypoxia-adapted CML cells that have characteristics of leukemic stem cells. In addition, colony forming ability of human primary AML and CML cells was inhibited by HP-β-CyD. Systemic administration of HP-β-CyD to mice had no significant adverse effects. These data suggest that HP-β-CyD is a promising anticancer agent regardless of disease or cellular characteristics.     

Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer’s drug candidates

A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer’s disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC₅₀=4.0–30.0 μΜ) and moderate ability for inhibition of Aβ_1–42 self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ₄₂ aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ_1–42 induced toxicity. Structure–activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.     

Vincristine-sulphate–loaded liposome-templated calcium phosphate nanoshell as potential tumor-targeting delivery system

Vincristine-sulfate–loaded liposomes were prepared with an aim to improve stability, reduce drug leakage during systemic circulation, and increase intracellular uptake. Liposomes were prepared by the thin-film hydration method, followed by coating with calcium phosphate, using the sequential addition approach. Prepared formulations were characterized for size, zeta potential, drug-entrapment efficiency, morphology by transmission electron microscopy (TEM), in vitro drug-release profile, and in vitro cell cytotoxicity study. Effect of formulation variables, such as drug:lipid ratio as well as nature and volume of hydration media, were found to affect drug entrapment, and the concentration of calcium chloride in coating was found to affect size and coating efficiency. Size, zeta potential, and TEM images confirmed that the liposomes were effectively coated with calcium phosphate. The calcium phosphate nanoshell exhibited pH-dependent drug release, showing significantly lower release at pH 7.4, compared to the release at pH 4.5, which is the pH of the tumor interstitium. The in vitro cytotoxicity study done on the lung cancer cell line indicated that coated liposomes are more cytotoxic than plain liposomes and drug solution, indicating their potential for intracellular drug delivery. The cell-uptake study done on the lung cancer cell line indicated that calcium-phosphate–coated liposomes show higher cell uptake than uncoated liposomes.     

New route for synthesizing poly(ethylene glycol)-acrylic acid hydrogels using γ-irradiation for drug delivery carriers

Biocompatible and pH-responsive poly(ethylene glycol) (PEG)-acrylic acid (AAc) hydrogels were prepared by new technique using γ-irradiation for controlled oral drug delivery. The gel fraction was over 80% and the equal amounts of PEG and AAc blended hydrogel had efficient insulin loading using equilibrium swelling. These hydrogels exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral or basic environments. The insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral/basic conditions. At the high pH solution, the gels swelled rapidly and over 70% of the insulin loaded was released over a period of 10 h. Within 2 h of administration of the insulin-containing gels, significant blood glucose reduction effects were observed in diabetic rats. The blood glucose reduction lasted for up to 10 h following administration.     

Siderophores as drug delivery agents: application of the “Trojan Horse” strategy

The outer membrane permeability barrier is an important resistance factor of bacterial pathogens. In combination with drug inactivating enzymes, target alteration and efflux, it can increase resistance dramatically. A strategy to overcome this membrane-mediated resistance is the misuse of bacterial transport systems. Most promising are those for iron transport. They are vital for virulence and survival of bacteria in the infected host, where iron depletion is a defense mechanism against invading pathogens. We synthesized biomimetic siderophores as shuttle vectors for active transport of antibiotics through the bacterial membrane. Structure activity relationship studies resulted in siderophore aminopenicillin conjugates that were highly active against Gram-negative pathogens which play a crucial role in destructive lung infections in cystic fibrosis patients and in severe nosocomial infections. The mechanism of action and the uptake of the compounds via specific iron siderophore transport routes were demonstrated. The novel conjugates were active against systemic Pseudomonas aeruginosa infections in mice with ED₅₀ values comparable to the quinolone ofloxacin and show low toxicity.     

Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents

A series of new 4β-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the compounds exhibited better growth-inhibition activities against tested cell lines than that of etoposide. Further, compounds 6g and 6i are also evaluated for their DNA topoisomerase-II (topo-II) inhibition activity and they exhibited significant inhibition of topo-II catalytic activity comparable to etoposide.     

