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Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum (195mPt) is a rich source of low-energy Auger electrons, which kills tumor cells by damaging DNA. Auger electrons damage cells over a very short range. Consequently, 195mPt-based radiopharmaceuticals should be targeted toward ​tumors to maximize radiotherapeutic efficacy and minimize Pt-based systemic toxicity. Herein, we show that systemically administered radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes specifically accumulate in intratibial bone metastatic lesions in mice. The 195mPt-BP complexes accumulate 7.3-fold more effectively in bone 7 days after systemic delivery compared to 195mPt-cisplatin lacking bone-targeting bisphosphonate ligands. Therapeutically, 195mPt-BP treatment causes 4.5-fold more γ-H2AX formation, a biomarker for DNA damage in metastatic tumor cells compared to 195mPt-cisplatin. We show that systemically administered 195mPt-BP is radiotherapeutically active, as evidenced by an 11-fold increased DNA damage in metastatic tumor cells compared to non-radioactive Pt-BP controls. Moreover, apoptosis in metastatic tumor cells is enhanced more than 3.4-fold upon systemic administration of 195mPt-BP vs. radioactive 195mPt-cisplatin or non-radioactive Pt-BP controls. These results provide the first preclinical evidence for specific accumulation and strong radiotherapeutic activity of 195mPt-BP in bone metastatic lesions, which offers new avenues of research on radiotherapeutic killing of tumor cells in bone metastases by Auger electrons., Graphical abstract Theranostic 195mPt-bisphosphonate complexes are effectively targeted toward ​metastatic bone lesions to kill metastatic tumor cells by combined local chemo- and radiotherapy.Image 1

The paper presents a wearable wireless system and a proprietary algorithm along with a preliminary study on the time gait variability analysis as a tool for early diagnosis. The system is non-invasive and it is composed by a set of Inertial Measurements Units (IMUs) positioned on the patient leg. Each unit in the set bases its operations on Bluetooth Low Energy (BLE) standard. Experimental results validating system capabilities are reported and discussed.

Control at a nanosize level is a fundamental rule in the production of biomimetic materials particularly in the case of bone substitutes where the chemical and biological properties are very much size dependent. Synthetic hydroxyapatite (HA) nanocrystals represent an elective material for bone substitutes, moreover their surface functionalization with bioactive molecules makes them able to transfer information to and to act selectively on the biological environment. In this paper we have investigated the adsorption and desorption of cis-diamminedichloroplatinum(II) (CDDP or cisplatin), alendronate, and the new platinum(II) complex di(ethylendiamineplatinum)medronate (DPM) towards two bio-mimetic synthetic hydroxyapatite nanocrystal materials having different crystal shape and chemico-physical properties. The adsorption and desorption kinetics are dependent upon the specific properties of the drugs and of the HA’s (needle-shaped HAns and plate-shaped HAps). It is found that in the adsorption process the two platinum compounds keep the nitrogen ligands while CDDP looses its chlorides. Despite their opposite charges, the negatively charged alendronate and the positively charged acquated CDDP are the most adsorbed, while the neutral DPM shows the lowest affinity towards the apatitic surface. Considering that HA surface is in all negatively charged, data suggest that in the case of the two platinum complexes adsorption kinetics are driven by electrostatic attractions. On the other hand, the HA-alendronate interaction appears to consist of a “ligand exchange” process between the phosphonate functions of the drug molecule and two phosphates groups located on the surface of the HA nanocrystals. There is also a modulating effect of the specific HA used: adsorption of positively charged aquated CDDP is favored on phosphate reacher HAns surface while adsorption of negatively charged alendronate is favored on calcium reacher HAps surface. The latter type of short-range electrostatic interactions (positively charged aquated CDDP anchored by phosphate anions and negatively charged alendronate anchored by calcium cations) appear to dominate the desorption kinetics. Therefore the drug release is greater for neutral DPM than for charged alendronate and aquated CDDP. Moreover, while the release per unit area of charged species (aquated CDDP and alendronate) is the same for the two types of HA’s, the release of DPM is faster for HAns, which is poorer in surface calcium, than for HAps. This work demonstrates that the properties of HA nanocrystals can be modulated in such a way to produce HA/biomolecule conjugates tailored for specific therapeutical applications.

