Maltotriose–Chlorin e6 Conjugate Linked via Tetraethyleneglycol as an Advanced Photosensitizer for Photodynamic Therapy. Synthesis and Antitumor Activities against Canine and Mouse Mammary Carcinoma Cells

Abstract

Glycoconjugated chlorins represent a promising class of compounds that meet the requirements for the third-generation photosensitizer (PS) for photodynamic therapy (PDT). We have focused on the use of glucose (Glc) to improve the performance of the PS based on the Warburg effect—a phenomenon where tumors consume higher Glc levels than normal cells. However, as a matter of fact, Glc-conjugation has a poor efficacy in hydrophilic modification; thus, the resultant PS is not suitable for intravenous injection. In this study, a Glc-based oligosaccharide, such as maltotriose (Mal 3 ), is conjugated to chlorin e6 (Ce6). The conjugation is assisted by two additional molecular tools, such as propargyl amine and a tetraethylene glycol (TEG) derivative. This route produced the target Mal 3 –Ce6 conjugate linked via the TEG spacer (Mal 3 –TEG–Ce6), which shows the required photoabsorption properties in the physiological media. The PDT test using canine mammary carcinoma (SNP) cells suggested that the antitumor activity of Mal 3 –TEG–Ce6 is extremely high. Furthermore, in vitro tests against mouse mammary carcinoma (EMT6) cells have been demonstrated, providing insights into the photocytotoxicity, subcellular localization, and analysis of cell death and reactive oxygen species (ROS) generation for the PDT system with Mal 3 –TEG–Ce6. Both apoptosis and necrosis of the EMT6 cells occur by ROS that is generated via the photochemical reaction between Mal 3 –TEG–Ce6 and molecular oxygen. Consequently, Mal 3 –TEG–Ce6 is shown to be a PS showing the currently desired properties.

Novel Chlorin e6-Curcumin Derivatives as a Potential Photosensitizer: Synthesis, Characterization, and Anticancer Activity

“…Gao et al reported that the Ce6-guanidine derivative associated with PDT induced apoptotic cell death in A549, the lung cancer cell line [40]. Similarly, Maltotriose-Ce6 derivatives have been shown to have both apoptotic and necrotic pathways to kill the tested breast cancer cell line (EMT6) [41]. The Bcl-2 family proteins play a crucial role in the process of cell death by apoptosis.…”

“…Pharmaceutics 2023, 15, x FOR PEER REVIEW 10 of 25apoptotic cell death in A549, the lung cancer cell line[40]. Similarly, Maltotriose-Ce6 derivatives have been shown to have both apoptotic and necrotic pathways to kill the tested breast cancer cell line (EMT6)[41].…”

Synergic Antitumor Effect of Photodynamic Therapy and Chemotherapy Mediated by Nano Drug Delivery Systems

“…In this nanoparticle, HA is combined with a highly effective photosensitizer (chlorin-e6) by adipicdihydrazide (ADH) as a linker. Chlorin-e6 is a second generation photosensitizer that is able to be activated by NIR light and is used for PDT [230]. In 2014, Shi and co-workers [121] synthesized a DOX-conjugated onto poly(ethyleneimine) (PEI)-fullerene (C60-PEI-DOX) to facilitate photosynamic therapy and chemotherapy in one system as well as evaluate its synergistic effect on cancer cells.…”

Oncological Applications of Photodynamic Therapy in Dogs and Cats

“…The cells exposed to 5 J/cm 2 of 671 nm red light suggested the antitumor activity of this photosensitizer is extremely high. Cell viability was reduced to 50% when 0.16 µM was used [165].…”