Rational drug design and synthesis of new α-Santonin derivatives as potential COX-2 inhibitors

Sesquiterpene compounds are widely known for their numerous pharmacological activities. Herein the focus of the authors was on α-Santonin, a sesquiterpene lactone from the Artemisia genus: the aim was to determine whether α-Santonin could be considered in the treatment of inflammation and pain. To this purpose, a small series of derivatives was designed and screened in silico against the enzyme COX-2 along with the parent compound. Drug-likeness parameters were also assessed. The compounds were eventually synthesized, and few were tested to determine their efficacy in the inhibition of COX-2 activity and expression. Overall, compound A2 was the only one with a detectable inhibitory potential of COX-2 activity whilst two of its ether derivatives demonstrated improved ability in the inhibition of COX-2 expression.     

Nose-to-brain peptide delivery – The potential of nanotechnology

Nose-to-brain (N-to-B) delivery offers to protein and peptide drugs the possibility to reach the brain in a non-invasive way. This article is a comprehensive review of the state-of-the-art of this emerging peptide delivery route, as well as of the challenges associated to it. Emphasis is given on the potential of nanosized drug delivery carriers to enhance the direct N-to-B transport of protein or peptide drugs. In particular, polymer- and lipid- based nanocarriers are comparatively analyzed in terms of the influence of their physicochemical characteristics and composition on their in vivo fate and efficacy. The use of biorecognitive ligands and permeation enhancers in order to enhance their brain targeting efficiency is also discussed. The article concludes highlighting the early stage of this research field and its still unveiled potential. The final message is that more explicatory PK/PD studies are required in order to achieve the translation from preclinical to the clinical development phase.     

Sustainable systems as organisms?

Schrödinger [Schrödinger, E., 1944. What is Life? Cambridge University Press, Cambridge] marvelled at how the organism is able to use metabolic energy to maintain and even increase its organisation, which could not be understood in terms of classical statistical thermodynamics. Ho [Ho, M.W., 1993. The Rainbow and the Worm, The Physics of Organisms, World Scientific, Singapore; Ho, M.W., 1998a. The Rainbow and the Worm, The Physics of Organisms, 2nd (enlarged) ed., reprinted 1999, 2001, 2003 (available online from ISIS website www.i- sis.org.uk)] outlined a novel “thermodynamics of organised complexity” based on a nested dynamical structure that enables the organism to maintain its organisation and simultaneously achieve non-equilibrium and equilibrium energy transfer at maximum efficiency. This thermodynamic model of the organism is reminiscent of the dynamical structure of steady state ecosystems identified by Ulanowicz [Ulanowicz, R.E., 1983. Identifying the structure of cycling in ecosystems. Math. Biosci. 65, 210–237; Ulanowicz, R.E., 2003. Some steps towards a central theory of ecosystem dynamics. Comput. Biol. Chem. 27, 523–530].The healthy organism excels in maintaining its organisation and keeping away from thermodynamic equilibrium – death by another name – and in reproducing and providing for future generations. In those respects, it is the ideal sustainable system. We propose therefore to explore the common features between organisms and ecosystems, to see how far we can analyse sustainable systems in agriculture, ecology and economics as organisms, and to extract indicators of the system's health or sustainability.We find that looking at sustainable systems as organisms provides fresh insights on sustainability, and offers diagnostic criteria for sustainability that reflect the system's health.In the case of ecosystems, those diagnostic criteria of health translate into properties such as biodiversity and productivity, the richness of cycles, the efficiency of energy use and minimum dissipation. In the case of economic systems, they translate into space-time differentiation or organised heterogeneity, local autonomy and sufficiency at appropriate levels, reciprocity and equality of exchange, and most of all, balancing the exploitation of natural resources – real input into the system – against the ability of the ecosystem to regenerate itself.     

Modified vaccinia virus Ankara as antigen delivery system: how can we best use its potential?

Safety-tested modified vaccinia virus Ankara (MVA) has been established as a potent vector system for the development of candidate recombinant vaccines. The versatility of the vector system was recently demonstrated by the rapid production of experimental MVA vaccines for immunization against severe acute respiratory syndrome associated coronavirus. Promising results were also obtained in the delivery of Epstein-Barr virus or human cytomegalovirus antigens and from the clinical testing of MVA vectors for vaccination against immunodeficiency virus, papilloma virus, Plasmodium falciparum or melanoma. Moreover, MVA is considered to be a prime candidate vaccine for safer protection against orthopoxvirus infections. Thus, vector development to challenge dilemmas in vaccinology or immunization against poxvirus bio-threat seems possible, yet the right choice should be made for a most beneficial use.     