Objective: To compare the efficacy of diet alone vs interdisciplinary therapy. Method: 256 women were divided into an interdisciplinary therapy group composed of 102 subjects and a control group composed of 154 subjects treated by means of diet alone. Results: 21.56% of the interdisciplinary group did not come for the 2 check-ups compared with 49.35% of the diet group (p>0.001). A weight loss of 5.88 kg and 4.18 kg for the interdisciplinary and the diet group was recorded 8 weeks after the start of the programme (second check-up). Discussion: Interdisciplinary therapy is necessary to personalize treatment and satisfy the patient’s desire and need for appropriate and effective management.

Aims: Dieting is a behavioral phenomenon which is becoming more frequent among adolescents and the search for weight loss, through dieting, may result in an unbalanced nutrition both quantitatively and qualitatively. Our study intended to look at the eating habits and behavior on a cohort of adolescent girls to verify the presence of unbalanced diets and the prevalence of eating disorders with particular attention to the partial syndromes (EDNOS). Methods: A cross-sectional double-stage study was carried out on a group of schoolgirls in the suburbs of Naples. We assessed anthropometrical measures, body composition (skinfolds and bioimpedance analysis), dietary intake by means of 3-day food records and we administered the Eating Disorder Inventory 2 and Psychosocial Factor Risk Questionnaire. A multidisciplinary and double-stage approach had been used to get a better diagnosis of eating disorders in our sample. Results: 156 adolescent girls, 14–18 years old, took part in our study. Height, weight, and BMI were 160.38 cm, 58 kg and 22.6, respectively. Analysis of food intake showed that all the values reported, with the exception of lipids and sodium, were below the recommendations by LARN. We observed a prevalence of 1.28% of bulimia nervosa, 1.28% of binge eating, and 10.25% of eating disorders not otherwise specified. EDI 2 and PRFQ confirmed how important drive for thinness and body dissatisfaction dimensions are when we deal with adolescent girls and with the phenomenon of dieting. The study confirmed the validity of the PRFQ questionnaire to evaluate mass media influence on body perception and eating behavior of adolescents. Conclusion: Multidisciplinary and well-designed studies are needed to systematically and accurately study eating habits and behavior of adolescents to tackle more efficiently the increasing spread of eating disorders and obesity.

The present study evaluated impaired eating behaviour in women seeking participation in a diet-based programme of weight reduction or achievement of ideal body weight. Forty-seven obese, 42 overweight and 14 normal-weight subjects, attending an Italian university outpatient clinic completed the Eating Disorder Inventory (EDI). Forty-eight mothers of primary school children (25 normal-weight and 23 overweight) were used as controls. The EDI consists of 8 subscales, 3 evaluating psychopathology related to eating disorders (drive for thinness, bulimia, body dissatisfaction) and 5 evaluating general psychopathology (intereoceptive awareness, ineffectiveness, maturity fears, perfectionism, interpersonal distrust). Significantly altered scores in the first three subscales were observed both in normal-weight and overweight outpatients compared to the controls. The overweight outpatients scored higher than the obese patients in terms of drive for thinness and bulimia and higher than the normal-weight women for terms of bulimia, body dissatisfaction and drive for thinness. The overweight controls scored significantly higher than the normal-weight controls in the first three subscales in the remaining subscales, mean values were also higher in the overweight group, though significance was only reached in the interpersonal distrust and interoceptive awareness subscales. Impaired eating behaviour is frequent in subjects seeking participation in weight reduction or ideal body weight achievement programmes.

The single-stranded oligonucleotide 5'-d(CCTCGCTCTC) (I) was reacted with the antitumor trans platinum iminoderivative trans-[PtCl(2){E-HN = C(OMe)Me}(2)] (trans-EE) and subsequently annealed with its complementary strand 5'-d(GAGAGCGAGG) (II). The platinated duplex was characterized by 1D and 2D proton NMR spectroscopy at 600 MHz. In agreement with previous studies by different techniques trans-EE was found to form a monofunctional adduct with the duplex involving the guanine residue. The modification by trans-EE has been found to induce only minor local distortion in the duplex geometry. Two key crosspeaks observed in the NOESY map corresponding to a close contact between G5-H8 and the methoxy and the methyl group, respectively, enabled us to dock the trans-EE complex with the duplex by geometry optimization. The results support the idea that the antitumor activity of trans-EE is related to lesion of DNA fundamentally different from that of cisplatin. Unexpectedly, the NOESY spectra indicated that at the high NaCl concentration used (0.2 M) the duplex was found to undergo slow deplatination. This was subsequently proved by HPLC. In a separate experiment on platination of the single strand in a salt free environment the HPLC analysis showed that the monofunctional adduct was not deplatinated, however, after 24 hours, additidnal minor isomers were detected.

The reaction of the potential anticancer drug kiteplatin, cis-[PtCl2(cis-1,4-DACH)], with oligomers of single- and double-stranded DNA ranging from 2 to 12 base pairs in length was performed as a model for DNA interaction. The potential for conformational flexibility of single-stranded adducts was examined with density functional theory (DFT) and compared with data from 1H-NMR 1D and 2D spectroscopy. This indicates the presence of multiple conformations of an adduct with d(GpG), but only one form of the adduct with d(TGGT). The importance of a suitable theoretical model, and in particular basis set, in reproducing experimental data is demonstrated. The DFT theoretical model was extended to platinated base pair step (GG/CC), allowing a comparison to the related compounds cisplatin and oxaliplatin. Adducts of kiteplatin with larger fragments of double-stranded DNA, including tetramer, octamer, and dodecamer, were studied theoretically using hybrid quantum mechanics/molecular mechanics methods. Structural parameters of all the base-paired models were evaluated and binding energies calculated in gas phase and in solution; these are compared across the series and also with the related complexes cisplatin and oxaliplatin, thus revealing insights into how kiteplatin binds to DNA and similarities and differences between this and related compounds. Graphical Abstract: [Figure not available: see fulltext.]

The anticancer activity of cisplatin is triggered by its formation of intrastrand adducts involving adjacent G residues of DNA. To obtain information on the different conformers that can be formed{,} carrier ligands such as 2{,}2[prime or minute]-bipiperidine{,} which provide large steric bulk near the platinum coordination plane and decrease the dynamic motion about the Pt-N7 bonds{,} were introduced ({"}retro-modelling{"} approach). In the present study we investigate the effect of cis-1{,}4-diaminocyclohexane (cis-1{,}4-DACH) on the formation{,} stability{,} and stereochemistry of (cis-1{,}4-DACH)Pt(ss-oligo) adducts (ss-oligo = d(GpG) with 3[prime or minute]- and/or 5[prime or minute]-substituents). Interesting features of this ligand{,} absent in previous retro-modelling studies{,} include the large bite angle (expected to impede the ease of interconversion between possible conformers){,} the presence of two protons on each nitrogen (a characteristic associated with antitumor activity){,} and the absence of chiral centres. The use of cis-1{,}4-DACH has made it possible to detect different conformers in a system containing a primary diamine carrier ligand associated with anticancer activity and to confirm the previous hypothesis that the coexistence of different conformers established in studies of retro models having relatively bulky ligands is not an artefact resulting from carrier-ligand bulk. Moreover{,} the data for the (cis-1{,}4-DACH)Pt(d(GpG)) and (cis-1{,}4-DACH)Pt(d(GGTTT)) adducts indicate that at a temperature close to the physiological one (40 [degree]C) HH1 and [capital Delta]HT1 conformers are present in comparable amounts. In contrast{,} at low temperature (close to 0 [degree]C) the equilibrium shifts dramatically toward the more stable HH1 conformer (for the (cis-1{,}4-DACH)Pt(d(TGGT)) adduct the HH1 conformer is always dominant{,} even at high temperature). Notably{,} (cis-1{,}4-DACH)PtCl2 (Kiteplatin) has been recently reinvestigated and found to be particularly active against colorectal cancer (including oxaliplatin-resistant phenotypes).

