Keratinocyte carcinomas (KC) are the most common malignant human neoplasms. Although surgery and destructive approaches are first-line treatments, topical therapies are commonly used. Due to limited uptake of topical agents across the skin barrier, clearance rates are often sub-optimal. In pre-clinical investigations, ablative fractional laser (AFL)-assisted drug delivery has demonstrated improved uptake of topical drugs commonly used to treat KC. In 22 clinical trials, the effect of AFL-assisted treatments has been investigated for actinic keratosis (AK; n = 14), Bowen's disease (BD; n = 5), squamous cell carcinoma (n = 1), and basal cell carcinoma (n = 7). The most substantial evidence currently exists for AFL-assisted photodynamic therapy for the treatment of AK and BD. AFL improved 12-months follow-up clearance rates of photodynamic therapy from 45.0–51.0% to 78.5–84.8% for AK and from 50.0–55.3% to 87.0–87.5% for BD. AFL-assisted pharmacological therapy is a promising tool for optimizing topical treatments of KC and its precursor lesions. Future developments include AFL-assisted immune activation, changing drug administration route of systemic therapies, and utilizing drug chemo-combinations.

In this two parts review we present an up-do-date description of different imaging methods available to map the localization of drugs on skin as a complement of established ex-vivo absorption studies. This first part deals with invasive methods and are grouped in two classes according to their underlying principles: i) methods using radioactivity such as autoradiography and ii) mass spectrometry methods such as MALDI and SIMS. For each method, a description of the principle is given along with example applications of imaging and quantifying drug delivery in human skin. Thanks to these techniques a better assessment of the fate of drugs is obtained, its localization on a particular skin structure, its potential accumulation, etc. A critical comparison in terms of capabilities, sensibility and practical applicability is included that will help the reader to select the most appropriate technique depending on the particular problem to be solved.

It has long been known that the generation of reactive oxygen species (ROS) is a major cause of injury after ischemia/reperfusion. More recently it has emerged that the predominant source of these ROS are the mitochondria, which are specifically damaged during prolonged ischemic episodes. Several strategies have been tested to attenuate mitochondrial damage and reperfusion ROS. Most successful has been ischemic preconditioning, a procedure in which repetitive short periods of ischemia and reperfusion reduce injury from a subsequent prolonged ischemia and reperfusion. Recently, ischemic postconditioning, whereby reperfusion after prolonged ischemia is repetitively interrupted for a short period, has also been shown to equally protect as ischemic preconditioning. Both procedures activate the same down-stream kinase pathways that minimize apoptosis and tissue damage. Endothelial nitric oxide synthase is a target of these kinase pathways and nitric oxide (NO) administration can mimic its protective effect. However, the optimal NO dose is difficult to determine and excess NO levels have been shown to be detrimental. A recently described physiological storage pool of NO, nitrite, has been shown to be a potent mediator of cytoprotection after ischemia/reperfusion that mechanistically reduces mitochondrial ROS generation at reperfusion. Here, we describe the sources, bioactivaton, and mechanisms of action of nitrite and discuss the potential of this simple anion as a therapeutic to protect against ischemia/reperfusion injury.

Photodynamic therapy (PDT), which involves systemic administration of photosensitizers (PSs) followed by local photoillumination, is a promising method for the treatment of solid tumors and other diseases. Recently, considerable efforts have been devoted to the development of nanocarriers for the PS delivery with the aim of avoiding non-specific phototoxicity to normal tissues such as the skin. Here, we discuss the biological significance of the use of nanocarrier-encapsulated PSs in PDT. Also, we report our recent achievements on the development of dendrimer photosensitizer-loaded micelles as nanocarriers for PS delivery. We found that our nanocarriers greatly enhanced the PDT efficacy in vitro and in vivo, and also significantly reduced the skin phototoxicity. These results indicate the importance of a development strategy for nanocarriers and their great potential for clinical use. In addition, this review discusses the development of nanocarriers for emerging PDT-related technologies such as photodynamic diagnosis (PDD) and photochemical internalization (PCI).