Targeted OUM1/PTPRZ1 silencing and synergetic CDT/enhanced chemical therapy toward uveal melanoma based on a dual-modal imaging-guided manganese metal–organic framework nanoparticles

Abstract

Metastasis and chemical resistance are the most serious problems in the treatment of highly aggressive uveal melanoma (UM). The newly identified lncRNA OUM1 is overexpressed in UM, functions as a catalyst and regulates protein tyrosine phosphatase (PTP) activity by binding to PTP receptor type Z1 (PTPRZ1), which plays an important role in cell proliferation, metastasis and chemotherapy resistance in the UM microenvironment. Hence, siRNAs that selectively knocking down the lncRNA OUM1 (siOUM1) and its target gene PTPRZ1 (siPTPRZ1) were designed to inhibit the OUM1/PTPRZ1 pathway to reduce PTP activity, and this reduction in activity interrupts protein tyrosine phosphorylation, suppresses UM proliferation and metastasis and improves cisplatin sensitivity in UM cells. Then, to overcome the limitations of the difficulty of drug administration and traditional therapeutics, the indocyanine green (ICG)-labeled manganese metal–organic framework (MOF) nanoparticles (NPs) were fabricated and linked with arginine-glycine-aspartate (RGD) peptide to carry siOUM1/siPTPRZ1 and cisplatin to achieve targeted siRNA interference-mediated therapy, enhanced cisplatin therapy and chemodynamic therapy. This NP system also has a dual-modal imaging ability because ICG is a near-infrared region fluorescent dye and manganese has the potential to be used in magnetic resonance imaging. This study verifies the significance of the newly discovered lncRNA OUM1 as a new therapeutic target for aggressive UM and provides a drug delivery NP system for precise treatment of UM accompanied with a dual-modal imaging ability. Graphical Abstract

Protein Tyrosine Phosphatase Receptor Zeta 1 as a Potential Target in Cancer Therapy and Diagnosis

“…However, mRNA levels of PTPRZ1 were not found significantly different between normal and tumor tissues in skin cutaneous melanoma [3]. In uveal melanoma cells, PTPRZ1 is overexpressed and positively affects proliferation and invasion in vitro [39].…”

“…The heparin-binding domain of VEGFA is also not involved [37,38], and the VEGFA domain that interacts with PTPRZ1 is still to be identified. Finally, it has recently been shown by using the RNA-chromatin immunoprecipitation assay that the long non-coding RNA (lncRNA) uveal melanoma formation-transcript 1 (OUM1) functions by directly binding to the PTPRZ1 protein in the cytoplasm of uveal melanoma cells, to enhance its TP activity [39], highlighting a novel pathway of PTPRZ1 regulation.…”

“…A more recent approach developed for the treatment of highly aggressive uveal melanoma was the construction of indocyanine green-labeled manganese metal-organic framework nanoparticles that carry siRNA for the lncRNA OUM1 and PTPRZ1, together with cisplatin. Nanoparticles were linked with the RGD peptide for targeting and were shown to kill uveal melanoma in vitro and delay tumor growth in vivo through selective siRNA knockdown and enhanced cisplatin cytotoxicity [39].…”

Nanomaterials‐Based Targeting of Long Non‐Coding RNAs in Cancer: A Cutting‐Edge Review of Current Trends

“…This method allows simultaneous fluorescence imaging of in vivo distribution (Figure 12). [165] The reviewed research shows that nanocarriers can encapsulate lncRNA-degrading agents such as siRNA, miRNA, ASO, and CRISPR-Cas9. Along with these ingredients, nanocarriers may include lncRNA-regulating drugs.…”

Manganese-based nanomaterials in diagnostics and chemodynamic therapy of cancers: new development

“…Due to the specific binding of RGD peptide with the overexpressed integrin αvβ3 receptor on the tumor cell membrane, specific targeting of tumor cells can be achieved. 55 Zhong et al designed a nanopreparation, TPP-DOX@MnBSA (TD@MB), which modifies DOX with TPP as a ligand, with mitochondria as the entry therapeutic target. TPP as a mitochondrial ligand can be absorbed by the mitochondrial membrane, and targeting TPP-DOX to the mitochondria can achieve tumor cell killing by destroying the mitochondria, while synergizing with Mn 2+ -mediated CDT can amplify the tumor-killing effect.…”