Delineating the effects of hot-melt extrusion on the performance of a polymeric film using artificial neural networks and an evolutionary algorithm.

The aim of this study was to utilize an artificial neural network (ANN) in conjunction with an evolutionary algorithm to investigate the relationship between hot melt extrusion (HME) process parameters and vaginal film performance. Investigated HME process parameters were: barrel temperature, screw speed, and feed rate. Investigated film performance attributes were: percent dissolution at 30 min, puncture strength, and drug content. An ANN model was successfully developed and validated with a root mean squared error of 0.043 and 0.098 for training and validation, respectively. Of all three assessed process parameters, the model revealed that barrel temperature has a significant impact on film performance. An increase in barrel temperature resulted in increased dissolution and punctures strength and decreased drug content. Additionally, a successful implementation of an evolutionary algorithm was carried out in order to demonstrate the potential applicability of the developed ANN model in film formulation optimization. In this analysis, the values predicted of film performance attributes were within 1% error of the experimental data. The findings of this study provide a quantitative framework to understand the relationship between HME parameters and film performance. This quantitative framework has the potential to be used for film formulation development and optimization.

Impact of a Pharmacist-Led Intervention on 30-Day Readmission and Assessment of Factors Predictive of Readmission in African American Men With Heart Failure.

Heart failure (HF) is responsible for more 30-day readmissions than any other condition. Minorities, particularly African American males (AAM), are at much higher risk for readmission than the general population. In this study, demographic, social, and clinical data were collected from the electronic medical records of 132 AAM patients (control and intervention) admitted with a primary or secondary admission diagnosis of HF. Both groups received guideline-directed therapy for HF. Additionally the intervention group received a pharmacist-led intervention. Data collected from these patients were used to develop and validate a predictive model to evaluate the impact of the pharmacist-led intervention, and identify predictors of readmission in this population. After propensity score matching, the intervention was determined to have a significant impact on readmission, as a significantly smaller proportion of patients in the intervention group were readmitted as compared to the control group (11.5% vs. 42.9%; p = .03). A predictive model for 30-day readmission was developed using K-nearest neighbor (KNN) classification algorithm. The model was able to correctly classify about 71% patients with an AUROC of 0.70. Additionally, the model provided a set of key patient attributes predictive of readmission status. Among these predictive attributes was whether or not a patient received the intervention. A relative risk analysis identified that patients who received the intervention are less likely to be readmitted within 30 days. This study demonstrated the benefit of a pharmacist-led intervention for AAM with HF. Such interventions have the potential to improve quality of life for this patient population.

A novel small-molecule arylsulfonamide causes energetic stress and suppresses breast and lung tumor growth and metastasis.

Neoplastic cells display reprogrammed metabolism due to the heightened energetic demands and the need for biomass synthesis of a growing tumor. Targeting metabolic vulnerabilities is thus an important goal for cancer therapy. Here, we describe a novel small-molecule arylsulfonamide (N-cyclobutyl-N-((2,2-dimethyl-2H-pyrano[3,2-b]pyridin-6-yl)methyl)-3,4-dimethoxybenzenesulfonamide) that exerts potent cytotoxicity and energetic stress on tumor cells while largely sparing non-cancerous human cells. In tumor cells, it stimulates glycolysis and accelerates glucose consumption. Consequently, intracellular ATP levels plummet, triggering activation of AMP-activated protein kinase (AMPK), and diminishing the mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1 (HIF-1) signaling. In orthotopic triple-negative breast cancer and subcutaneous lung cancer mouse models, this arylsulfonamide robustly suppresses primary tumor growth, inhibits the formation of distant metastases to the lung, and extends mouse survival while being very well tolerated. These therapeutic effects are further potentiated by co-administration of 2-deoxy-D-glucose (2-DG), a glucose analog and glycolysis inhibitor. Collectively, our findings provide preclinical proof of concept for the further development of this arylsulfonamide in combination with 2-DG towards cancer treatment.

