Precise Subcellular Organelle Targeting for Boosting Endogenous‐Stimuli‐Mediated Tumor Therapy

Abstract

to their noninvasive and specific treatment modality from selective irradiation. [1b] However, external energy, such as light, ionizing radiation or ultrasound, is required in these therapies, which obstructs their further development due to the limited penetration depth of the laser, safety concerns of radiation, therapeutic resistance and spatio-temporal constraints of some specific equipments. In-depth exploiting the differences between the tumor microenvironment (TME) and normal organs provides an alternative way that without specific devices. Take full advantage of the TME, endogenousstimuli-mediated therapy is a novel concept in tumor treatment.The TME, mainly composed of tumor cells, vessels, lymphatic vessels, immune cells, fibroblasts, and extracellular matrix (ECM), [4] which provides a suitable environment for survival, division, angiogenesis, and metastasis of tumor cells. During the growth of tumor tissue, some regions are hypoxic [5] due to abnormal vascularization and inferior blood accommodation. [6] Normal cells can decompose glucose into pyruvate through glycolysis in the cytoplasm under normoxic conditions and the generated pyruvate is transported to the mitochondria and further decomposed into carbon dioxide, [7] which is known as tricarboxylic acid cycle (TCA). In hypoxic tumor tissues, the TCA pathway is restricted due to the insufficiency of oxygen supply. Instead, pyruvate is reduced to lactic acid to produce energy with much lower efficiency. This process on the one hand increases the consumption of glucose and pyruvate, and on the other hand increases acidity of the extracellular TME (pH value: 6.5-6.8) due to the secreted lactic acid. [8] Another noteworthy property of the TME is the increased level of reactive oxygen species (ROS). [9] The term ROS mainly includes hydrogen peroxide (H 2 O 2 ), singlet oxygen ( 1 O 2 ), hydroxyl radical (•OH), superoxide (•O 2 − ), ozone, lipid peroxides, hypochlorous acid, which often determines many biological responses and metabolic processes within the tumor [10] directly and/or indirectly. [11] Increased expression of ROS-scavenging enzymes and antioxidant molecules could balance the high levels of ROS, which may contribute to the accommodative response of tumor cells to many therapies. [12] For example, glutathione (GSH) plays a vital role in the protection of cells against lectrophilic and oxidative stress as it is engaged in the metabolism and detoxification process of many cytotoxic and carcinogenic species with the oxidation of GSH to its oxidized Though numerous external-stimuli-triggered tumor therapies, including phototherapy, radiotherapy, and sonodynamic therapy have made great progress in cancer therapy, the low penetration depth of the laser, safety concerns of radiation, the therapeutic resistance, and the spatio-temporal constraints of the specific equipment restrict their convenient clinical applications. What is more, the inherent physiological barriers of the tumor microenvironment (TME), including hypoxia, heterogeneity, and...

Pan‑cancer analyses reveal the regulation and clinical outcome association of PCLAF in human tumors

“…In the diseases in the TISIDB database, the expression of PCLAF was found to be positively correlated with activated CD4 T cells (Act CD4) and type 2 T helper (Th2) cells, suggesting that PCLAF may play a specific role in tumor immune infiltration. Mounting evidence has demonstrated that the tumor microenvironment (TME) plays a predominant role in the occurrence and development of tumors, which may accelerate the deterioration of tumors ( 62 , 63 ). Among the TISIDB database, in BRCA, Glioma, NSCLC, and UCEC, PCLAF was found to be highly expressed in CD8 T cells, regular CD4 T cells, CD8-poor T cells, monocytes or macrophages, and proliferating T cell fibroblasts, which suggests that PCLAF is closely related to tumor TME.…”

Nucleus-Targeting Phototherapy Nanodrugs for High-Effective Anti-Cancer Treatment

“…Hf-HI-4COOH achieved effective tumor-killing effects while avoiding damage to the skin and normal organs under low power density (0.3 W/cm 2 ) laser irradiation due to their high photothermal conversion efficiency and the intrinsic nucleus-targeting property. The tumor extracellular space is slightly acidic (pH = 6.5–6.8) because the tumor microenvironment is rich in lactate ( Zhen et al, 2021 ; Huang et al, 2022 ; Zhu et al, 2022 ). To further improve the targeting of cancer therapy, Phuong et al (2020) developed a slightly acidic environment-responsive carbon dot/TiO 2 nanocomposites for nucleus-targeting PTT.…”

“…But the nucleus is not completely isolated from the cytoplasm for the nuclear pore complexes (NPCs) embedded in the nuclear membrane mediate material exchange and information transfer. NPC is a hydrophilic channel with a nuclear pore of ∼39 nm ( Zhen et al, 2021 ), through which hydrophilic small molecules can be diffused into the nucleus ( Zimmerli et al, 2021 ). However, most biomacromolecules are difficult to enter the nucleus via passive diffusion due to their large size.…”

Sequential Drug Delivery in Targeted Cancer Therapy

“…At the cellular targeting level, by conjugation of targeting moieties on the surface of nanoparticles, they could specifically target cancer cells with overexpressed receptors and increase cellular uptake and improve drug delivery efficiency [ 13 ]. For the subcellular level, researchers mainly focused on the organelle-targeted therapy that can further activate specific cellular pathways, enabling them to kill cancer cells [ 14 , 15 , 16 ].…”