Coordinated N,N',N"-trimethyldiethylenetriamine (Me3dien) has several possible configurations: two have mirror symmetry (R,S configurations at the terminal nitrogens) and the terminal N-Me's anti or syn with respect to the central N-Me (anti-(R,S) and syn-(R,S) isomers, respectively), and two are nonsymmetrical (R,R and S,S configurations at terminal nitrogens, rac denotes a 1:1 mixture of the two isomers). For each configuration, two Me3dienPtG atropisomers can be formed (anti or syn orientation of central N-Me and G 06, G = guanine derivative), and these can be observed since the terminal N-Me's decrease the rate of G rotation about the Pt-N7 bond. In symmetrical syn-(R,S)-Me3dienPtG derivatives with G = 9-EtG and 3'-GMP, the anti rotamer, which can form O6-NH H-bonds, was slightly favored over the syn rotamer but never more than 2:1. This anti rotamer is also favored by lower steric repulsion between the terminal N-Me's and G O6; thus, the contribution of O6-NH H-bonding to the stability of the anti rotamer could be rather small. With G = 5'-GMP, an O6-NH H-bond in the anti rotamer and a phosphate-NH H-bond in the syn rotamer can form. Only the syn rotamer was detected in solution, indicating that NH H-bonds to 5'-phosphate are far more important than to O6, particularly since steric factors favor the anti rotamer. Interconversion between rotamers was faster for syn-(R,S)- than for rac-Me3dien derivatives. This appears to be determined by a smaller steric impediment to G rotation of two "quasi equatorial" N-Me's, both on one side of the platinum coordination plane (syn-(R,S) isomer), than one "quasi equatorial" and one "quasi axial" N-Me on either side of the coordination plane (rac isomer).

In the present study two nanocrystalline apatites have been investigated as bone-specific drug delivery devices to be used for treatment of bone tumors either by local implantation or by injection. In order to assess how the Ca/P ratio can influence the adsorption and release of anticancer platinum-bisphosphonate complexes, two kinds of apatite nanocrystals having different Ca/P ratios but similar morphologies, degree of crystallinity, and surface areas have been synthesized and characterized. The two platinum-bisphosphonate complexes considered were the bis-{ethylenediamineplatinum(ii)}-2-amino-1-hydroxyethane-1,1-diyl-bisphosphonate and the bis-{ethylenediamineplatinum(ii)}medronate. The Ca/P ratio plays an important role in the adsorption as well as in the release of the two drugs. In fact, the apatite with a higher Ca/P ratio showed greater affinity for both platinum complexes. Also the chemical structure of the two Pt complexes appreciably affects their affinity towards as well as their release from the two kinds of apatites. In particular, the platinum complex whose bisphosphonate contains a free aminic group showed greater upload and smaller release. The cytotoxicity of the Pt complexes released from the apatite was tested against human cervical, colon, and lung cancer cells as well as against osteosarcoma cells. In agreement with previous work, the Pt complexes released were found to be more cytotoxic than the unmodified complexes.

