Improvements in Drug-Delivery Properties by Co-Encapsulating Curcumin in SN-38-Loaded Anticancer Polymeric Nanoparticles.

SN-38 is an immensely potent anticancer agent although its use necessitates encapsulation to overcome issues of poor solubility and stability. Since SN-38 is a notoriously challenging drug to encapsulate, new avenues to increase encapsulation efficiency in polymer nanoparticles (PNPs) are needed. In this paper, we show that nanoprecipitation with curcumin (CUR) increases SN-38 encapsulation efficiencies in coloaded SN-38/CUR-PNPs based on poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL-b-PEG) by up to a factor of 10. In addition, we find a dramatic decrease in PNP polydispersities, from 0.34 to 0.07, as the initial CUR-to-polymer ratio increases from 0 to 10, with only a modest increase in PNP size (from 40 to 55 nm). Compared to coloaded PNP formation using nanoprecipitation in the bulk or in a gas-liquid, a two-phase microfluidic reactor shows similar trends with respect to CUR content, although improvements in SN-38 encapsulation efficiencies both with and without CUR are found using the microfluidic method. Additional precipitation studies without copolymer suggest that CUR increases the dispersion of SN-38 in the solvent medium of micelle formation, which may contribute to the observed encapsulation enhancement. Cytotoxicity studies of unencapsulated SN-38/CUR mixtures show that addition of CUR does not significantly affect SN-38 potency against either U87 (glioblastoma) or A204 (rhabdomyosarcoma) cell lines. However, we find significant differences in the potencies of SN-38/CUR-PNP formulations depending on initial CUR amounts, with an optimized formulation showing subnanomolar cytotoxicity against A204 cells, significantly more potent than either free SN-38 or PNPs containing only SN-38.

Microfluidic Manufacturing of SN-38-Loaded Polymer Nanoparticles with Shear Processing Control of Drug Delivery Properties.

Two-phase gas-liquid microfluidic reactors provide shear processing control of SN-38-loaded polymer nanoparticles (SN-38-PNPs). We prepare SN-38-PNPs from the block copolymer poly(methyl caprolactone- co-caprolactone)- block-poly(ethylene oxides) (P(MCL- co-CL)- b-PEO) using bulk and microfluidic methods and at different drug-to-polymer loading ratios and on-chip flow rates. We show that, as the microfluidic flow rate ( Q) increases, encapsulation efficiency and drug loading increase and release half times increase. Slower SN-38 release is obtained at the highest Q value ( Q = 400 µL/min) than is achieved using a conventional bulk preparation method. For all SN-38-PNP formulations, we find a dominant population (by number) of nanosized particles (<50 nm) along with a small number of larger aggregates (>100 nm). As Q increases, the size of aggregates decreases through a minimum and then increases, attributed to a flow-variable competition of shear-induced particle breakup and shear-induced particle coalescence. IC25 and IC50 values of the various SN-38-PNPs against MCF-7 cells show strong flow rate dependencies that mirror trends in particle size. SN-38-PNPs manufactured on-chip at intermediate flow rates show both minimum particle sizes and maximum potencies with a significantly lower IC25 value than the bulk-prepared sample. Compared to conventional bulk methods, microfluidic shear processing in two-phase reactors provides controlled manufacturing routes for optimizing and improving the properties of SN-38 nanomedicines.

In vitro experiments showing enhanced release of doxorubicin from Doxil® in the presence of ammonia may explain drug release at tumor site.

The anticancer nanodrug Doxil®, a pegylated liposomal doxorubicin (PLD), accumulates at the tumor site due to the enhanced permeability and retention effect. However, the mechanism of doxorubicin release from the liposome within the tumor is unknown. We propose that ammonia produced at the tumor site by glutaminolysis enhances release. Using tumor cells in culture, we show that PLD, when ammonia is present, kills tumor cells with an efficacy similar to that of free doxorubicin, while PLD without ammonia and ammonia without PLD have very poor cytotoxicity. We confirm in tumor mouse models that ammonium/ammonia levels measured at the tumors are in the millimolar range, much higher than in the plasma of these mice. This is a new concept of stimulus-response, therapeutically efficacious drug release in tumors, with ammonia derived from tumor cell glutaminolysis acting as the stimulus. There may also be additional microenvironment-related variables that influence therapeutic efficacy. FROM THE CLINICAL EDITOR: The use of liposomal platform as a drug carrier has brought success to Doxil. Nonetheless, the underlying mechanism of drug release at tumor site and subsequent tumor killing was largely unknown. In this article, the authors demonstrated in their experiments that higher ammonia level in the tumor environment was the main mechanism for drug release.

