**2. Drug delivery strategies**

Considering the light attenuation by tissue due to the presence of chromophores and to scattering, the wavelength range preferable for PDT is about 650–850 nm, which is known as the 'optical window' for PDT [8]. Once the light penetration can be handled to reach the whole lesion, the remaining concern is to optimize the drug permeation to improve treatment rate success, especially obtaining the improvement of the response of thicker lesions, which shall increase the possibility to make PDT the treatment of choice for those lesions.

Human skin is a complex organ structured to protect the body. The skin layers organization and constitution, as represented in **Figure 1** (*stratum corneum* (SC), epidermis, dermis, and hypodermis) confer its properties of tensile strength and mechanical resistance [9]. For this reason, skin becomes a barrier for the permeation of precursors, which implies an important limitation of topical PDT, with a direct influence on the incubation time and treatment success. The SC is the skin's outermost layer, and it is considered the main barrier to percutaneous absorption.

Although PpIX precursors have a low molecular weight, the PpIX accumulation after as much as three hours of incubation using exclusively topical application of the cream achieves depths up to 1–2 mm. However, the tissue heterogeneities imply in a non-uniform distribution of the produced PpIX, and portions of the lesion do not produce sufficient PS, impairing the treatment effectiveness [10, 11].

#### **Figure 1.**

*Representation of human skin layers. Both physical and chemical methods can be explored to overcome the skin barriers and improve topical drug delivery.*

Several techniques have been developed to overcome skin barriers and provide penetration enhancement. There are physical and chemical pretreatment strategies to improve drug delivery that can facilitate precursor permeation through skin and into the lesions, allowing PpIX to be produced in deeper layers and also to be distributed more homogeneously.
