Photoactivated Lysosomal Escape of a Monofunctional Pt^II Complex Pt‐BDPA for Nucleus Access

Abstract

Aphotosensitizing monofunctional Pt complex, Pt-BDPA, was prepared with aB ODIPY chromophore.A part from its DNAbinding ability,this complex displays emission at ca. 578 nm and as inglet oxygen quantum yield of 0.133. Confocal imaging revealed that this complex was sequestered in lysosomes via endocytosis in the dark, preventing its access to the nucleus.P rofiting from its photoinduced ROS generation ability,t his complex undergoes lysosomal escape to access the nucleus upon photoirradiation. The photoinduced ROSs till cause ad rop in intracellular GSH, favoring the stability of Pt-BDPAa nd contributing to its nuclear DNA accessibility.This complex displayed distinct cytotoxicity to all tested tumor cell lines upon photoirradiation, and the IC 50 values were ca. 3-6 mm,w hicha re distinctly lower than those found with only dark incubation (IC 50 > 50 mm). These results are consistent with photoactivated lysosomal escape of this photosensitizing Pt complex to access the nucleus.

Tumor Microenvironment-Specific Chemical Internalization for Enhanced Gene Therapy of Metastatic Breast Cancer

“…To investigate whether the intracellular ROS could disrupt the endo-/lysosomal membrane, the integrity of the lysosomal membrane was revealed by the acridine orange (AO) which emits red fluorescence in the acidic lysosome and green fluorescence in the cytosol and nucleus [18]. As shown in Figure 4(a), the red and green fluorescence was emitted from 4T1 cells incubated with MSNs, suggesting the integrated lysosomal membrane.…”

“…Photochemical internalization (PCI), a spatiotemporally controllable technology [13], has been developed for enhancing cytosolic release of trapped molecules in endocytic vesicles by photochemical disruption of the endo-/lysosomal membrane using light and photosensitizers [14][15][16]. Lightinduced reactive oxygen species (ROS) formation is the critical factor that causes membrane leakage with translocation of the internalized molecules into the cytosol [17,18]. Although PCI has exhibited significant improvement in gene transfection efficiency, its clinical application is limited by the insufficient light penetration depth.…”

Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance

“…Under the weakly acidic conditions of tumor cells, the abundant amine groups in PEI can be protonated, which triggers the large inflow of protons, chloride counterions, and water into the endo/lysosomes, promoting endo/lysosomal rupture through high osmotic pressure which is known as the “proton-sponge effect” [ 34 ]. This trait helps to enhance the intracellular retention of drugs loaded by nanocarriers after endocytosis and avoid the enzymatic degradation of drugs by lysosomes [ 35 ]. In addition, a GSH consumption strategy was simultaneously performed in present study.…”

Amplified Antitumor Efficacy By A Targeted Drugs Retention and Chemosensitization Strategies-Based “Combo” Nanoagent Together With PD-L1 Blockade In Reversing Multidrug Resistance

“…Under the weakly acidic conditions of tumor cells, the abundant amine groups in PEI can be protonated, which triggers the large in ow of protons, chloride counterions, and water into the endo/lysosomes, promoting endo/lysosomal rupture through high osmotic pressure which is known as the "proton-sponge effect" [27]. This trait is helpful to enhance the intracellular retention of drugs loaded by nanocarriers after endocytosis and avoid the enzymatic degradation of drugs by lysosomes [28]. Besides, a GSH consumption strategy was simultaneously performed in this study.…”