Combined Delivery of Let-7b MicroRNA and Paclitaxel via Biodegradable Nanoassemblies for the Treatment of KRAS Mutant Cancer.

In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG5K-VE4-DET20 copolymer formed nanoassemblies when mixed with the neutral PEG5K-VE4 copolymer at 1:8 weight ratio, which were investigated as the nanocarriers for combined delivery of paclitaxel and let-7b mimic. We found that the PEG5K-VE4-DET20 nanoassemblies could entrap paclitaxel for an extended period and burst release the drug in the presence of cathepsin B, demonstrating the biodegradability of the copolymers. At N/P ratio of 12:1, the PEG5K-VE4-DET20 nanoassemblies formed stable polyplexes with let-7b mimic, which were efficiently taken up by tumor cells and underwent endosomal escape. In non-small cell lung cancer A549 cells that harbor mutant KRAS, paclitaxel and let-7b mimic-loaded nanoassemblies (N-PTX/let-7b) markedly potentiated the cytotoxicity of paclitaxel, induced apoptosis, and diminished the invasiveness of tumor cells. In mice bearing subcutaneous A549 xenografts, intravenous administration of N-PTX/let-7b retarded tumor growth more efficaciously than Taxol. Our study demonstrates the promise of the PEG5K-VE4-DET20 nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics.

Reduction-responsive crosslinked micellar nanoassemblies for tumor-targeted drug delivery.

PURPOSE: The purpose of the study was to devise and evaluate crosslinked nanoassemblies to achieve enhanced drug delivery to tumors. METHODS: A novel copolymer comprised of polyethylene glycol 5000 (PEG114), Vitamin E (VE) and thioctic acid (TA) with a molar ratio of PEG114:VE:TA at 1:4:4 was synthesized. The resulting PEG114-VE4-TA4 copolymer self-assembled into micelles, which formed polydisulfide crosslinks catalyzed by dithiothreitol. Employing paclitaxel as a model drug, the crosslinked PEG114-VE4-TA4 micelles were characterized for the physicochemical and biological properties. The pharmacokinetics and anticancer efficacy of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles were assessed in a human ovarian cancer xenograft murine model. RESULTS: The crosslinked PEG114-VE4-TA4 micelles demonstrated markedly improved thermodynamic and kinetic stability. The disulfide crosslinks were responsive to the intracellular level of glutathione, which caused rapid disassembly of the micelles and accelerated drug release. Intravenous administration of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles yielded approximately 3-fold and 5-fold higher plasma concentration than the non-crosslinked micelles and Taxol®, respectively, leading to increased drug accumulation in the tumor. Importantly, paclitaxel-loaded crosslinked micelles exerted superior tumor growth repression compared to the non-crosslinked counterparts and Taxol®. CONCLUSIONS: These results suggest that the crosslinked PEG114-VE4-TA4 nanocarrier system is a promising platform for the delivery of hydrophobic anticancer agents.

Enhanced tumor delivery of gemcitabine via PEG-DSPE/TPGS mixed micelles.

Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic, non-small-cell lung, breast, and ovarian cancers. The major deficiencies of current gemcitabine therapy, however, are its rapid metabolic inactivation and narrow therapeutic window. Herein, we employed polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as a delivery system, to improve the pharmacokinetic characteristics of gemcitabine and enhance its antitumor efficacy. By conjugating stearic acid to gemcitabine and subsequently encapsulating stearoyl gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination of gemcitabine was delayed in vitro and in vivo. Importantly, compared to free gemcitabine, GemC18-loaded micelles pronouncedly prolonged the circulation time of gemcitabine and elevated its concentration in the tumor by 3-fold, resulting in superior antitumor efficacy in mice bearing human pancreatic cancer BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS mixed micelles as a nanocarrier system for the delivery of gemcitabine to achieve safer and more efficacious therapeutic outcomes.