Cellular Uptake Mechanism of Paclitaxel Nanocrystals Determined by Confocal Imaging and Kinetic Measurement...

Nanocrystal formulation has become a viable solution for delivering poorly soluble drugs including chemotherapeutic agents. The purpose of this study was to examine cellular uptake of paclitaxel nanocrystals by confocal imaging and concentration measurement. Imaging and quantitative results suggest that nanocrystals could be directly taken up by cells as solid particles, likely via endocytosis. Moreover, it was found that polymer treatment to drug nanocrystals, such as surface coating and lattice entrapment, significantly influenced the cellular uptake. While drug molecules are in the most stable physical state, nanocrystals of a poorly soluble drug are capable of achieving concentrated intracellular presence enabling needed therapeutic effects....
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Reactivity of Triacetone Triperoxide and Diacetone Diperoxide: Insights from Nuclear Fukui Function...

Triacetone triperoxide (TATP) is more sensitive than diacetone diperoxide (DADP) in the solid-state explosion. To explain this reactivity difference, we analyzed the electronic structures and properties of the crystals of both compounds by using Ab initio method to calculate the structures of their individual molecules as well as their lattice structures and particularly calculating Nuclear Fukui function to gain insight into the sensitivity of the initial, rate-determining step of their decomposition. Our results indicate that TATP and DADP crystal structures exhibit significantly different electronic properties. Most notably, the electronic structure of the TATP crystal shows asymmetry among its reactive oxygen atoms as supported by magnitudes of their nuclear Fukui functions. The greater explosion sensitivity of crystalline TATP may be attributed to the properties of its electronic structure. The electronic calculations provided valuable insight into the decomposition sensitivity difference between TATP and DADP crystals....
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Polymorphism and Solid-to-Solid Phase Transitions of a Simple Organic Molecule, 3-Chloroisonicotinic Acid...

Three polymorphs (I, II, and III) have been discovered for 3-chloroisonicotinic acid. The torsion angle between the aromatic ring and the carboxylic acid in form I differs from that of forms II and III, which are similar. All three polymorphs form hydrogen-bonded chains based on the acid–pyridine heterosynthon. Despite the conformational similarity between forms II and III, the hydrogen-bonded chains in form II alternate in direction while those in form III all point in the same direction. Study of the phase behaviors of the three forms by differential scanning calorimetry, hot-stage microscopy, and thermogravimetric analysis revealed two solid-to-solid phase transitions from the metastable forms II and III to the most stable form I. Sublimation of 3-chloroisonicotinic acid also led to form I. A higher-temperature polymorph seemed to be possible but remained elusive. Lattice energy and hydrogen bonding strength calculations provided further insight into the stability of the polymorphs. A search of conformational space for the molecule suggested possibly additional polymorphs of this simple compound. The system may be valuable for further solid-state structure–property relationship studies....
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Solid-State Identity of 2-Hydroxynicotinic Acid and Its Polymorphism...

2-Hydroxynicotinic acid (2-HNA), a derivative of nicotinic acid, was found to exist in four polymorphs. In the solid state, 2-HNA is actually present as its tautomer, 2-oxo-1,2-dihydro-3-pyridinecarboxylic acid (2-ODHPCA). Theoretical studies showed that 2-ODHPCA is more energetically favored than 2-HNA.
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Solution Chemistry and Its Implication on Nucleation of Conformational Polymorphs: A Computational Study of Tolfenamic Acid by Explicit Solvation...

Major solution species of tolfenamic acid were simulated in ethanol by molecular dynamics. Interaction energies among solute and solvent molecules were evaluated by hybrid quantum mechanics and molecular mechanics methods. The results underscore the implication by the mutual dependency between intermolecular interaction and molecular conformation on nucleation mechanism.
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Intermolecular Interactions in Organic Crystals: Gaining Insight from Electronic Structure Analysis by Density Functional Theory...

Conceptual density functional theory is exploited to extend the HSAB (hard and soft acids and bases) principle for investigating the locality and regioselectivity of intermolecular interactions in organic crystals. Local hardness and softness, facilitated by Hirshfeld analysis, appear to quantitatively characterize the strength of intermolecular interactions.
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Development and Evaluation of Transferrin-Stabilized Paclitaxel Nanocrystal Formulation...

The aim of the present study was to prepare and evaluate a paclitaxel nanocrystal-based formulation stabilized by serum protein transferrin in a non-covalent manner. Interestingly, the Taxol® formulation showed higher antitumor activity than the paclitaxel-transferrin formulation, achieving a 93.3% tumor inhibition rate 12 days post initial dosing. However, the paclitaxel-transferrin formulation showed a lower level of toxicity, which is indicated by a steady increase in body weight of mice over the treatment period. In comparison, treatment with Taxol® resulted in toxicity issues as body weight decreased. These results suggest the potential benefit of using a serum protein in a non-covalent manner in conjunction with paclitaxel nanocrystals as a promising drug delivery model for anticancer therapy....
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The Effect of Substituents on the Hydrogenation of an Aldehyde Catalyzed by Knölker’s Catalyst...

