Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects.

Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis.

Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling.

With this issue of the Journal of Pharmaceutical Sciences, we celebrate the nearly 6 decades of contributions to mechanistic-based modeling and computational pharmaceutical sciences. Along with its predecessor, The Journal of the American Pharmaceutical Association: Scientific Edition first published in 1911, JPharmSci has been a leader in the advancement of pharmaceutical sciences beginning with its inaugural edition in 1961. As one of the first scientific journals focusing on pharmaceutical sciences, JPharmSci has established a reputation for publishing high-quality research articles using computational methods and mechanism-based modeling.

Effects of Molecular Interactions on Miscibility and Mobility of Ibuprofen in Amorphous Solid Dispersions With Various Polymers.

Hydrogen bonds (HBs) in amorphous solid dispersions may influence physical stability through effects on both drug miscibility and mobility. Amorphous solid dispersions containing the HB-donor ibuprofen (IBP) alone or with one of four model polymers (poly(vinyl pyrrolidone) [PVP], poly(vinyl pyrrolidone/vinyl acetate) [PVP/VA], poly(vinyl acetate) [PVA], or polystyrene [PST]) were monitored by molecular dynamics simulation. HB distributions and contributions of electrostatic, van der Waals, and internal interactions to miscibility and mobility were analyzed versus drug concentration.

Predicting Solubility/Miscibility in Amorphous Dispersions: It Is Time to Move Beyond Regular Solution Theories.

The evolving challenges associated with the development of poorly soluble drug molecules have been met with major advances in drug solubilization. In particular, amorphous solid dispersion technology is becoming an increasingly important option to enhance oral bioavailability by creating prolonged drug supersaturation to maximize the driving force for intestinal absorption. A primary concern in the development of amorphous solid dispersions is their physical stability, leading to increasing interest in predictive methodologies to assess the propensity for drug crystallization under various storage conditions.

Equilibrium solubility measurement of compounds with low dissolution rate by Higuchi's Facilitated Dissolution Method. A validation study.

Incubation time plays a critical role in the accurate measurement of equilibrium solubility of compounds. Substances which dissolve very slowly generally need long incubation times (days or weeks) to reach equilibrium. However, long times may pose several problems, such as decomposition of solute, molding of buffer, and drifting of pH.

Ion-Pairing Contribution to the Liposomal Transport of Topotecan as Revealed by Mechanistic Modeling.

Actively loaded liposomal formulations of anticancer agents have been widely explored due to their high drug encapsulation efficiencies and prolonged drug retention. Mathematical models to predict and optimize drug loading and release kinetics from these nanoparticle formulations would be useful in their development and may allow researchers to tune release profiles. Such models must account for the driving forces as influenced by the physicochemical properties of the drug and the microenvironment, and the liposomal barrier properties.

Molecular Dynamics Simulation of Amorphous Hydroxypropylmethylcellulose and Its Mixtures With Felodipine and Water.

Understanding drug-polymer molecular interactions, their miscibility, supersaturation potential, and the effects of water uptake may be invaluable for selecting amorphous polymer dispersions that can maximize the oral bioavailability of poorly water-soluble drugs. Molecular dynamics simulations were performed using a model for hydroxypropylmethylcellulose (HPMC) resembling the substitution patterns found experimentally. HPMC at low and high water contents (0.

Hydrogen Bonding Interactions in Amorphous Indomethacin and Its Amorphous Solid Dispersions with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl acetate) Studied Using (13)C Solid-State NMR.

Hydrogen bonding interactions in amorphous indomethacin and amorphous solid dispersions of indomethacin with poly(vinylpyrrolidone), or PVP, and poly(vinylpyrrolidone-co-vinyl acetate), or PVP/VA, were investigated quantitatively using solid-state NMR spectroscopy. Indomethacin that was (13)C isotopically labeled at the carboxylic acid carbon was used to selectively analyze the carbonyl region of the spectrum. Deconvolution of the carboxylic acid carbon peak revealed that 59% of amorphous indomethacin molecules were hydrogen bonded through carboxylic acid cyclic dimers, 15% were in disordered carboxylic acid chains, 19% were hydrogen bonded through carboxylic acid and amide interactions, and the remaining 7% were free of hydrogen bonds.

