Cucurbit[n]uril binding of platinum anticancer complexes

The encapsulation of cisplatin by cucurbit[7]uril (Q[7]) and multinuclear platinum complexes linked via a 4,4′-dipyrazolylmethane (dpzm) ligand by Q[7] and cucurbit[8]uril (Q[8]) has been studied by NMR spectroscopy and molecular modelling. The NMR studies suggest that some cisplatin binds in the cucurbituril cavity, while cis-[PtCl(NH3)2(H2O)]+ only binds at the portals. Alternatively, the dpzm-linked multinuclear platinum complexes are quantitatively encapsulated within the cavities of both Q[7] and Q[8]. Upon encapsulation, the non-exchangeable proton resonances of the multinuclear platinum complexes show significant upfield shifts in 1H NMR spectra. The H3/H3* resonances shift upfield by 0.08 to 0.55 ppm, the H5/H5* shift by 0.9 to 1.6 ppm, while the methylene resonances shift by 0.74 to 0.88 ppm. The size of the resonance shift is dependent on the cavity size of the encapsulating cucurbituril, with Q[7] encapsulation producing larger shifts than Q[8]. The upfield shifts of the dpzm resonances observed upon cucurbituril encapsulation indicate that the Q[7] or Q[8] is positioned directly over the dpzm linking ligand. The terminal platinum groups of trans-[{PtCl(NH3)2}2μ-dpzm]2+ (di-Pt) and trans-[trans-{PtCl(NH3)2}2-trans-{Pt(dpzm)2(NH3)2}]4+ (tri-Pt) provide a barrier to the on and off movement of cucurbituril, resulting in binding kinetics that are slow on the NMR timescale for the metal complex. Although the dpzm ligand has relatively few rotamers, encapsulation by the larger Q[8] resulted in a more compact di-Pt conformation with each platinum centre retracted further into each Q[8] portal. Encapsulation of the hydrolysed forms of di-Pt and tri-Pt is considerably slower than for the corresponding Cl forms, presumably due to the high-energy cost of passing the +2 platinum centres through the cucurbituril portals. The results of this study suggest that cucurbiturils could be suitable hosts for the pharmacological delivery of multinuclear platinum complexe

Area change of glaciers in the Canadian Rocky Mountains, 1919 to 2006

Glaciers in the Canadian Rocky Mountains constitute an important freshwater resource. To enhance our understanding of the influence climate and local topography have on glacier area, large numbers of glaciers of different sizes and attributes need to be monitored over periods of many decades. We used Interprovincial Boundary Commission Survey (IBCS) maps of the Alberta–British Columbia (BC) border (1903–1924), BC Terrain Resource Information Management (TRIM) data (1982–1987), and Landsat Thematic Mapper (TM) and Enhanced Thematic Mapper (ETM+) imagery (2000–2002 and 2006) to document planimetric changes in glacier cover in the central and southern Canadian Rocky Mountains between 1919 and 2006. Over this period, glacier cover in the study area decreased by 590 ± 70 km<sup>2</sup> (40 ± 5%), 17 of 523 glaciers disappeared and 124 glaciers fragmented into multiple ice masses. Glaciers smaller than 1.0 km<sup>2</sup> experienced the greatest relative area loss (64 ± 8%), and relative area loss is more variable with small glaciers, suggesting that the local topographic setting controls the response of these glaciers to climate change. Small glaciers with low slopes, low mean/median elevations, south to west aspects, and high insolation experienced the largest reduction in area. Similar rates of area change characterize the periods 1919–1985 and 1985–2001; −6.3 ± 0.6 km<sup>2</sup> yr<sup>−1</sup> (−0.4 ± 0.1% yr<sup>−1</sup>) and −5.0 ± 0.5 km<sup>2</sup> yr<sup>−1</sup> (−0.5 ± 0.1% yr<sup>−1</sup>), respectively. The rate of area loss, however, increased over the period 2001–2006; −19.3 ± 2.4 km<sup>2</sup> yr<sup>−1</sup> (−2.0 ± 0.2% yr<sup>−1</sup>). Applying size class-specific scaling factors, we estimate a total reduction in glacier cover in the central and southern Canadian Rocky Mountains for the period 1919–2006 of 750 km<sup>2</sup> (30%)

Quantifying the contribution of glacier runoff to streamflow in the upper Columbia River Basin, Canada