Square-planar [PtX 2 (Me 2 PHEN)] complexes (Me 2 PHEN=2,9-dimethyl-1,10-phenanthroline) behave as a spring trap and react with an extra ligand (L) to give the addition product [PtX 2 (L)(Me 2 PHEN)] in which the Me 2 PHEN plane is perpendicular to the coordination plane of the other three ligands. For X=I and L=PY or APY (PY, pyridine, APY, 2-amino-pyridine) the addition product has monocoordinated Me 2 PHEN. The free and coordinated ends of Me 2 PHEN are in rapid exchange at room temperature but the exchange becomes slow, in the NMR time scale, at low temperature (213 K). In chloroform solution and at room temperature, the addition product is indefinitely stable in the case of PY while in the case of APY displacement of a iodo ligand by the free end of Me 2 PHEN and formation of the cationic species [PtI(L)(Me 2 PHEN)]I take place in a few hours. An anchimeric assistance of the exocyclic aminic-group of APY in the release of the iodide ion is suggested. The displacement of the iodide is also favored by solvents of higher solvating ability and/or dielectric constants such as methanol. The single crystal X-ray structures of [PtI(APY)(Me 2 PHEN)]I·2CHCl 3 ( 1 ·2CHCl 3 ) and [PtI(MeCY)(Me 2 PHEN)]I·CH 3 OH ( 2 ·CH 3 OH) (MeCY, 1-methyl-cytosine) have revealed that the steric repulsion towards cis -ligands is smaller for the APY and MeCY ligands than for I and that chloroform can give intermolecular interactions with the phenanthroline moiety which can compete with stacking interactions between phenanthroline ligands.

This study widens the role of biomimetic hydroxyapatite (HA) nanocrystals as bone substitutes and describes how they can be used as bone-specific drug delivery devices for in situ treatment of bone tumors upon local implantation. The adsorption and release kinetics of bis-{ethylenediamineplatinum(II)}-2-amino-1-hydroxyethane-1,1-diyl-bisphosphonate and bis-{ethylenediamineplatinum(II)}medronate on two kinds of HA nanocrystals having different morphologies, crystallinity degrees and surface areas have been investigated. The different chemical structures of the two Pt complexes appreciably affect not only the affinity towards the two kinds of HA, but also their release. The Pt complex loading is slightly greater for the HA characterized by lower crystallinity and higher surface area, with respect to the more crystalline one. The cytotoxicity of Pt complexes released from the HA were tested against human cervix carcinoma cells and, interestingly, were found to be more cytotoxic than the unmodified complexes. The released Pt species are therefore the active dichloridoethylenediamineplatinum(II) or related solvato species formed by Pt-bisphosphonate bond breaking.

Four novel hybrid drugs [Pt(acy)2(Me2phen)]I2 (1), [Pt(pen)2(Me2phen)](NO3)2 (2), [Pt(acy)2(phen)](NO3)2 (3), and [Pt(pen)2(phen)](NO3)2 (4) have been prepared by reaction of the antiviral guanine derivatives acyclovir (acy) and penciclovir (pen) with platinum complexes having 2,9-Me2-1,10-phenanthroline (Me2phen) and 1,10-phenanthroline (phen) as carrier ligands. Both the Me2phen and phen carrier ligands are able to hinder rotation of the guanine bases about the Pt−N(7) bonds rendering the interconversion among rotamers very slow on the NMR time scale. A favourable dipole−dipole interaction between the cis-coordinated purine bases stabilises the HT rotamers, which are the only species detected in solution. The stability in a physiological medium and the anti-HIV properties in vitro of the complexes have been evaluated. In a 0.1 M solution of NaCl, the compounds with Me2phen (1 and 2) were found to be very stable while the compounds with phen (3 and 4) underwent displacement of one purine base by a chloride ion. This rather unexpected result may have some relevance in connection with the stability of major DNA adducts of cisplatin in which two guanines are cross-linked by a Pt(NH3)2 moiety. Although none of the complexes showed anti-HIV activity, complexes 1 and 2, bearing methyl substituents in the ortho positions of the phenanthroline, were much more cytotoxic than 3 and 4. This is probably due to a greater stability of the former complexes in biological media caused by the presence of the two methyl groups wrapping the metal centre and inhibiting the nucleophilic attack of an incoming ligand at the platinum centre.