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Abstract: Zoledronic acid (ZOL) is a potent amino-bisphosphonate used for the treatment of bone metastases with recently reported antitumor activity. However, the short plasma half-life and rapid accumulation in bone limits the use of ZOL as an antitumor agent in extraskeletal tissues. Therefore, we developed stealth liposomes encapsulating ZOL (LipoZOL) to increase extraskeletal drug availability. Compared to free ZOL, LipoZOL induced a stronger inhibition of growth of a range of different cancer cell lines in vitro. LipoZOL also caused significantly larger inhibition of tumor growth and increased the overall survival in murine models of human prostate cancer and multiple myeloma, in comparison with ZOL. Moreover, a strong inhibition of vasculogenetic events without evidence of necrosis in the tumor xenografts from prostate cancer was recorded after treatment with LipoZOL. We demonstrated both antitumor activity and tolerability of LipoZOL in preclinical animal models of both solid and hematopoietic malignancies, providing a rationale for early exploration of use of LipoZOL as a potential anticancer agent in cancer patients. From the Clinical Editor: The short plasma half-life and rapid accumulation in bone limits the use of zoledronic acid as an antitumor agent in extraskeletal tissues. Therefore, stealth liposomes encapsulating ZOL (LipoZOL) have been developed to increase extraskeletal drug availability. [Copyright &y& Elsevier]

Abstract: The trans-resveratrol (t-res), a non-flavonoid polyphenol extracted from different plants, has recently earned interest for application on the skin for different applications. In this work, the potential of nanocarriers, namely transfersomes and ethanol-containing vesicles, to deliver t-res into/through the skin was investigated. Thus, transfersomes with different surfactants, namely polysorbate 80 (Tw80), sodium cholate (SC) and sodium deossicholate (SDC) and ethanol-containing vesicles with different lipid composition, namely soy phosphatidylcholine (SPC) and cholesterol (chol), encapsulating t-res were prepared and characterized. The nanocarriers had a mean diameter ranging between 83 and 116nm with a high t-res encapsulation efficiency (≥70%). Moreover, cytotoxicity as well as the inhibition of production of reactive oxygen species (ROS) and lipid peroxidation, following incubation of H2O2-stimulated human keratinocyte (HaCaT) with t-res, as free or encapsulated into the nanocarriers, were investigated. Only blank nanocarriers containing Tw80 or ethanol were cytotoxic and led to increase of ROS, but this effect was not observed when using nanocarriers encapsulating t-res. Finally, permeation studies on porcine skin carried out on Franz diffusion cells, showed that only ethanol-containing vesicles based SPC were able to promote t-res permeation through the skin. [Copyright &y& Elsevier]

Abstract: Zoledronic acid (ZOL) is a drug whose potent anti-cancer activity is limited by its short plasma half-life and rapid uptake and accumulation within bone. We have recently proposed new delivery systems to avoid ZOL accumulation into the bone, thus improving extra-skeletal bioavailability. In this work, we have compared the technological and anti-cancer features of either ZOL-containing self-assembly PEGylated nanoparticles (NPs) or ZOL-encapsulating PEGylated liposomes (LIPO-ZOL). ZOL-containing NPs showed superior technological characteristics in terms of mean diameter, size distribution, and ZOL encapsulation efficiency, compared to LIPO-ZOL. Moreover, the anti-cancer activity of NPs in nude mice xenografted with prostate cancer PC3 cells was higher than that one induced by LIPO-ZOL. In addition, NPs induced the complete remission of tumour xenografts and an increase of survival time higher than that one observed with LIPO-ZOL. It has also to be considered that PC3 tumour xenografts were almost completely resistant to the anti-cancer effects induced by free ZOL. Both nanotechnological products did not induce toxic effects not affecting the mice weight nor inducing deaths. Moreover, the histological examination of some vital organs such as liver, kidney and spleen did not find any changes in terms of necrotic effects or modifications in the inflammatory infiltrate. On the other hand, NPs but not LIPO-ZOL caused a statistically significant reduction of the tumour associated macrophages (TAM) in tumour xenografts. This effect was paralleled by a significant increase of both necrotic and apoptotic indexes. The effects of the NPs were also higher in terms of neo-angiogenesis inhibition. These results suggest the future preclinical development of ZOL-encapsulating NPs in the treatment of human cancer. [Copyright &y& Elsevier]

