Low-Dose Near-Infrared Light-Activated Mitochondria-Targeting Photosensitizers for PDT Cancer Therapy.
Wenyu Wu KlinglerNadine GigerLukas SchneiderVipin BabuChristiane KönigPatrick SpielmannRoland H WengerStefano FerrariBernhard SpinglerPublished in: International journal of molecular sciences (2022)
Phthalocyanines (Pcs) are promising candidates for photodynamic therapy (PDT) due to their absorption in the phototherapeutic window. However, the highly aromatic Pc core leads to undesired aggregation and decreased reactive oxygen species (ROS) production. Therefore, short PEG chain functionalized A 3 B type asymmetric Pc photosensitizers (PSs) were designed in order to decrease aggregation and increase the aqueous solubility. Here we report the synthesis, characterization, optical properties, cellular localization, and cytotoxicity of three novel Pc-based agents ( LC31 , MLC31 , and DMLC31Pt ). The stepwise functionalization of the peripheral moieties has a strong effect on the distribution coefficient (log P ), cellular uptake, and localization, as well as photocytotoxicity. Additional experiments have revealed that the presence of the malonic ester moiety in the reported agent series is indispensable in order to induce photocytotoxicity. The best-performing agent, MLC31 , showed mitochondrial targeting and an impressive phototoxic index (p.i.) of 748 in the cisplatin-resistant A2780/CP70 cell line, after a low-dose irradiation of 6.95 J/cm 2 . This is the result of a high photocytotoxicity (IC 50 = 157 nM) upon irradiation with near-infrared (NIR) light, and virtually no toxicity in the dark (IC 50 = 117 μM). Photocytotoxicity was subsequently determined under hypoxic conditions. Additionally, a preliminarily pathway investigation of the mitochondrial membrane potential (MMP) disruption and induction of apoptosis by MLC31 was carried out. Our results underline how agent design involving both hydrophilic and lipophilic peripheral groups may serve as an effective way to improve the PDT efficiency of highly aromatic PSs for NIR light-mediated cancer therapy.
Keyphrases
- photodynamic therapy
- cancer therapy
- low dose
- reactive oxygen species
- drug delivery
- oxidative stress
- fluorescence imaging
- cell death
- high dose
- dna damage
- liquid chromatography
- amino acid
- cell cycle arrest
- radiation induced
- drug release
- endoplasmic reticulum stress
- computed tomography
- solid phase extraction
- risk assessment
- human health
- simultaneous determination
- endoplasmic reticulum
- climate change
- diffusion weighted imaging
- water soluble
- signaling pathway
- high resolution