Image‐Guided TME‐Improving Nano‐Platform for Ca²⁺ Signal Disturbance and Enhanced Tumor PDT

Abstract

Dysfunction of the calcium balancing system and disruption of calcium distribution can induce abnormal intracellular calcium overload, further causing serious damage and even cell death, which provides a potential therapeutic approach for tumor treatment. Herein, a nano-platform, which includes UCNPs-Ce6@RuR@mSiO 2 @PL-HA NPs (UCRSPH) and SA-CaO 2 nanoparticles, is prepared for improving the tumor micro-environment (TME), Ca 2+ signal disturbance as well as enhanced photodynamic tumor therapy (PDT). UCRSPH combined with SA-CaO 2 can alter TME and relieve hypoxia of the tumor to realize self-reinforcing PDT under near-IR irradiation (980 nm). The ruthenium red (RuR) in the UCRSPH NPs can be released to the cytoplasm after endocytosis of the nanoparticles, target Ca 2+ channel proteins on the endoplasmic reticulum and mitochondria, sarcoplasmic reticulum Ca 2+ -ATPase (SERCA), and mitochondrial calcium uniporter (MCU). The combined participation of nanoparticles and RuR promotes Ca 2+ imbalance and cytoplasmic calcium overload with the assistance of CaO 2 , and provides tumor cells higher sensitivity to PDT. Furthermore, the nano-platform also provides fluorescence imaging and calcification computed tomography imaging for in vivo treatment guidance. In conclusion, this image-guided nano-platform show potential for highly specific, efficient combined therapy against tumor cells with minimal side-effects to normal cells by integrating TME improvement, self-reinforcing PDT, and Ca 2+ signal disturbance.

Connecting Calcium-Based Nanomaterials and Cancer: From Diagnosis to Therapy

“…d Ca 2+ channel proteins inhibitor ruthenium red inhibited the sarcoplasmic reticulum Ca 2+ -ATPase of endoplasmic reticulum (left panel) and the mitochondrial calcium uniporter of mitochondrial (right panel) to induce calcium overload. e The Bio-TEM image at 0 h (left panel) and 6 h (right panel) after UCRSPH + SA-CaO 2 NPS was incubated with 4T1 tumor cells for 5 min [ 73 ]. Copyright 2021, Wiley–VCH …”

“…In general, the high intracellular ROS levels are conducive to the accumulation of cytoplasmic Ca 2+ [ 142 ]. On this basis, Jiang et al reported a combined drug delivery nano-platform, including UCNPsCe 6 @RuR@mSiO 2 @PL-HA (UCRSPH) and CaO 2 @HASA NPs (SA-CaO 2 ) to achieve Ca 2+ signal dysfunction [ 73 ]. CaO 2 can simultaneously produce ROS and release calcium ions, inducing calcium channel imbalance and calcium overload.…”

“…14 a and b, 3 days after a single injection, the tumor area on CT image became significantly brighter, and microcalcification became more obvious after multiple injections [ 28 ]. In another similar case, Jiang and co-workers reported a CaO 2 -based nanoparticles to disturb Ca 2+ signal and enhance PDT [ 73 ]. Dense microcalcification was occurred in the tumor region five days after treatment, and the CT signal was enhanced after 10 days (Fig.…”

“… Copyright 2019, Elsevier. c CT images at 3, 5, and 10 days after UCRSPH + SA-CaO 2 + laser therapy [ 73 ]. Copyright 2021, Wiley–VCH.…”

Nanoplatform-mediated calcium overload for cancer therapy

“…6). 56 In the cytoplasm of the tumor cells, the incorporated RuR played a role in targeting and damaging the Ca 2+ channel proteins, effectively impacting the Ca 2+ balance. Meanwhile, the CaO 2 component was able to provide adequate Ca 2+ and O 2 for the Ca 2+ overload mediated ion-interference therapy, and UCNPs-Ce6 mediated PDT.…”