## 1 Introduction  
Photodynamic therapy (PDT) is a noninvasive modality that can be used to treat cancers and certain oral and infectious diseases [1; 2]. PDT involves the action of a photosensitizer (PS), oxygen, and light in combination to form reactive oxygen species (ROS) to kill cancer cells. In summary, upon absorption of a photon of light, a PDT sensitizer is promoted from the ground state (S\({}_{0}\)) to the short-lived first excited state (S\({}_{1}\)) and can undergo conversion to the first excited triplet state (T\({}_{1}\)) through intersystem crossing. Subsequently, the energy of the first triplet state can be transferred to the surrounding molecular oxygen (\({}^{3}\)O\({}_{2}\)) to form a reactive species such as singlet oxygen (\({}^{1}\)O\({}_{2}\)), and the sensitizer returns to S\({}_{0}\). This cycle can be repeated multiple times, depending on the photostability of the sensitizer. Studies have shown that the energy gap between T1 and S0 impacts the efficiency of the photosensitizer employed in PDT [3; 4]. The higher the energy difference, the more efficient the energy transfer and the more efficient the sensitizer. The minimum energy difference (\(\Delta\)ES\({}_{0}\)-T\({}_{1}\)) needed between the two states in order for a fluorescent dye to function as a sensitizer (\({}^{1}\)O\({}_{2}\) producer) for PDT is 0.98 eV [5]. In this regard, molecular modeling tools can be used to screen potential photosensitizers for PDT use, by calculating \(\Delta\)ES\({}_{0}\)-T\({}_{1}\). In addition to the efficiency of \({}^{1}\)O\({}_{2}\) production, other factors that may impact cellular-level PDT efficacy include: (1) biodistribution of the sensitizer employed, (2) subcellular localization of sensitizers(i.e., to mitochondria or nuclei) [6; 7], and (3) utilization of 100-200 nm nanoparticles to enhance photosensitizer delivery into cells. Nanoparticles within this size range are large enough to avoid rapid renal clearance and small enough to avoid removal by clearance via the reticuloendothelial system [6; 8; 9]. In the present work, zinc phthalocyanine (ZnPc) was chosen as the bench-mark sensitizer for our PDT studies. This dye-metal complex is from the porphyrin family, characterized by a hetero-aromatic system comprising 18 \(\pi\) bonds. What makes this structure attractive for PDT is its good photostability and relatively long triplet-state lifetime [10]. The higher molar extinction coefficient of ZnPc compared to porphyrin dyes such as protoporphyrin IX is also attractive because it lowers both the dose level required for treatments and the associated side effects [11]. The main shortcoming of ZnPc is its low solubility in aqueous and organic solvents, which limits its utility for PDT. Generally, solubility limitations can also be overcome by the addition of suitable ligands in either of ZnPc's peripheral positions (\(\alpha\), \(\beta\); cf. Figure 1). It is known that the incorporation of alkyl groups can improve lipophilicity, which increases biological tissue distribution and volume of distribution. Incorporation of more or larger alkyl groups often reduces water solubility but occasionally this can increase water solubility through lowering the crystal lattice energy. Comparing branched vs. unbranched alkyl groups, the presence of multiple unbranched alkyl groups can lead to a large lipophilic surface area. Besides increasing the lipophilicity of ZnPc, it is also necessary for these compounds to have water solubility for the purpose of intravenous injection. Specifically, efforts have been made to improve water solubility of ZnPc compounds, through the introduction of hydrophilic groups such as -CO\({}_{2}\)H and -SO\({}_{3}\)H.  
Other attempts to overcome water insolubility have involved methods designed to encapsulate ZnPc into liposome or polymeric nanoparticles. In one study, ZnPc was encapsulated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles having a diameter size of 227 to 450 nm utilizing the emulsion evaporation method [12].