**4. Chemical methods**

Currently, only three commercial pro-drugs are licensed for topical PDT use: 5-aminolevulinic acid (ALA, Levulan®), methyl aminolevulinate (MAL, Metvix®), and the nanoemulsion containing ALA (nc-ALA, Ameluz®) [53]. Besides the physical methods to improve the delivery of these drugs, there are chemical approaches that have been explored for drug formulation modifications, and the use of agents that modify the heme cycle or enhance PpIX formation. Thus, the chemical methods to improve PpIX availability mostly treat on the effects over these substances.

#### **4.1 Prodrugs**

To enhance ALA penetration through the SC, other prodrugs with longer, more lipophilic carbon chains have been explored [54]. In this context, MAL – which has a methyl group associated with the ALA molecule – already presented more lipophilicity properties and increased selectivity.

The use of even more carbon chains has been tested, such as ethyl-ALA, propyl-ALA, butyl-ALA. The main concern about their use is related to the numerous chemical steps necessary to perform the esterification processes for those molecules [55]. The pro-drug hexyl-ALA has been tested in pre-clinical studies [18, 56]. A pilot clinical trial reported that these molecules presented a greater penetration with lower concentrations compared with ALA or MAL which could reduce adverse reactions and decreases the PDT costs [57]. Despite that, ALA and its ester MAL are still the most commonly chosen and investigated molecules to be used as PpIX pro-drugs for PDT.

One aspect explored in literature for the enhancement of the PpIX prodrugs in cells is the addition of iron chelators. Iron has a crucial role in cells within the heme synthetic route, bound to PpIX molecules to form hemoglobin, thus hindering this process preserves the number of available PpIX molecules within cells. Different chelators have been investigated so far as and, such as desferrioxamine, thiosemicarbazones, pyridoxalisonicotinoyl hydrazone, and di-2-pyridyl-derived iron chelators, among others [58–60]. However, yet thiosemicarbazones have been approved for phase II tests [61], the use of these chelators is still under discussion, due to toxicity versus efficacy issues.

#### **4.2 Differentiation-promoting agents**

In addition to the drug choice, different vehicles such as creams, gels, patch systems, lotions, liposomes, nanoparticles, powders, and microemulsions have been developed to overcome the penetration issue [13].

The commercial creams Levulan® and Metvix® are prepared with 20% w/w and 16% w/w concentration of prodrug, respectively. Both of them have been

*Strategies to Improve Drug Delivery in Topical PDT DOI: http://dx.doi.org/10.5772/intechopen.94374*

widely used with acceptable clearance rates and cosmetic outcomes. Aiming to increase the stability of the cream, the molecule of ALA at 7.8% concentration in a nanoemulsion-based gel has been used to produce the Ameluz® formulation. A multicentric study compared this gel formulation with the Metvix® cream in the treatment of AK, demonstrating similar response and tolerance [62].

A patch is an adhesive system used for topical or systemic drug delivery. For PDT, there is a commercial patch (Alacare®) containing 2 mg of ALA per cm2 . A clinical trial using Alacare® for the PDT treatment of actinic cheilitis (AC) demonstrated high clinical efficacy, good tolerability, and favorable cosmetic effects [63]. However, in the case of thick skin lesions without physical pretreatment, this protocol might be less efficient.

#### **4.3 Nanoformulations**

Nanotechnology has an important role in the pharmaceutical industry for the development of new formulations. Studies are concentrated on obtaining drugs with more solubility, biodistribution, bioavailability, uptake, and excretion, decreasing drugs' toxicity, [64] and there are different vehicles to promote drug delivery by nanostructures.

Nanoparticles (NP) used to be defined as a particle with a size up to 100 nm in any direction [65]. Lucky *et al.* described the nanoparticles used in PDT based on their performed functions or tasks as PSs, PS carriers, and PS energy transducers [66].

Among the several NP possibilities, liposomes are one of the most used for topical PDT applications. Liposomes are vesicles made up of one or more phospholipid bilayers oriented concentrically around an aqueous compartment to act as drug carriers. This nanostructure has been explored for topical PDT to enhance the PS penetration into the skin while decreasing its absorption into systemic circulation. Examples of PSs currently encapsulated in liposomes for topical PDT are ALA, temoporfin (mTHPC, commercially available as Foscan®), and methylene blue. In most studies, liposomal ALA induced a higher PpIX synthesis than free ALA nonencapsulated delivery [67].

Other structures are more commonly used for systemic applications of PDT, such as nanofibers and nanomicelles [68, 69] but they are off the scope of this chapter, yet their results are also promising for PDT application.

#### **4.4 Thermogenic and vasodilating substances**

Thermogenic and vasodilating substances have been reported as promising to favor the permeation of drugs on the skin [70, 71]. In PDT, vasodilation also increases the oxygen supply in the tissue, which can further optimize the effectiveness of the treatment.

A study was carried out investigating the association of the substances: menthol, methyl nicotinate, and ginger associated with ALA and MAL. The association of methyl nicotinate with MAL demonstrated 50% higher PpIX production after three hours of incubation compared with the cream containing only MAL. These preclinical results are promising as a possible strategy for decreasing the DLI and increase the PpIX production in skin lesions [72].

### **5. Conclusion**

This chapter presented several approaches reported in the literature for the improvement of topical PDT outcome. Some of the techniques here presented to address the task of increasing the availability of PS are increasingly being incorporated to PDT protocols, whereas others are very incipient. Yet, the challenge of making PS available is still an open field, plenty of room for further investigation.
