No abstract

ABSTRACT-PURPOSE.Comparative drug release kinetics from nanoparticles was carried out using conventional and our novel models with the aim of finding a general model applicable to multi mechanistic release. Theoretical justification for the two best general models was also provided for the first time. METHODS. Ten conventional models and three models developed in our laboratory were applied to release data of 32 drugs from 106 nanoparticle formulations collected from literature. The accuracy of the models was assessed employing mean percent error (E) of each data set, overall mean percent error (OE) and number of Es less than 10 percent. RESULTS. Among the models the novel reciprocal powered time (RPT), Weibull (W) and log-probability (LP) ones produced OE values of 6.47, 6.39 and 6.77, respectively. The OEs of other models were higher than 10%. Also the number of errors less than 10% for the models was 84.9, 80.2 and 78.3 percents of total number of data sets. CONCLUSIONS. Considering the accuracy criteria the reciprocal powered time model could be suggested as a general model for analysis of multi mechanistic drug release from nanoparticles. Also W and LP models were the closest to the suggested model RPT.

Background : Ocular drug delivery is an extremely challenging area due to its restrictive barrier functionalities. Objective : Drug transport via corneal/non-corneal routes involves several intricate biological processes such as drug penetration across the ocular barriers and transfer to the anterior or posterior chambers, thus the influence of these processes on the pharmacotherapy of the eye should be fully addressed. Methods : To pursue the impacts of such impediments in novel drug therapy, recent publications were reviewed regarding advanced strategies such as nanomedicines. Conclusion : The ocular barriers are highly specialized and selectively control the inward/outward traverse of compounds, hence a better understanding of these biological obstacles would provide a platform to advance ophthalmic drug therapy towards specified delivery/targeting with minimal adverse consequences.

The current paper provides an overview of current knowledge on the structure and function of the eye. It describes in depth the different parts of the eye that are involved in the ocular manifestations seen in the mucopolysaccharidoses (MPS). The MPS are a group of rare inheritable lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) in cells and tissues all over the body, leading to widespread tissue and organ dysfunction. GAGs also tend to accumulate in several tissues of the eye, leading to various ocular manifestations affecting both the anterior (cornea, conjunctiva) and the posterior parts (retina, sclera, optic nerve) of the eye.

Of the non-viral vectors, cationic lipid (CL) formulations are the most widely studied for the delivery of genes, antisense oligonucleotides and gene silencing nucleic acids such as small interfering RNAs. However, little is known about the impact of these delivery systems on global gene expression in target cells. In an attempt to study the geno-compatibility of CL formulations in target cells, we have used microarrays to examine the effect of Lipofectin and Oligofectamine on the gene expression profiles of human A431 epithelial cells. Using the manufacturer's recommended CL concentrations routinely used for gene delivery, cDNA microarray expression profiling revealed marked changes in the expression of several genes for both Lipofectin- and Oligofectamine-treated cells. Data from the 200 spot arrays housing 160 different genes indicated that Lipofectin or Oligofectamine treatment of A431 cells resulted in more than 2-fold altered expression of 10 and 27 genes, respectively. The downstream functional consequences of CL-induced gene expression alterations led to an increased tendency of cells to enter early apoptosis as assessed by annexin V-FITC flow cytometry analyses. This effect was greater for Oligofectamine than Lipofectin. Observed gene expression changes were not sufficient to induce any significant DNA damage as assessed by single cell gel electrophoresis (COMET) assay. These data highlight the fact that inadvertent gene expression changes can be induced by the delivery formulation alone and that these may, ultimately, have important safety implications for the use of these non-viral vectors in gene-based therapies. Also, the induced non-target gene changes should be taken into consideration in gene therapy or gene silencing experiments using CL formulations where they may potentially mask or interfere with the desired genotype and/or phenotype end-points.

Introduction: Desired clinical outcome of pharmacotherapy of brain diseases largely depends upon the safe drug delivery into the brain parenchyma. However, due to the robust blockade function of the blood-brain barrier (BBB), drug transport into the brain is selectively controlled by the BBB formed by brain capillary endothelial cells and supported by astrocytes and pericytes. Methods: In the current study, we have reviewed the most recent literature on the subject to provide an insight upon the role and impacts of BBB on brain drug delivery and targeting. Results: All drugs, either small molecules or macromolecules, designated to treat brain diseases must adequately cross the BBB to provide their therapeutic properties on biological targets within the central nervous system (CNS). However, most of these pharmaceuticals do not sufficiently penetrate into CNS, failing to meet the intended therapeutic outcomes. Most lipophilic drugs capable of penetrating BBB are prone to the efflux functionality of BBB. In contrast, all hydrophilic drugs are facing severe infiltration blockage imposed by the tight cellular junctions of the BBB. Hence, a number of strategies have been devised to improve the efficiency of brain drug delivery and targeted therapy of CNS disorders using multimodal nanosystems (NSs). Conclusions: In order to improve the therapeutic outcomes of CNS drug transfer and targeted delivery, the discriminatory permeability of BBB needs to be taken under control. The carrier-mediated transport machineries of brain capillary endothelial cells (BCECs) can be exploited for the discovery, development and delivery of small molecules into the brain. Further, the receptor-mediated transport systems can be recruited for the delivery of macromolecular biologics and multimodal NSs into the brain.

No abstract

Polypropylenimine (PPI) dendrimers appear attractive non-viral vectors for the delivery of genes, antisense oligonucleotides, and small interfering RNA (siRNA). However, the effects of these synthetic gene delivery vectors on global gene expression are poorly understood. Here we have examined the toxicogenomics of generation 2 (DAB-8) and generation 3 (DAB-16) PPI dendrimers in two human cell lines. At concentrations and treatment protocols routinely used for gene and oligonucleotide transfection, PPI dendrimers alone elicited marked changes in endogenous gene expression in A431 epithelial cells. The extent of PPI-induced gene changes appeared to be dependent on the dendrimer generation as the number of genes affected was greater with G3 compared to G2 PPI dendrimers in A431 cells. The signature of DAB16-induced gene changes in A549 cells was different to those elicited in A431 cells implying a strong dependence on cell type. The DAB-16 polymer complexed with DNA (dendriplexes) also elicited marked gene expression changes in A549 cells but with a signature that was different from the polymer alone implying that dendriplexes are "recognised" by cells as chemical entities that are distinct from the polymer alone. Alterations in expression of a variety of gene ontologies were observed including those involved in defence responses, cell proliferation and apoptosis. Although there was a tendency for increased DNA damage in cells treated with DAB16 alone or its DNA dendriplexes as detected by the COMET assay, these differences were not statistically significant. These data show for the first time that PPI-dendrimers, separate from their capability as transfection reagents, can intrinsically alter the expression of many endogenous genes that could potentially lead to them exerting multiple biological effects in cells. The impact and consequences of polymer-induced gene changes should guide their rational use as delivery systems for gene-based therapeutics.