Abstract: The chemical conversion of simvastatin from the lactone (SVL) to the hydroxyacid (SVA) form is becoming an intriguing issue associated with the pharmacological use of SVL. On this matter, recent findings suggest that SVL complexation with cyclodextrins (CDs) may be a useful strategy to affect its aqueous solubility and chemical stability. In this work, a reverse-phase high-performance liquid chromatography (RP-HPLC) method able to selectively identify and quantify SVL and SVA has been set up, validated and applied to follow SVL hydrolysis in the presence of HPβCD. The combination of stability results with simvastatin/HPβCD stability constants achieved from UV–vis measurements and solubility/dissolution studies allowed to get an insight into SVL/HPβCD, SVA/HPβCD and SVL/SVA equilibria taking place in aqueous solution. Results show that in the presence of HPβCD the aqueous SVL/SVA equilibrium is shifted versus the hydroxyacid form. UV–vis results, showing that the lactone and the open-ring form of simvastatin interact with HPβCD in a similar extent, suggest that hydrolysis occurs also on SVL/HPβCD complex, thus supporting a mode of interaction that does not involve the lactone ring. This hypothesis is strengthened by NMR analysis performed on SVA, HPβCD and their inclusion complex, which indicates that the lactone ring is not included in HPβCD hydrophobic cavity. Finally, results suggest that particular attention must be paid to SVL lactonization in aqueous solution when using CD-based formulations and in demonstrating their effective benefit for a specific therapeutic use. [Copyright &y& Elsevier]

Abstract: The enantioselective retention of thirteen β-blockers on HPLC stationary phases supporting human serum albumin (HSA) or α1-acid glycoprotein (AGP) was investigated. Eight β-blockers were enantiomerically resolved on the AGP column whereas only four β-blockers were resolved on the HSA column. Moreover, interactions between β-blockers and AGP were much stronger than those with HSA. Retention values on both HSA and AGP for less retained enantiomers related well with various lipophilicity parameters, with the best relationships found with values obtained on HPLC stationary phases supporting phospholipids, i.e. the so-called Immobilized Artificial Membrane (IAM). Differently from n-octanol lipophilicity values, these values encode both lipophilic. Electrostatic intermolecular recognition forces which may be involved in the interaction between ionized analytes, such as β-blockers, and proteins. However, their effectiveness to describe non-specific interactions with serum–proteins for other classes of drugs needs further investigations. Analyses performed on AGP with eluent containing dimethyloctylamine (DMOA) as the displacer demonstrated that enantioselective sites bind to both (−)-forms and (+)-forms, but the binding to (−)-forms is stronger. The enantiomer competition to bind to a same site may be relevant from a pharmacokinetic point of view when racemic mixtures are administered. Finally, in contrast to previously reported data in the literature, we found that AGP can bind enantioselectively not only the more lipophilic congeners but also the less lipophilic ones. [Copyright &y& Elsevier]

Abstract: The retention of 10 quinolone antibacterial agents on HPLC stationary phases supporting human serum albumin (HSA) or α1-acid glycoprotein (AGP) was investigated. Among ofloxacine and flumequine, the two chiral compounds in the selected set, only the latter showed a split chromatographic peak and only on HSA but not on AGP, indicating that enantioselective specific sites play only a minor role in the retention. The retention of quinolones, which included four acidic and six zwitterionic congeners, was correlated with various lipophilicity scales: (i) theoretically calculated values, c log P, (ii) values measured at pH 7.4 by the shake-flask method, log D 7.4, and (iii) values extrapolated by retention data measured by ion-pair reversed-phase high performance liquid chromatography (RP-HPLC). We assumed that the latter values, log P i.p., were close to the lipophilicity of the neutral forms, log P N, for both acidic and zwitterionic congeners. No relationship was found between retention on serum proteins and c log P values, whereas a reasonable relationship was found with log D 7.4 values, but only when the two subclasses, acidic and zwitterionic congeners, were considered separately. The relationship between retention data on serum proteins and log P i.p. values indicated that the affinity for serum proteins depends on the lipophilicity of the neutral forms only for log P values up to 1.5. Above this value, protein retention does not further increase, becoming almost constant. Based on both the observations above reported and the small values of the slopes of regression equations, we conclude that the interaction of the more lipophilic quinolones, mainly the zwitterions, with serum proteins is not governed uniquely by lipophilicity but also by other mechanisms, probably of electrostatic nature. [Copyright &y& Elsevier]

