**1. Introduction**

Yet topical photodynamic therapy (PDT) principle is simple and the technique is full of potential to provide an effective treatment for very common malignant and pre-malignant diseases, achieving satisfactory outcomes for a varied number of lesion types with a single approach is not feasible.

Light delivery is successful depending essentially on the ability to provide the best combination of the most suitable wavelength for the drug of choice and the optical properties of the tissue, which determine if light reaches the extension of tissue necessary and if undesired side effects will show up.

Conversely, characteristics on the photosensitizer (PS) accumulation in target tissues are less dependent on direct control of the therapist than light delivery. Further, PS accumulation also defines the light dose (fluency). Therefore, PS accumulation must be properly dealt with in order to provide enhancement of the efficacy of PDT, and presenting the most relevant aspects reported in the literature concerning the strategies to do so is the scope of this chapter.

Topical PDT has been widely applied as a treatment option for pre-malignant lesions such as actinic keratosis (AK) and also for non-melanoma skin cancer (NMSC) lesions [1] such as basal cell carcinoma (BCC) and Bowen disease (BD). The treatment involves the topical application of a PS precursor, followed by the waiting for the drug light interval (DLI) to promote the PS accumulation into the lesion, after which the localized irradiation takes place. Depending on the protocol, this sequence can be repeated with intervals of one week [2–5] or on the same day [6].

The molecules more commonly used worldwide are the aminolevulinic acid (ALA) and its derivative, methyl aminolevulinate (MAL). Both of them can promote protoporphyrin IX (PpIX) endogenous accumulation in cells. The DLI for these drugs can vary from 1 to 4 hours [7], depending on the protocol treatment chosen for the lesion type.

Being clinical PDT still a very empirical field, and since the protocols choices are decisive in determining the therapy outcome, several strategies, both physical and chemical, have been developed aiming to increase the availability of PS *in loco* to increase topical PDT outcome.
