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.

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.

These results suggest that the crosslinked PEG114-VE4-TA4 nanocarrier system is a promising platform for the delivery of hydrophobic anticancer agents.

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.