An in vitro assessment of liposomal topotecan simulating metronomic chemotherapy in combination with radiation in tumor-endothelial spheroids.

Low dose metronomic chemotherapy (LDMC) refers to prolonged administration of low dose chemotherapy designed to minimize toxicity and target the tumor endothelium, causing tumor growth inhibition. Topotecan (TPT) when administered at its maximum tolerated dose (MTD) is often associated with systemic hematological toxicities. Liposomal encapsulation of TPT enhances efficacy by shielding it from systemic clearance, allowing greater uptake and extended tissue exposure in tumors.

Mechanistic model and analysis of doxorubicin release from liposomal formulations.

Reliable and predictive models of drug release kinetics in vitro and in vivo are still lacking for liposomal formulations. Developing robust, predictive release models requires systematic, quantitative characterization of these complex drug delivery systems with respect to the physicochemical properties governing the driving force for release. These models must also incorporate changes in release due to the dissolution media and methods employed to monitor release.

Adsorption of Polyvinylpyrrolidone and its Impact on Maintenance of Aqueous Supersaturation of Indomethacin via Crystal Growth Inhibition.

This study explored the adsorption and crystal growth inhibitory effects of polyvinylpyrrolidone (PVP) on indomethacin crystals in an aqueous medium. A solution depletion method was used to construct adsorption isotherms of PVPs with different molecular weights and N-vinylpyrrolidone onto indomethacin crystals. The affinity for and extent of maximum adsorption of PVP on indomethacin crystals were significantly higher than that of N-vinylpyrrolidone, which was attributed to cooperative interactions between PVP and the surface of indomethacin.

Determination of key parameters for a mechanism-based model to predict Doxorubicin release from actively loaded liposomes.

Despite extensive study of liposomal drug formulations, reliable predictive models of release kinetics in vitro and in vivo are still lacking. Progress in the development of robust, predictive release models has been hindered by a lack of systematic, quantitative characterization of these complex drug delivery systems with respect to the myriad of factors that may influence drug release kinetics and the wide range of dissolution media/methods employed to monitor release. In this paper, the key processes and parameters needed to develop a complete mechanism-based model for doxorubicin release from actively loaded liposomal formulations resembling Doxil(®) are determined.

Insights into accelerated liposomal release of topotecan in plasma monitored by a non-invasive fluorescence spectroscopic method.

A non-invasive fluorescence method was developed to monitor liposomal release kinetics of the anticancer agent topotecan (TPT) in physiological fluids and subsequently used to explore the cause of accelerated release in plasma. Analyses of fluorescence excitation spectra confirmed that unencapsulated TPT exhibits a red shift in its spectrum as pH is increased. This property was used to monitor TPT release from actively loaded liposomal formulations having a low intravesicular pH.

Release, partitioning, and conjugation stability of doxorubicin in polymer micelles determined by mechanistic modeling.

Purpose: To better understand the mechanistic parameters that govern drug release from polymer micelles with acid-labile linkers.

Methods: A mathematical model was developed to describe drug release from block copolymer micelles composed of a poly(ethylene glycol) shell and a poly(aspartate) core, modified with drug binding linkers for pH-controlled release [hydrazide (HYD), aminobenzoate-hydrazide (ABZ), or glycine-hydrazide (GLY)]. Doxorubicin (Dox) was conjugated to the block copolymers through acid-labile hydrazone bonds.

Molecular dynamics simulation of amorphous hydroxypropyl-methylcellulose acetate succinate (HPMCAS): polymer model development, water distribution, and plasticization.

Molecular models for HPMCAS polymer have been developed for molecular dynamics (MD) simulation that attempt to mimic the complex substitution patterns in HPMCAS observed experimentally. These molecular models were utilized to create amorphous HPMCAS solids by cooling of the polymeric melts at different water contents to explore the influence of water on molecular mobility, which plays a critical role in stability and drug release from HPMCAS-based solid matrices. The densities found for the simulated amorphous HPMCAS were 1.

Effect of precipitation inhibitors on indomethacin supersaturation maintenance: mechanisms and modeling.

This study quantitatively explores the mechanisms underpinning the effects of model pharmaceutical polymeric precipitation inhibitors (PPIs) on the crystal growth and, in turn, maintenance of supersaturation of indomethacin, a model poorly water-soluble drug. A recently developed second-derivative UV spectroscopy method and a first-order empirical crystal growth model were used to determine indomethacin crystal growth rates in the presence of model PPIs. All three model PPIs including HP-β-CD, PVP, and HPMC inhibited indomethacin crystal growth at both high and low degrees of supersaturation (S).