β-Diglycosidases from microorganisms as industrial biocatalysts: biochemical characteristics and potential applications

Flavonoid glycoside degradation can proceed through two alternative enzymatic pathways: one that is mediated by monoglycosidases, and the other catalyzed by a diglycosidase. β-Diglycosidase performs the flavonoid deglycosylation in a single reaction. The characterized β-diglycosidase activities recognize the following disaccharidic sugar moieties: β-primeverose, acuminose, vicianose, and β-rutinose. The present paper reviews the biochemical characteristics and potential industrial applications of microbial β-diglycosidases that break down plant diglycoconjugated flavonoids.

     

β-Cyclodextrin polymer nanoparticles as carriers for doxorubicin and artemisinin: a spectroscopic and photophysical study

The association of doxorubicin (DOX) and artemisinin (ART) to a β-CyD-epichlorohydrin crosslinked polymer (pβ-CyD), organized in nanoparticles of ca. 15 nm size, was investigated in neutral aqueous medium by circular dichroism (CD), UV-vis absorption and fluorescence. The stability constants and the absolute CD spectra of the drug complexes were determined by global analysis of multiwavelength data from spectroscopic titrations. The polymer pβ-CyD proved able to disrupt the DOX dimer when the latter is the predominant form of DOX in solution. The spectroscopic and photophysical properties of the complexes evidenced an alcohol-like environment for ART and an improved inherent emission ability for DOX in the nanoparticle frame.     

The computational study of the γ-Fe2O3 nanoparticle as Carmustine drug delivery system: DFT approach

In the present study, it is attempted to scrutinize the properties of the maghemite nanoparticle as a Carmustine drug delivery system by means of the density functional theory calculations regarding their geometries, adsorption energies, vibrational frequencies, and topological features of the electron density. Based on the density functional theory results, it is found that the interaction between Carmustine drug molecule and maghemite nanoparticle is weak; so that, the adsorption of the Carmustine drug is typically physisorption. It is also found that the intermolecular hydrogen bonds between the drug and the nanoparticle play the significant role in the stability of the physisorption configurations. The nature of the intermolecular interactions has been explored by calculation of the electron densities and their Laplacian at the bond critical points using Atoms-in-Molecule theory. Moreover, natural bond orbital analysis indicates that the Carmustine molecule can be adsorbed on the nanoparticle surface with a charge transfer from the Carmustine drug to the nanoparticle.     

β2-Microglobulin as a potential factor for the expansion of mesenchymal stem cells

Multipotent mesenchymal stem cells (MSCs) hold great promise in regenerative medicine, but one of the biggest challenges facing for their application is the ex vivo expansion to obtain enough undifferentiated cells. Fetal bovine serum (FBS), which can elicit possible contaminations of prion, virus, zoonosis or immunological reaction against xenogenic serum antigens, still remains essential to the culture formulations. There is an urgent need to identify potential factors for the undifferentiated expansion of MSCs to reduce the use of FBS or eventually replace it. A previously recognized housekeeping gene, β2-microglobulin (β2M), is demonstrated to act as a novel growth factor to stimulate the undifferentiated ex vivo expansion and preserve the pluripotency of adult MSCs from various sources. The use of β2M might have promising implications for future clinical application of MSCs.     

Dihydro-β-agarofuran sesquiterpenes isolated from Celastrus vulcanicola as potential anti-Mycobacterium tuberculosis multidrug-resistant agents

In the present study, we report four new dihydro-β-agarofuran sesquiterpenes (1-4), which were isolated from the leaves of Celastrus vulcanicola, in addition to five derivatives (5-9). Their stereostructures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, X-ray studies, chemical correlations and biogenetic means. Compounds 1-9 and the previously reported sesquiterpenes 10-25 have been tested as potential antimycobacterial agents against sensitive and resistant Mycobacterium tuberculosis strains. 1α-Acetoxy-6β,9β-dibenzoyloxy-dihydro-β-agarofuran (20) exhibited antituberculosis activity against the MDR TB strain with a MIC value of 6.2 μg/mL, comparable to or better than isoniazid or rifampin, two of the best first-line drugs commonly used in the treatment of TB. The structure-activity relationship is discussed.     

Substituted tetrahydro-β-carbolines as potential agents for the treatment of human papillomavirus infection

The identification and optimization of a series of substituted tetrahydro-β-carbolines with potent activity against human papillomavirus is described. Structure–activity studies focused on the substitution pattern and chirality of the β-carboline ring system are discussed. Optimization of these parameters led to compounds with antiviral activities in the low nanomolar range.     

Novel tacrine–benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer’s Disease

Abstract

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ_1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.