**1. Introduction**

Nanoparticles based on conductive polymers have emerged as a promising material for applications in targeted photothermal medical therapies [1,2]. In this therapy, nanoparticles could be placed at different tissue-penetration depths and convert irradiated energy from the near-infrared (NIR) region into thermal energy [3,4]. Several conductive polymers, such as polyaniline, polypyrrole, etc., could be used for photothermal therapies due to their biocompatibility and excellent photothermal conversion performance [5–8]. Within these conductive polymers, polypyrrole is one of the most widely used for developing nanomaterials for biomedical applications [9]. Furthermore, polypyrrole-based nanostructures are being studied because of their strong absorption in the NIR region (λ = 700–1200 nm) [2]. For instance, polypyrrole nanoparticles (PPN) could generate heat suitable to ablate cancer cells through their effective photon-to-thermal energy transfer [10–12]. Moreover, PPN could be used singly or combined with chemotherapy agents [11].

Furthermore, PPN shows high specificity and excellent anti-cancer effects in cellular and animal experiments [13]. The elevated temperature could thus target cancer cells while avoiding significant side effects on normal cells. The latter is based on the higher heat tolerance of normal cells compared to cancer cells [14]. However, the photothermal

**Citation:** Peñuñuri-Miranda, O.; Olivas-Martinez, M.; Ibarra-Espinoza, J.A.; Rodríguez-Córdova, R.J.; Hernández-Giottonini, K.Y.; Fernández-Quiroz, D.; Zavala-Rivera, P.; Lucero-Acuña, A. Spatiotemporal Temperature Distribution of NIR Irradiated Polypyrrole Nanoparticles and Effects of pH. *Polymers* **2022**, *14*, 3151. https://doi.org/10.3390/ polym14153151

Academic Editor: Edina Rusen

Received: 19 July 2022 Accepted: 29 July 2022 Published: 2 August 2022

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application of polypyrrole-based materials is still in its early stages. Further research is required to understand and improve its potential performance under diverse in vitro or in vivo scenarios. In this context, one of the most common PPN preparation methods is oxidative chemical polymerization, consisting of a facile one-step aqueous dispersion polymerization that could be used with poly(vinyl alcohol) as stabilizing agent [15]. This method allows, up to some degree, the tuning of PPN properties by changing the stabilizing agent, varying the stabilizing agent concentration, and adjusting the molar ratios of the oxidative agent and the pyrrole monomer [16].

The modeling of heat dissipation from suspended nanoparticles irradiated at different wavelengths has been reported previously [17–19]. Roper et al. determined the efficiency of transducing resonant continuous-wave irradiation to bulk heat by a gold NP suspension by analyzing thermal energy transfer in a thermally isolated system with a macroscopic linearized heat transfer model that incorporates radiation and conduction [20]. The calculation of the photothermal transduction efficiency requires theoretical analysis of the experimental data [20–23]. Huang et al. analyzed the temperature distribution with a two-dimensional model for either fluid or tissue containing gold nanorods, based on the Pennes' bioheat equation, with an additional term to account for energy released by the gold nanorods [24].

In this work, the chemical oxidative polymerization technique was used to prepare PPN, and their properties at different pH values were studied. Furthermore, the spatiotemporal temperature distributions of NIR-irradiated PPN were experimentally evaluated under different particle concentrations and pH values. An unsteady-state three-dimensional heat transfer model that describes the temperature behavior of the suspensions by considering conduction, photothermal heating from laser irradiation, and heat generation due to the water absorption was developed. The model was validated with experimentally obtained temperature measurements of PPN suspensions irradiated in the NIR region. This mathematical approach allows the prediction of the nanoparticle spatiotemporal temperature distributions and could help improve the doses of bioactive NPs and times of light irradiation at different pH values to reach the desired temperatures in photothermal therapies.

#### **2. Materials and Methods**

#### *2.1. Materials*

Pyrrole (reagent grade, 98%), iron (III) chloride hexahydrate (reagent grade, 97%, FeCl3·6H2O), and polyvinyl alcohol (86.7–88.7% hydrolysis, Mw~31,000 a.m.u, PVA) were purchased from Sigma Aldrich, Inc., St. Louis, MO, USA. The pyrrole monomer was purified by distillation under vacuum and inert atmosphere conditions before use.

#### *2.2. Synthesis of PPN*

PPN were synthesized by the oxidative chemical polymerization of pyrrole using ferric chloride as oxidant and PVA as stabilizer [15,25,26]. A schematic of the synthesis of PPN is presented in Figure 1. A total of 20 mL of an aqueous solution of 7.5% of PVA (% *w/v*) was kept under magnetic stirring at 500 pm, at 5 ◦C (Figure 1A). Then, 4.6 mmol of ferric chloride ([FeCl3]/[monomer] = 2.3) was added to a PVA solution. The mixture reacts for 1 h to reach equilibrium, forming the PVA/iron cation complex (orange solution) (Figure 1B). Then, 2 mmol of pyrrole monomer was added to the PVA/iron cation complex solution. The solution turned black-green, indicating that polymerization started (Figure 1C), and the polymerization process was allowed to react for 4 h with continuous stirring and at 5 ◦C. Then, PPN was washed by three centrifugation cycles at 22,096× *g* (14,500 rpm) for 35 min, where supernatant was discarded, and the precipitate was resuspended in deionized water. Finally, PPN was collected and stored at 4 ◦C for further use. All experiments were performed in triplicate.

**Figure 1.** PPN synthesis scheme by chemical oxidation of pyrrole. (**A**) PVA solution at 5 ◦C; (**B**) formation of PVA/iron complex, and (**C**) polymerization of pyrrole and formation of PPN.