Dynamic, nonsink method for the simultaneous determination of drug permeability and binding coefficients in liposomes.

Drug release from liposomal formulations is governed by a complex interplay of kinetic (i.e., drug permeability) and thermodynamic factors (i.

Water uptake, distribution, and mobility in amorphous poly(D,L-lactide) by molecular dynamics simulation.

An explicit all-atom computational model for amorphous poly(lactide) (PLA) was developed. Molecular dynamics simulations of PLA glasses were conducted to explore various molecular interactions and predict certain physical properties. The density of a newly formed PLA glass aged for 100 ns at 298 K was 1.

The role of pH and ring-opening hydrolysis kinetics on liposomal release of topotecan.

The use of liposomal delivery systems for the treatment of cancer has been extensively researched because of their passive targeting to the vasculature of solid tumors. While their potential to provide prolonged retention and high drug encapsulation is desirable for anticancer agents, a mechanistic understanding is required to optimize and design liposomal drug delivery systems capable of controllable release tailored to tumor type and patient. Topotecan (TPT) is a topoisomerase I inhibitor that undergoes reversible, pH-sensitive ring-opening hydrolysis.

Bilayer composition, temperature, speciation effects and the role of bilayer chain ordering on partitioning of dexamethasone and its 21-phosphate.

Purpose: Models to predict membrane-water partition coefficients (Kp) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical state, and pH.

Methods: DMPC:mPEG DMPE, DPPC:mPEG DPPE, and DSPC:mPEG DSPE (95:5 mol%) liposomes were prepared by thin film hydration.

Determination of drug release kinetics from nanoparticles: overcoming pitfalls of the dynamic dialysis method.

Dynamic dialysis is one of the most common methods for the determination of release kinetics from nanoparticle drug delivery systems. Drug appearance in the "sink" receiver compartment is a consequence of release from the nanoparticles into the dialysis chamber followed by diffusion across the dialysis membrane. This dual barrier nature inherent in the method complicates data interpretation and may lead to incorrect conclusions regarding nanoparticle release half-lives.

A shift in energy metabolism anticipates the onset of sarcopenia in rhesus monkeys.

Age-associated skeletal muscle mass loss curtails quality of life and may contribute to defects in metabolic homeostasis in older persons. The onset of sarcopenia occurs in middle age in rhesus macaques although the trigger has yet to be identified. Here, we show that a shift in metabolism occurs in advance of the onset of sarcopenia in rhesus vastus lateralis.

Maintenance of supersaturation II: indomethacin crystal growth kinetics versus degree of supersaturation.

This study compares the kinetics of crystal growth of indomethacin from supersaturated suspensions at varying degrees of supersaturation (2 ≤ S ≥ 9) in the presence of seed crystals of the γ-form of indomethacin, the lowest energy polymorph. At high S (6 ≤ S ≥ 9), the crystal growth was first order with rate coefficients (kG ) that were nearly constant and consistent with the value predicted for bulk-diffusion control. At lower S (<6), kG values were significantly smaller, decreasing approximately linearly with a decrease in S.

Molecular dynamics simulation of amorphous indomethacin-poly(vinylpyrrolidone) glasses: solubility and hydrogen bonding interactions.

Amorphous drug dispersions are frequently employed to enhance solubility and dissolution of poorly water-soluble drugs and thereby increase their oral bioavailability. Because these systems are metastable, phase separation of the amorphous components and subsequent drug crystallization may occur during storage. Computational methods to determine the likelihood of these events would be very valuable, if their reliability could be validated.

Quantification of trans-2,6-difluoro-4'-N,N-dimethylaminostilbene in rat plasma: application to a pharmacokinetic study.

trans-2,6-Difluoro-4'-N,N-dimethylaminostilbene (DFS), a synthetic stilbene, displayed potent pre-clinical anti-cancer activities exceeding that observed for naturally occurring resveratrol. In this study, a simple and sensitive HPLC method was developed and validated to quantify DFS in rat plasma. The lower limit of quantification (LLOQ) was 5 ng/ml.