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A Ratiometric Fluorescence Probe for Cisplatin: Investigating Intracellular Reduction of Platinum(IV) Prodrug Complexes
摘要： Pt(IV) prodrug strategy has emerged as an excellent alternative to tackle the problems associated with conventional Pt(II) drug therapy. However, there is a lack of tools to study how this new class of Pt(IV) drugs are processed at the cellular level. Herein, we report the first ratiometric fluorescence probe designed for detecting cisplatin, applied to investigate Pt(IV) anticancer complexes in biological systems. The probe was able to distinguish between cisplatin and its Pt(IV) derivatives, allowing us to probe the intracellular reduction of Pt(IV) prodrug complexes. The correlation between the amount of active Pt(II) species available after intracellular reduction of Pt(IV) complexes to their cytotoxicity and the role glutathione plays in their reduction were investigated.
关键词： Fluorescence probes,Ratiometric,Glutathione,Platinum prodrugs,Anticancer
更新于2025-09-23 15:21:21
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Light-Triggered Dual-Modality Drug Release of Self-Assembled Prodrug-Nanoparticles for Synergistic Photodynamic and Hypoxia-Activated Therapy
摘要： Photodynamic therapy (PDT) leads to tumor hypoxia which could be utilized for the activation of hypoxia-activated prodrugs (HAPs). However, conventional photosensitizer-loaded nanoformulations suffer from aggregation-caused quenching (ACQ) effect, which limits the efficiency of PDT and synergistic therapy. Herein, prodrug-nanoparticles (NPs) are prepared by the self-assembly of heterodimeric prodrugs composed of pyropheophorbide a (PPa), hypoxia-activated prodrug PR104A, and a thioether or thioketal linkage. In addition, a novel dual-modality drug release pattern is proposed on the basis of the structural states of prodrug-NPs. Under light irradiation, PR104A is released via photoinduced electron transfer (PET) due to the aggregating state of prodrugs. With the disassembly of prodrug-NPs, ACQ effect relieves, PPa produces singlet oxygen which further promotes the reactive oxygen species (ROS)-sensitive release of PR104A. Such prodrug-NPs turn the disadvantage of the ACQ effect to facilitate drug release, demonstrating high-efficiency synergy in combination with PDT and hypoxia-activated therapy.
关键词： aggregation-caused quenching,Photodynamic therapy,drug release,photoinduced electron transfer,hypoxia-activated prodrugs,reactive oxygen species
更新于2025-09-23 15:19:57
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Photoactivable elimination of tumorigenic human induced pluripotent stem cells using a lectin-doxorubicin prodrug conjugate
摘要： Human pluripotent stem cells (hPSCs) are attractive resources for regenerative medicine but medical applications are hindered by their tumorigenic potential. Previously, we identified a hPSC-specific lectin probe, rBC2LCN, through comprehensive glycome analysis using high-density lectin microarrays. Here, we developed a lectin-doxorubicin (DOX) prodrug conjugate with controllable photolysis activation for the elimination of tumorigenic human induced pluripotent stem cells. rBC2LCN was fused with a biotin-binding protein, Tamavidin (BC2Tama), and the fusion protein was expressed in Escherichia coli and purified using affinity chromatography. BC2Tama was then conjugated with doxorubicin-photocleavable biotin (DOXPCB). The BC2Tama-DOXPCB conjugates were observed to bind to the hPSCs followed by internalization. Upon ultraviolet light exposure, doxorubicin was released inside the cells, which allowed specific killing of the hPSCs. Thus, BC2Tama-DOXPCB should be useful for the targeted elimination of hPSCs contained in hPSC-derived cell therapy products. This is the first report of the generation of lectin-prodrug conjugates. BC2Tama should be applicable for the targeted delivery of various types of biotinylated compounds into hPSCs.
关键词： prodrugs,pluripotent stem cells,tumorigenicity,lectin
更新于2025-09-19 17:15:36
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Biological activity of PtIV prodrugs triggered by riboflavin-mediated bioorthogonal photocatalysis
摘要： We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of PtIV prodrugs. In this study, we show how the combination of light and Rf with two PtIV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf-mediated activation of the cisplatin and carboplatin prodrugs cis,cis,trans-[Pt(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) and cis,cis,trans-[Pt(NH3)2(CBDCA)(O2CCH2CH2CO2H)2] (2, where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions. Such photoactivation mode occurs to a considerable extent intracellularly, as demonstrated for 1 by uptake and cell viability experiments. 195Pt NMR, DNA binding studies using circular dichroism, mass spectrometry and immunofluorescence microscopy were performed using the Rf-1 catalyst-substrate pair and indicated that cell death is associated with the efficient light-induced formation of cisplatin. Accordingly, Western blot analysis revealed signs of DNA damage and activation of cell death pathways through Rf-mediated photochemical activation. Phosphorylation of H2AX as indicator for DNA damage, was detected for Rf-1 in a strictly light-dependent fashion while in case of free cisplatin also in the dark. Photochemical induction of nuclear pH2AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system.
关键词： riboflavin,pancreatic cancer,DNA damage,PtIV prodrugs,photocatalysis
更新于2025-09-10 09:29:36
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Hybrid Nanomedicine Fabricated from Photosensitizer-Terminated Metal-Organic Framework Nanoparticles for Photodynamic Therapy and Hypoxia-Activated Cascade Chemotherapy
摘要： During photodynamic therapy (PDT), severe hypoxia often occurs as an undesirable limitation of PDT owing to the O2-consuming photodynamic process, compromising the effectiveness of PDT. To overcome this problem, several strategies aiming to improve tumor oxygenation are developed. Unlike these traditional approaches, an opposite method combining hypoxia-activated prodrug and PDT may provide a promising strategy for cancer synergistic therapy. In light of this, azido-/photosensitizer-terminated UiO-66 nanoscale metal–organic frameworks (UiO-66-H/N3 NMOFs) which serve as nanocarriers for the bioreductive prodrug banoxantrone (AQ4N) are engineered. