EMT blockage strategies: Targeting Akt dependent mechanisms for breast cancer metastatic behaviour modulation.

Epithelial Mesenchymal Transition (EMT) is an event where epithelial cells acquire mesenchymal-like phenotype. EMT can occur as a physiological phenomenon during tissue development and wound healing, but most importantly, EMT can confer highly invasive properties to epithelial carcinoma cells. The impairment of E-cadherin expression, an essential cell-cell adhesion protein, together with an increase in the expression of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin, characterize the EMT process and are usually correlated with tumor migration, and metastization. A wide range of micro-environmental and intracellular factors regulate tumor development and progression. The dynamic cross-talk between the adhesion-related proteins such as E-cadherin and the EMT-related transcription factors, with special focus on TWIST, will be discussed here, with the aim of finding a suitable biological pathway to be used as potential target for cancer therapy. Emerging concepts such as the role of the PI3K/AKT/TWIST pathway in the regulation of the E-cadherin expression will be highlighted, since it seems to be consistently involved in cells EMT. The well-known efficacy of the RNA interference as a tool to silence the expression of specific proteins has come into focus as a strategy to control different tumor sub-populations. Despite the oligonucleotides enormous sensitivity and low in vivo stability, new (nano)technological solutions are expected to enable RNAi clinical application in cancer therapy.

Biodistribution of lipid nanoparticles: a comparative study of pulmonary versus intravenous administration in rats.

The advent of nanomedicine and increase knowledge on cellular and molecular biology has opened new opportunities on the clinical field. Selective drug targeting and protection of healthy tissues rules the rising interest that is being devoted to drug delivery system strategies, considering that the accurate choice of the carrier molecule will determine the pharmacokinetics and pharmacodynamics of drugs, yielding higher therapeutic efficacy. Despite the improvements in surgery and immunological approaches, tumor staging and cancer therapy remains a challenge, typically because they are ineffective in advanced stages of the disease, but also due to the conventional administration route (intravenous), and consequently the non-specificity of the potentially toxic drugs. The issue currently under the spotlight in drug targeting is the concept of drug delivery systems (DDS) and the impact that is inherent to their selectivity. Moreover, these particulate systems bring forth the possibility of using alternative routes to the conventional intravenous administration. This article reviews the applications of gamma-scintigraphic image technique to evaluate the advances and research on DDS engineering to the pulmonary administration, and the dependency of lung particle removal mechanism on both the administration route and the particulate system characteristic, based on literature data, as well as through the experimental studies performed in our group.

Lymphatic uptake of lipid nanoparticles following endotracheal administration.

A previous publication reported the uptake into the lymphatics of pulmonary administered lipid nanoparticles (LN), after aerosolization and inhalation. In the present study LN clearance from the lungs and lymphatic uptake were further evaluated after endotracheal administration. Nanoparticles prepared with gliceryl behenate were radiolabelled by association to the lipophilic tracer D,L-hexamethylpropylene amine oxime (HMPAO) coupled with 99mTc. Labelling efficiency was 97% and stability in body fluids was demonstrated in vitro. Wistar rats were treated by endotracheal administration and lymphatic uptake was determined upon organ sampling. Endotracheally delivered LN are rapidly eliminated from rat lungs and accumulation in para-aortic, axillary and inguinal lymph nodes starts almost immediately after administration. Translocation of LN across the lung mucosa and their uptake into the lymphatics demonstrate their usefulness as potential drug carriers for lung cancer therapy, as well as for immunization purposes.