Uptake of imatinib-loaded polyelectrolyte complexes by BCR-ABL+ cells: a long-acting drug-delivery strategy for targeting oncoprotein activity

Rationale & aim: Imatinib mesylate (IM), a selective tyrosine kinase inhibitor of the oncoprotein BCR-ABL, is the 'gold standard' for patients with chronic myeloid leukemia (CML) but the drug does not eliminate CML stem cells, leading to disease relapse on drug discontinuation. At present, much effort is focused on delivery carriers that can increase the intracellular retention and antileukemic impact of IM. We previously validated IM-loaded polyelectrolyte microcapsules as effective purging agents to eradicate BCR-ABL(+) cells from CML patient autografts. The aim is to develop controlled release carriers that can increase the intracellular retention and functionality of IM in leukemia cells. Materials & methods: Herein, novel polyelectrolyte complexes were used as model carriers for IM in a CML cell line (KU812) and CD34(+) cells freshly isolated from patients. Results & discussion: Polyelectrolyte complexes promoted a long-acting BCR-ABL kinase inactivation that was necessary to promote apoptosis at approximately twofold lower intracellular IM dose compared with the microscale formulation polyelectrolyte microcapsules. Conclusion: IM-loaded polyelectrolyte complexes can be used as more efficient delivery devices for overcoming drug resistance of BCR-ABL(+) leukemic cells. Original submitted 26 September 2012; Revised submitted 17 July 2013

Cell Uptake and Validation of Novel PECs for Biomedical Applications

This pilot study provides the proof of principle for biomedical application of novel polyelectrolyte complexes (PECs) obtained via electrostatic interactions between dextran sulphate (DXS) and poly(allylamine hydrochloride) (PAH). Scanning electron microscopy (SEM) and atomic force microscopy (AFM) showed that DXS/PAH polyelectrolyte complexes were Monodispersed with regular rounded-shape features and average diameters of 250 nm at 2 : 1 weight ratios of DXS/PAH. Fluorescently labelled DXS and fluorescein-isothiocyanate- (FITC-)conjugate DXS were used to follow cell uptake efficiency of PECs and biodegradability of their enzymatically degradable DXS-layers by using confocal laser scanning microscopy (CLSM). Moreover, quantitative MTT and Trypan Blue assays were employed to validate PECs as feasible and safe nanoscaled carriers at single-cell level without adverse effects on metabolism and viability

Therapeutic PCL scaffold for reparation of resected osteosarcoma defect

Abstract Osteosarcomas are highly malignant tumors, which develop rapid growth and local infiltration, inducing metastases that spread primarily in the lung. Treatment of these tumors is mainly based on pre- and post-operative chemotherapy and surgery of the primary tumor. Surgical resection though, generates bone defects. Reparation of these weaknesses presents formidable challenges to orthopedic surgery. Medicine regenerative grafts that act as both tumor therapy with constant local drug delivery and tissue regeneration may provide a new prospect to address this need. These implants can provide sustained drug release at the cancer area, decreasing systemic second effects such as inflammation, and a filling of the resected tissues with regenerative biomaterials. In this study microporous poly-ε-caprolactone (PCL) scaffolds have been developed for sustained local release of anti-inflammatory drug dexamethasone (DXM), used as drug model, in cancer medicine regenerative field. The microporous PCL matrix of the scaffolds supported the attachment, proliferation and osteogenic differentiation of osteoblast-like cells, while the polyelectrolyte multilayers, anchored to the inner pore surfaces, sustained locally DXM release. These microporous scaffolds demonstrate the ability to deliver DXM as a localized tumor therapy and to promote proliferation and differentiation of osteoblast-like cells in vitro

Capsid-like biodegradable poly-glycolic acid nanoparticles for a long-time release of nucleic acid molecules

Gene therapy can be described as the direct transfer of genetic material to cells or tissue for the treatment of inherited and acquired diseases. Viral vectors have long been proven to be the most efficient and stable vectors for transgene delivery into the cell, but they still have some safety issues. Non-viral nanosystems can overcome these safety problems and limitations of viral vectors. FDA-approved polymers are particularly attractive for gene delivery applications. Here, sustained release of plasmid DNA encoding the EGFP protein, used as a model, showed efficient delivery through new capsid-like biodegradable polyglycolic acid (PGA) nanoparticles (NPs). PGA NPs showed a mean size of 135 nm, with a polyhedron structure. Prior to loading into the PGA NPs, the pT7-EGFP plasmid was complexed with pH- and enzyme-responsive polycation polymers in order to guarantee high loading, stability, and controlled plasmid release over time. Our PGA NPs are hemocompatible, non-cytotoxic and have the ability to protect the gene cargo from DNase and serum action. Further, our PGA NPs exhibited a controlled and sustained transfection of cells that grow in suspension (human T lymphocytes, Jurkat) and adherent cell lines (human neuroblastoma cells, SH-SY5Y, and human cervix carcinoma cells, HeLa), with respect to transfection with commercial Lipofectamine 3000. In addition, our PGA NPs showed the ability to penetrate into 3D neurospheres, allowing transfection of inner cells. Our capsid-like NPs, thanks to their properties of biocompatibility, biodegradability, hemocompatibility, and sustained plasmid release, can be used as an efficient tool for transfection to overcome the problems of viral vectors

Drug Prescription and Delirium in Older Inpatients: Results From the Nationwide Multicenter Italian Delirium Day 2015-2016

Objective: This study aimed to evaluate the association between polypharmacy and delirium, the association of specific drug categories with delirium, and the differences in drug-delirium association between medical and surgical units and according to dementia diagnosis. Methods: Data were collected during 2 waves of Delirium Day, a multicenter delirium prevalence study including patients (aged 65 years or older) admitted to acute and long-term care wards in Italy (2015-2016); in this study, only patients enrolled in acute hospital wards were selected (n = 4,133). Delirium was assessed according to score on the 4 "A's" Test. Prescriptions were classified by main drug categories; polypharmacy was defined as a prescription of drugs from 5 or more classes. Results: Of 4,133 participants, 969 (23.4%) had delirium. The general prevalence of polypharmacy was higher in patients with delirium (67.6% vs 63.0%, P =.009) but varied according to clinical settings. After adjustment for confounders, polypharmacy was associated with delirium only in patients admitted to surgical units (OR = 2.9; 95% CI, 1.4-6.1). Insulin, antibiotics, antiepileptics, antipsychotics, and atypical antidepressants were associated with delirium, whereas statins and angiotensin receptor blockers exhibited an inverse association. A stronger association was seen between typical and atypical antipsychotics and delirium in subjects free from dementia compared to individuals with dementia (typical: OR = 4.31; 95% CI, 2.94-6.31 without dementia vs OR = 1.64; 95% CI, 1.19-2.26 with dementia; atypical: OR = 5.32; 95% CI, 3.44-8.22 without dementia vs OR = 1.74; 95% CI, 1.26-2.40 with dementia). The absence of antipsychotics among the prescribed drugs was inversely associated with delirium in the whole sample and in both of the hospital settings, but only in patients without dementia. Conclusions: Polypharmacy is significantly associated with delirium only in surgical units, raising the issue of the relevance of medication review in different clinical settings. Specific drug classes are associated with delirium depending on the clinical setting and dementia diagnosis, suggesting the need to further explore this relationship