Abstract: The aim of this work was to develop dry powders intended for insulin pulmonary delivery. To this purpose, large porous particles (LPP) made of poly(lactide-co-glycolide) (PLGA) were produced by the double emulsion-solvent evaporation technique. Hydroxypropyl-β-cyclodextrin (HPβCD), also known as absorption enhancer for pulmonary protein delivery, was tested as aid excipient to optimize the aerodynamic behaviour of the microparticles. Several microsphere formulations, differing in HPβCD and insulin loadings, were produced and their properties compared. A contemporary release of insulin and HPβCD from the system can be achieved by selecting appropriate formulation conditions. HPβCD-containing LPP with flow properties and dimensions suitable for aerosolization and deposition in deep regions of the lung following inhalation were produced. In conclusion, the developed system turns to be of great potential for the combined delivery of the protein and the adsorption promoter in the respiratory tract. [Copyright &y& Elsevier]

Abstract: The chromatographic capacity factors (k′) of 10 β-adrenoceptor antagonists (“β-blockers”) were measured on three different immobilized artificial membrane-phosphatidylcholine (IAM-PC) HPLC stationary phases, namely IAM-PC-MG, IAM-PC-DD2, and IAM-PC-DD. The two former phases are made of phosphatidylcholine as found in biomembranes and differ each other in end-capping of free propylamino residues whereas the latter is made of single-chain phosphatidylcholine analogues. On IAM-PC-DD2 we found that structurally unrelated neutral compounds give a single correlation between log k′ values and the respective octanol/water partition coefficients (log P), as previously observed on IAM-PC-MG phase. This was not observed on the IAM-PC-DD phase. IAM chromatography was performed at a pH of the aqueous eluent (7.0) close to the physiological pH 7.4. Retention on all IAM phases showed a biphasic pattern, being proportional to log P N (lipophilicity of neutral forms) for more lipophilic congeners (log P N >1.90), and quite constant for the others. The comparison of β-blocker retention with that of neutral compounds on IAM-PC-MG and IAM-PC-DD2 suggests that they can interact with phospholipids as strongly or more strongly than neutral isolipophilic compounds, despite their being more than 98% in their ionized form. Therefore, we hypothesize that electrostatic interactions play a pivotal role in the interactions between β-blockers and membrane phospholipids. [Copyright &y& Elsevier]

Segmented poly(ether-ester-amide)s (PEEAs) derived from poly(∊-caprolactone) oligomers, sebacoyl chloride, hydrophilic diamide-diamines based on short sequences of ethylenoxy groups and containing amino acids, were used to produce matrix systems intended for the delivery of metronidazole in the periodontal pocket. PEEAs are soluble in chloroform and insoluble in water and show Mn values in the range 8.5–18.6 kDa. The melting temperatures (53–59 °C) are close to that of poly(∊-caprolactone) (PCL) with a similar Mn. The water absorption of PEEAs is improved if compared with that of pure PCL and depends on both the length of oxyethylene sequences and the amino acid number, as well as on copolymer composition. Loaded-films containing 20% (w/w) of metronidazole were prepared by compression-molding. The release rate was diffusive in the first stage, whereas also other mechanisms, probably polymer degradation, contributed to the slower second phase. The rate of medium penetration within the film depended on PEEA hydrophilicity and crystallinity and was the main determinant governing the drug release rate. The opportunity to control effectively drug release rates by modulating the composition, and in turn the properties, of PEEAs is an attracting feature for their use in a number of drug delivery systems. [Copyright &y& Elsevier]