A concerted hydrogen-transfer route was found to be the most kinetically feasible mechanism for the hydrogenation of aldehyde catalyzed by the Knölker catalyst.
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Pharmacokinetics and Treatment Efficacy of Camptothecin Nanocrystals on Lung Metastasis...

In this study, we further determined the pharmacokinetics of camptothecin nanocrystals in rats and investigated treatment efficacy in mice against metastatic lung tumors. The results show that camptothecin nanocrystals were capable of eliciting greater antimetastatic efficacy and achieve a longer survival time in the murine model compared with camptothecin salt solution. The study suggests that using engineered, solid nanoparticles may be a feasible approach in the treatment of lung cancer and lung metastatic cancer....
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From Competition to Commensuration by Two Major Hydrogen-Bonding Motifs...

Acid−acid and acid−pyridine hydrogen-bonding motifs are two competing synthons encountered frequently in organic crystals. Through crystal engineering, a unique structure reported in this work shows the coexistence of both synthons by a molecule with single carboxyl and pyridine functional groups.
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The Mechanism for the Hydrogenation of Ketones Catalyzed by Knölker’s Iron-Catalyst...

Knölker's iron-based catalysts have some value in “green” transformations given the relatively low toxicity of iron compared to more commonly used precious-metal catalysts. Density functional methods have been used to extensively explore the use of an iron catalyst for hydrogen-transfer processes. Several inner- (with substrate coordination) and outer-sphere mechanisms (with no substrate coordination) were analyzed using a semi-simplified system. An outer-sphere route involving a concerted hydrogen-transfer to the substrate was found to be the most kinetically feasible mechanism, with a free energy barrier of only 10.2 kcal mol−1. This mechanism was then used to explore the complete system at the same theoretical level. The real system had a higher free energy barrier (20.7 kcal mol−1) which is due to the steric effect of the substituent group. All the calculated results were in good agreement with the experimental results....
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Pre-Nucleation Self-Association of Tolfenamic Acid: Solution Chemistry and Implication on Polymorph Formation...

The majority of pharmaceutical products are formulated as solids in the crystalline state. With the potential to exist in different crystalline modifications or polymorphs, each solid form bears its own physical and chemical properties, influencing directly bioavailability and manufacturability of the final dosage form. In view of the importance of crystalline form selection in the drug development process, it is imperative for pharmaceutical scientists to work arduously on various aspects of polymorphism, ranging from fundamental understanding of the phenomenon at the molecular level to practical utilization of a specific crystalline form. One common feature of organic crystals is the existence of distinct molecular conformations in different polymorphic structures, known as conformational polymorphism. Conformational polymorphs are routinely observed in drug development, produced when crystal growth conditions vary. Crystallization from solution involves nucleation and crystal growth, the mechanisms that influence the polymorphic outcome. The embryonic solute aggregate has been recognized to play a critical role in dictating the final crystal structure, and solution conditions are also known to drastically influence the self-association behavior of solute molecules during crystallization, affecting crystal packing of organic molecules. For the crystal growth of conformational polymorphs, changes in molecular conformation not only determine the growth kinetics, but also influence the nature and strength of interactions present in the crystal structures. How conformation and intermolecular interaction affect each other underlines the intricacy and the wonder of crystal growth of the organic. Thus, the overall goal of this research is to provide the fundamental understanding of the extent to which solution conditions influence the molecular conformation in the solid-state of a model drug, tolfenamic acid. By combining experimental studies with advanced computational tools, this dissertation offers novel insights into solution species during pre-nucleation and molecular packing of conformational polymorphs of tolfenamic acid. In-depth understanding of the underlying connection between molecular conformation and crystal packing will help advance the knowledge required for rational control of crystal growth....
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Biodistribution and Bioimaging Studies of Hybrid Paclitaxel Nanocrystals: Lessons Learned of the EPR Effect and Image-Guided Drug Delivery...

Hybrid paclitaxel nanocrystals (200 nm) were produced by crystallization from a solution and tested in animals. The results raise questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging in tracking drug distribution and pharmacokinetics.
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Two Major Pre-Nucleation Species that are Conformationally Distinct and in Equilibrium of Self-Association...

To understand how solution chemistry governs polymorphic formation of organic crystals, solution NMR measurements of tolfenamic acid were conducted in ethanol.
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In Vivo Investigation of Hybrid Paclitaxel Nanocrystals with Dual Fluorescent Probes for Cancer Theranostics...

To develop novel hybrid paclitaxel (PTX) nanocrystals, in which bioactivatable (MMPSense® 750 FAST) and near infrared (Flamma Fluor® FPR-648) fluorophores are physically incorporated, and to evaluate their anticancer efficacy and diagnostic properties in breast cancer xenograft murine model.
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Natural Orbital Fukui Function and Application in Understanding Cycloaddition Reaction Mechanisms...

A new condensed form of the Fukui function, the natural orbital Fukui function (NOFF), is proposed and derived from natural bond orbital occupancy. It is defined as the change in natural bond orbital occupancy upon electronic perturbation (electron addition to, or depletion from, a molecular system). Applying NOFF to a series of cycloaddition reactions (e.g., [4 + 2] and [2 + 1] cycloadditions) illustrates the effectiveness of the concept in interpreting bond breakage and formation mechanisms....
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