Glacier melt provides important contributions to streamflow in many mountainous regions. Hydrologic model calibration in glacier-fed catchments is difficult because errors in modelling snow accumulation can be offset by compensating errors in glacier melt. This problem is particularly severe in catchments with modest glacier cover, where goodness-of-fit statistics such as the Nash-Sutcliffe model efficiency may not be highly sensitive to the streamflow variance associated with glacier melt. While glacier mass balance measurements can be used to aid model calibration, they are absent for most catchments. We introduce the use of glacier volume change determined from repeated glacier mapping in a guided GLUE (generalized likelihood uncertainty estimation) procedure to calibrate a hydrologic model. This approach is applied to the Mica basin in the Canadian portion of the Columbia River Basin using the HBV-EC hydrologic model. Use of glacier volume change in the calibration procedure effectively reduced parameter uncertainty and helped to ensure that the model was accurately predicting glacier mass balance as well as streamflow. The seasonal and interannual variations in glacier melt contributions were assessed by running the calibrated model with historic glacier cover and also after converting all glacierized areas to alpine land cover in the model setup. Sensitivity of modelled streamflow to historic changes in glacier cover and to projected glacier changes for a climate warming scenario was assessed by comparing simulations using static glacier cover to simulations that accommodated dynamic changes in glacier area. Although glaciers in the Mica basin only cover 5% of the watershed, glacier ice melt contributes up to 25% and 35% of streamflow in August and September, respectively. The mean annual contribution of ice melt to total streamflow varied between 3 and 9% and averaged 6%. Glacier ice melt is particularly important during warm, dry summers following winters with low snow accumulation and early snowpack depletion. Although the sensitivity of streamflow to historic glacier area changes is small and within parameter uncertainties, our results suggest that glacier area changes have to be accounted for in future projections of late summer streamflow. Our approach provides an effective and widely applicable method to calibrate hydrologic models in glacier fed catchments, as well as to quantify the magnitude and timing of glacier melt contributions to streamflow

Self-assembled palladium and platinum coordination cages: Photophysical studies and anticancer activity

Self-assembled coordination cages are interesting as drug delivery systems. Therefore, the synthesis of new ML (M = Pd, Pt) molecular cages, derived from highly fluorescent, rigid polyaromatic ligands is reported and the first PtL cage with a ligand consisting of three pyridine moieties is described. Photophysical properties were examined showing high quantum yieldsof up to 48% for the methoxy-functionalized ligands. Coordination of the ligands to palladium and platinum ions reduces the metallocages' fluorescence, however. The host-guest chemistry of the palladium cage with cisplatin is investigated confirming the encapsulation. The cages encapsulating cisplatin show a significantly increased cytotoxicity towards A549 (human lung adenocarcinoma) cells compared to cisplatin, and thus appear to be promising delivery vectors for the anticancer drug cisplatin

The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles

The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity using ex vivo models. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin's neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug's myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy

Cucurbit [7] uril encapsulated cisplatin overcomes resistance to cisplatin induced by Rab25 overexpression in an intraperitoneal ovarian cancer model

Background Ovarian cancer is the most fatal of gynaecological malignancies, usually detected at a late stage with intraperitoneal dissemination. Appropriate preclinical models are needed that recapitulate both the histopathological and molecular features of human ovarian cancer for drug-efficacy analysis. Methods Longitudinal studies comparing cisplatin performance either alone or in a novel cisplatin-based delivery-system, cucurbit[7]uril-encapsulated cisplatin (cisplatin@CB[7]) were performed on subcutaneous (s.c.) and intraperitoneal (i.p.) xenografts using the human ovarian cancer cell line A2780 stably expressing the small GTPase Rab25, which allows A2780 intraperitoneal growth; and luciferase, to allow tumour load measurement by non-invasive bioluminescent imaging. Results Rab25 expression induced cisplatin resistance compared to the parental cell line as assessed by the MTT assay in vitro. These findings did not translate in vivo, where cisplatin resistance was determined by the microenvironment. Subcutaneous xenografts of either parental A2780 or cisplatin-resistant Rab25-expressing A2780 cells presented similar responses to cisplatin treatment. In contrast, increased cisplatin resistance was only detected in i.p. tumours. Treatment of the cisplatin-resistant i.p. model with the novel cisplatin@CB[7] delivery system resulted in a substantial reduction of i.p. tumour load and increased necrosis. Conclusions Poor clinical performance of novel chemotherapeutics might reflect inappropriate preclinical models. Here we present an ovarian i.p. model that recapitulates the histopathological and chemoresistant features of the clinical disease. In addition, we demonstrate that the novel cisplatin-delivery system, cisplatin@CB[7] may have utility in the treatment of drug-resistant ovarian human cancers

Nanoparticles: the future for platinum drugs or a research red herring?

Tese de doutoramento em Estudos Clássicos e em Educação, apresentada à Faculdade de Letras da Universidade de Coimbra e à Universidade Estadual de MaringáA presente tese tem como objetivo analisar nas réplicas do corpus antidonatista de Agostinho (354-430), Bispo de Hipona (norte da África), como o seu conceito de universalidade da Igreja está vinculado a um caráter educativo, isto é, como locus ideal formativo, argumento que respondeu ao processo de ascensão do catolicismo no final da Antiguidade. Para tanto, a pesquisa se sustentou em uma metodologia que contempla a necessidade de desvendar as transformações sociais do mundo romano em meio à integração do Império com o catolicismo, e tal situação, longe de ser um processo idílico, como demonstra a crise donatista – dissidência religiosa e política da província romana da África – conduziu Agostinho a elaborar uma argumentação sobre a relação Igreja e Império, em que este, por adotar o cristianismo como religião, deveria assumir a tarefa de auxiliador do catolicismo, inclusive, como força disciplinar. Com investigação em dados historiográficos, ou seja, respaldado pela lógica histórica, foi possível apreender como o clero elaborou uma visão de mundo (modelador de comportamentos) e articulou meios para sua relação de dominação que possibilitou à Igreja católica ascender como instituição organizadora da sociedade: em suma, o conceito agostiniano de Igreja foi tomado em sua historicidade, a Antiguidade Tardia. A rigor, Agostinho apontou como resposta aos problemas sociais de sua época a defesa de uma instituição ideal e/ou idealizada: a Igreja, definida em sua universalidade como “Católica”. Para demonstrar isto, defendeu-se a tese de que três dimensões educativas fundamentaram o seu pensamento: primeiro, o papel formativo atribuído ao clérigo, sobretudo o bispo, desde o seu exercício pedagógico a partir da cathedra até a sua colegialidade episcopal na elaboração do magistério católico; segundo: a defesa de uma prática pedagógica com a disciplina ecclesiastica tendo em vista corrigir erros comportamentais e doutrinais para a unidade dos cristãos; e por último, a ideia da possibilidade de mudança inerente à condição humana como lógica da transformação e, conforme pensou, a santificação dos cristãos, mas cujo proveito dependeria do percurso educativo desenvolvido na Igreja.Current thesis analyzes the anti-Donatist response corpus of St. Augustine (354-430), Bishop of Hippo, northern Africa, as his concept of the universality of the Church linked to the educational trait, or rather, as the ideal formative locus. It was actually the argument to the process of the ascension of Catholicism at the end of Antiquity. Current research has been foregrounded on the methodology of revealing the social transformations of the Roman worldview within the integration of the Roman Empire and Catholicism. These conditions, which did not constitute an idyllic process as the Donatist crisis (a religious and political dissidence of the Roman province in Africa) showed, caused Augustine to construct his arguments on the Church-Empire relationship in which the latter factor should have an auxiliary role by adopting Christianity as its religion, even within a disciplinary stance. Historiographical data foregrounded on a historical logic revealed how the clergy elaborated a worldview (a modeler of behavior) and fabricated means for domination by which the Catholic Church could become a society-organizing institution. In other words, the Augustinian concept of the Church derived from its historicity, or Late Antiquity. Strictly speaking, Augustine assumed the defense of an ideal and idealized institution, or rather, the Church defined as Catholic or Universal, as a response to the social problems of his age. Current thesis shows three educational dimensions that were the bases of his argument: first, the formative role of the clergy, especially the bishop, ranging from his pedagogical exercise on the cathedra to the episcopal collegiality in the elaboration of the Catholic magisterium; second, the defense of a pedagogical practice through the disciplina ecclesiastica, aiming at the correction of behavior and doctrinal errors for the union of all Christians; third, the idea of the possibility of change, inherent to the human condition, as a logic of transformation and, in his view, the sanctification of Christians whose success would depend on the educational course developed by the Church

Cucurbit[n]urils as excipients in pharmaceutical dosage forms

Native, unfunctionalised cucurbit[n]urils (n = 6, 7, or 8) have shown enormous potential as excipients in medical formulations for improving drug delivery. Specific benefits include improved drug stability, solubility, controlled or triggered release, taste masking, inducing drug pKa shifts and as antidotes. Base on in vitro and in vivo models, cucurbit[n]urils have been found to have little systemic toxicity, although they do show some specific organ toxicity, and appear to not affect developmental biology. Cucurbit[n]urils readily form hydrates in the solid state, which leads to pseudo-crystal polymorphs that can ultimately affect cucurbit[n]uril–drug complex solubility, bioavailability and through these drug effectiveness. In creating cucurbit[n]uril-based dosage forms, it has been found that the macrocycles can interact with other excipients in the formulation in both the solid state and solution. While the nature of the solid-state interactions are unclear, several studies of solutions have shown that some excipients are incompatible with cucurbit[n]urils as they can cause precipitates and will compete with the drugs for binding within the cavity. To date, cucurbit[n]urils have been formulated into five different dosage forms: oral solid tablet, topical cream, eye drop, implantable hydrogel and nasal insert.Ni

Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η 6-bip)Os(4-CO 2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η 6-p-cym)RuCl(dap)] + (p-cym = p-cymene) (5), and [(η 6-p-cym)RuCl(imidazole-CO 2H)(PPh 3)] + (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC 50 = 63 ± 2 μ in MCF-7 cells and IC 50 = 26 ± 3 μ in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 ± 2.6 μ in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society