Cell penetrating peptides in ocular drug delivery: State of the art.

Despite the increasing number of effective therapeutics for eye diseases, their treatment is still challenging due to the presence of effective barriers protecting eye tissues. Cell Penetrating Peptides (CPPs), synthetic and natural short amino acid sequences able to cross cellular membrane thanks to a transduction domain, have been proposed as possible enhancing strategies for ophthalmic delivery. In this review, a general description of CPPs classes, design approaches and proposed cellular uptake mechanisms will be provided to the reader as an introduction to ocular CPPs application, together with an overview of the main problems related to ocular administration. The results obtained with CPPs for the treatment of anterior and posterior segment eye diseases will be then introduced, with a focus on non-invasive or minimally invasive administration, shifting from CPPs capability to obtain intracellular delivery to their ability to cross biological barriers. The problems related to in vitro, ex vivo and in vivo models used to investigate CPPs mediated ocular delivery will be also addressed together with potential ocular toxicity issues.

New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53.

BACKGROUND: p53 is a transcription factor with tumour suppressor properties, which is able to induce mitochondrial apoptosis independently of its transcriptional activity. We recently synthesised two new compounds (ISA27 and SM13), which block p53-MDM2 interaction and induce apoptosis in p53 wild-type (WT) tumour cells. The aim of this study was to verify the effectiveness of these compounds in tumours carrying a mutated form of p53 gene with no transcriptional activity. METHODS: In vitro we evaluated the effectiveness of our compounds in cancer cell lines carrying WT, mutated and null p53 gene. In vivo study was performed in Balb/c nude mice and the mitochondrial-dependent apoptotic signalling was evaluated by western blot. RESULTS: Both ISA27 and SM13 reduced cell proliferation and induced apoptosis in vitro in cells carrying either p53 WT or mutated gene, suggesting that its effect is independent from p53 transcriptional activity. On the contrary, SM13 had no effect in a p53 null cell line. In vivo, ISA27 and SM13 induced cancer cell death in a dose-dependent manner through the activation of the mitochondrial-dependent death signalling in p53-mutated cells. In vivo, SM13 reduced tumour growth. CONCLUSIONS: Our study proposes SM13 as anticancer compound to use for the treatment of p53-dependent tumours, even in the absence of p53 transcriptional activity.