Abstract
Photodynamic therapy (PDT) is a potential non-invasive approach for application in oncological diseases, based on the activation of a photosensitizer (PS) by light at a specific wavelength in the presence of molecular oxygen to produce reactive oxygen species (ROS) that trigger the death tumor cells. In this context, porphyrins are interesting PS because they are robust, have high chemical, photo, thermal, and oxidative stability, and can generate singlet oxygen (1O2). However, porphyrins exhibit low solubility and a strong tendency to aggregate in a biological environment which limits their clinical application. To overcome these challenges, we developed hybrid nanostructures to immobilize 5,10,15,20-tetrakis[(4-carboxyphenyl) thio-2,3,5,6-tetrafluorophenyl] (P), a new third-generation PS. The biological effect of this system was evaluated against bladder cancer (BC) cells with or without light exposition. The nanostructure composed of lipid carriers coated by porphyrin-chitosan (P-HNP), presented a size of ca. 130 nm and low polydispersity (ca. 0.25). The presence of the porphyrin-chitosan (P-chitosan) on lipid nanoparticle surfaces increased the nanoparticle size, changed the zeta potential to positive, decreased the recrystallization index, and increased the thermal stability of nanoparticles. Furthermore, P-chitosan incorporation on nanoparticles increased the stability and enhanced the self-organization of the system and the formation of spherical structures, as observed by small-angle X-ray scattering (SAXS) analysis. Furthermore, the immobilization process maintained the P photoactivity and improved the photophysical properties of PS, minimizing its aggregation in the cell culture medium. In the photoinduction assays, the P-HNP displayed high phototoxicity with IC50 3.2-folds lower than free porphyrin. This higher cytotoxic effect can be correlated to the high cellular uptake of porphyrin immobilized, as observed by confocal images. Moreover, the coated nanoparticles showed mucoadhesive properties interesting to its application in vivo. Therefore, the physical and chemical properties of nanoparticles may be relevant to improve the porphyrin photodynamic activity in BC cells.
Highlights
Photodynamic therapy (PDT) is a non-invasive approach to treat oncological and non-oncological diseases (Figueira et al, 2014; Kwiatkowski et al, 2018; Mesquita et al, 2018a,b; Gazzi et al, 2019; Negri et al, 2019; Castro et al, 2020; Gomes et al, 2020; Lee et al, 2020)
Porphyrins have been immobilized or encapsulated in nanostructures as a strategy to avoid the potential problems intrinsic to these compounds, such as aggregation (Zhou et al, 2016). This strategy may increase the delivery of these compounds within the target cells, leading to an interesting intracellular localization to potentialize the effect of this PS on PDT (Lavado et al, 2015; Zhao et al, 2016; Kwiatkowski et al, 2018)
Our group developed solid lipid–polymer hybrid nanoparticles to immobilize porphyrin on its surface, a new particle that has not to date been explored in the PDT area
Summary
Photodynamic therapy (PDT) is a non-invasive approach to treat oncological and non-oncological diseases (Figueira et al, 2014; Kwiatkowski et al, 2018; Mesquita et al, 2018a,b; Gazzi et al, 2019; Negri et al, 2019; Castro et al, 2020; Gomes et al, 2020; Lee et al, 2020). Due to the easy access to the bladder and the high exposition of malignant tissue on the bladder surface in cases of NMIBC, PDT has been suggested to enhance the effectiveness of BC therapy (Agostinis et al, 2011; Gomes et al, 2020) Several porphyrins and their reduced derivatives (chlorins) have been developed and used in the clinic and clinical trials for cancer treatment (e.g., Photofrin or 5-ALA) (Dougherty, 2002; Master et al, 2013; Li et al, 2015; Zhang et al, 2016; Kou et al, 2017; dos Santos et al, 2019). This study reports on the immobilization of the new 5,10,15,20-tetrakis[(4-carboxyphenyl) thio-2,3,5,6tetrafluorophenyl] porphyrin (P) (Supplementary Figure S1) in a biodegradable hybrid nanoparticle of the NLCs coated with chitosan, aiming to minimize the aggregation process, enhance cellular uptake, and improve the efficiency of this PS in PDT against BC cells. The overall shape of the p(r) curve provides indications of the particle shape in the system (Oliveira, 2011)
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