Parenting and environmental risk : an examination of child loss and maternal involvement among Bofi foragers in Central Africa.

The majority of adaptationist models and research related to parenting strategies have focused on extrinsic or population-level risk as predictors of parenting. However, some researchers have called for greater consideration of cultural factors as well as on intracultural variation in parenting. This study uses a biocultural approach to examine intracultural variation in environmental risk and parenting among the Bofi foragers in Central Africa. In particular, we examine 30 mothers' experiences of child loss as a predictor of variation in maternal involvement (proximity, holding, and affection) with their young children. Multivariate and univariate analyses indicate that child loss accounted for substantial variation in maternal behaviors and was predictive of maternal holding and the expression of physical affection. In sum, our findings indicate that intracultural variation in child loss is predictive of maternal involvement with young children and that a biocultural approach is useful in explaining this variation.

Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain.

High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.

Charge transfer in photoacids observed by stark spectroscopy.

The charge redistribution upon photoexcitation is investigated for a series of pyrene photoacids to better understand the driving force behind excited-state proton-transfer processes. The changes in electric dipole for the lowest two electronic transitions ( (1)L b and (1)L a) are measured by Stark spectroscopy, and the magnitudes of charge transfer of the protonated and deprotonated states are compared. For neutral photoacids studied here, the results show that the amount of charge transfer depends more upon the electronic state that is excited than the protonation state. Transitions from the ground state to the (1)L b state result in a much smaller change in electric dipole than transitions to the (1)L a state. Conversely, for the cationic (ammonium) photoacid studied, photoexcitation of a particular electronic state results in much smaller charge transfer for the protonated state than for the deprotonated state.

Stark spectroscopy of mixed-valence systems.

Many mixed-valence systems involve two or more states with different electric dipole moments whose magnitudes depend upon the charge transfer distance and the degree of delocalization; these systems can be interconverted by excitation of an intervalence charge transfer transition. Stark spectroscopy involves the interaction between the change in dipole moment of a transition and an electric field, so the Stark spectra of mixed-valence systems are expected to provide quantitative information on the degree of delocalization. In limiting cases, a classical Stark analysis can be used, but in intermediate cases the analysis is much more complex because the field affects not only the band position but also the intrinsic bandshape. Such non-classical Stark effects lead to widely different bandshapes. Several examples of both classes are discussed. Because electric fields are applied to immobilized samples, complications arise from inhomogeneous broadening, along with other effects that limit our ability to extract unique parameters in some cases. In the case of the radical cation of the special pair in photosynthetic reaction centres, where the mixed-valence system is in a very complex but structurally well-defined environment, a detailed analysis can be performed.

Vibrational stark effect probes for nucleic acids.

The vibrational Stark effect (VSE) has proven to be an effective method for the study of electric fields in proteins via the use of infrared probes. To explore the use of VSE in nucleic acids, we investigated the Stark spectroscopy of nine structurally diverse nucleosides. These nucleosides contained nitrile or azide probes in positions that correspond to both the major and minor grooves of DNA. The nitrile probes showed better characteristics and exhibited absorption frequencies over a broad range; that is, from 2253 cm-1 for 2'-O-cyanoethyl ribonucleosides 8 and 9 to 2102 cm(-1) for a 13C-labeled 5-thiocyanatomethyl-2'-deoxyuridine 3c. The largest Stark tuning rate observed was |Deltamu| = 1.1 cm(-1)/(MV/cm) for both 5-cyano-2'-deoxyuridine 1 and N2-nitrile-2'-deoxyguanosine 7. The latter is a particularly attractive probe because of its high extinction coefficient (epsilon = 412 M-1cm-1) and ease of incorporation into oligomers.

3H-[1,2,4]-Triazolo[5,1-i]purin-5-amine derivatives as adenosine A2A antagonists.

A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles.