**1. Introduction**

Photodynamic therapy (PDT) is a promising method of treatment that can be used to solve a number of problems, from the destruction of bacteria and viruses to the treatment of cancer. This method is based on the use of three factors: light, a special light-sensitive substance—photosensitizer (PS) and oxygen from the environment to generate cytotoxic oxygen or free radicals [1,2]. Although this technique is now most widely used to treat dermatological diseases and various skin malignancies, its prospects in the destruction of various pathogens cannot be ignored, especially given the permanent emergence of new,

**Citation:** Yeshchenko, O.A.; Kutsevol, N.V.; Tomchuk, A.V.; Khort, P.S.; Virych, P.A.; Chumachenko, V.A.; Kuziv, Y.I.; Marinin, A.I.; Cheng, L.; Nie, G. Thermoresponsive Zinc TetraPhenylPorphyrin Photosensitizer/Dextran Graft Poly(N-IsoPropylAcrylAmide) Copolymer/Au Nanoparticles Hybrid Nanosystem: Potential for Photodynamic Therapy Applications. *Nanomaterials* **2022**, *12*, 2655. https:// doi.org/10.3390/nano12152655

Academic Editors: Wei Chen and Derong Cao

Received: 21 June 2022 Accepted: 30 July 2022 Published: 2 August 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

antibiotic-resistant bacterial strains [3,4]. The main advantage of antibacterial PDT (APDT) over conventional antibiotics is that the bacteria do not show resistance to PDT even after repeated sessions of treatment.

For advances in nanobiology and nanomedicine, there is an urgen<sup>t</sup> need for new hybrid functional materials based on biocompatible polymers [5–10]. A variety of biocompatible water-soluble polymers can be used to increase the bioavailability of a variety of drugs, as well as to improve drug pharmacokinetics, such as controlled delivery of drugs directly into cells and their controlled release [11]. Polymers can be used as an effective matrix for in situ synthesis of metal nanoparticles (NPs) with narrow size distribution [12–15], preventing the aggregation of NPs. An encapsulation of photosensitizers in a polymer matrix avoids aggregation of hydrophobic photosensitizer molecules, which significantly increases their photodynamic efficiency in biological media [16].

Recently, thermoresponsive polymers have attracted much attention from researchers, since such polymers are the basis for the creation of locally temperature-controlled nanoactuators [17–19]. In particular, poly (N-isopropylacrylamide) (PNIPAM) were used as a potential basis for the fabrication of hybrid nanosystems for applications in biology and medicine [20]. In aqueous phase, PNIPAM undergoes a phase LCST transition (lower critical solution temperature) at 32 ◦C from hydrophilic to hydrophobic phase, which leads to a sharp shrinking of the polymer molecule [21–23]. Such temperature induced shrinking can be used for the controlled release (at a given temperature) of certain molecules (e.g., drugs) initially bound to the PNIPAM macromolecule [24]. Additionally, a temperature-induced change (decrease) in the distance between molecules and plasmonic nanoparticles (NPs) leads to a change (increase) in the strength of molecule–NP coupling. This, in principle, may change the magnitude of the plasmon enhancement of electronic processes in molecules, such as absorption, emission and scattering of light, photocatalysis, generation of singlet oxygen, etc. [25–28]. The use of PNIPAM with a star-like structure allows for an increase the phase transition point by approximately 2–4 ◦C compared to the corresponding temperature of PNIPAM with a linear structure [26]. In addition, the Au and Ag NPs grown in situ in a branched polymer in aqueous solution have significantly higher stability than NPs grown in a linear polymer [29]. The temperature and related laser-induced phase transitions and the possibility of changing its parameters for hybrid nanosystems based on PNIPAM with a star structure (D-g-PNIPAM) and Au (Ag) NPs was shown in recent works [30–33].

Porphyrin and its derivatives are the promising photosensitizers used in particular for antibacterial and antitumor therapy [34,35]. Their advantages include high stability, efficient absorption of visible light, low dark toxicity, long life in the triplet state, highly efficient photogeneration of singlet oxygen and ease of their modification. However, there is a serious problem—the vast majority of porphyrins are hydrophobic, and therefore in living organisms they have a tendency to aggregation, which significantly reduces their photodynamic efficiency [35]. In recent years, metal porphyrins have attracted considerable attention. The PDT activity of porphyrin metal complexes depends on the type of metal due to the paramagnetic effect [36]. Zinc is added to the porphyrin ring to provide ring stability and to maintain the pronounced photodynamic efficiency of the porphyrin based PS. Such porphyrin metal complexes, e.g., zinc tetraphenylporphyrin (ZnTPP), are similar to natural porphyrin and are widely used in biology and medicine. The presence of Zn atom in the porphyrin ring has been reported to reduce mitochondrial binding and promote cell membrane binding due to complexation with phospholipid phosphate groups, which enhances the PDT efficiency [37].

Gold nanoparticles (Au NPs) are widely used in many biological applications. They are less toxic than Ag NPs [38,39]. Recently, the high antitumor efficiency has been demonstrated for some gold-based compounds [40,41]. A well-known approach to enhance the various electronic processes (light absorption, fluorescence, Raman scattering, photocatalysis, etc.) in the molecules is to place the molecules near the plasmonic metal nanoparticles or nanostructures [25–28]. In such nanoparticles, the localized surface plasmon resonance

(LSPR) is excited by an external light, as a result, there is a significant increase in the electromagnetic field strength in the vicinity of plasmonic NPs, causing an increased optical response of the molecules located in the enhanced field area. Accordingly, the plasmon-enhanced light absorption by PS molecule located near the metal NP in a hybrid nanosystem would result in a more efficient photogeneration of singlet oxygen, therefore, an increase in the efficiency of PDT of the nanosystem [18,42–45]. In addition, small Au NPs have antibacterial activity against pathological bacteria due to high ability to penetrate the cell [46]. Another phenomenon with a plasmonic nature that can be used for PDT purposes is the photo-induced heating of metal NPs, plasmon heating. Due to an extremely low quantum yield of fluorescence of metal NPs, almost all of the light energy absorbed by the nanoparticle is converted to thermal energy. As a result, metal NPs act as highly efficient local nanoheaters. The effect of plasmon heating has a resonant character, i.e., it becomes strongest under the resonance of the frequencies of exciting light and LSPR in metal NP [47–49]. Thus, plasmon heating of metal NPs can be efficiently used for the photothermal therapy of cancer and bacterial diseases [50–53].

Here, we present the results of the chemical synthesis, the size and morphological characteristics, spectroscopic properties and APDT activity of the aqueous solution of ZnTPP/D-g-PNIPAM/AuNPs triple hybrid nanosystem. This hybrid nanosystem contains zinc tetraphenylporphyrin (ZnTPP) photosensitizer, thermoresponsive dextran poly (N-isopropylacrylamide) graft copolymer (D-g-PNIPAM) and Au NPs. Our work demonstrates that ZnTPP/D-g-PNIPAM/AuNPs nanosystem exhibits a significant plasmon enhancement of the singlet oxygen photogeneration, see scheme in Figure 1. ZnTPP/D-g-PNIPAM/AuNPs shows a high potential for thermally driven and controlled photodynamic rapid inactivation of microorganisms.

**Figure 1.** Scheme representing the structure of ZnTPP/D-g-PNIPAM/AuNPs hybrid macromolecule as well as the plasmon enhancement of singlet oxygen generation.
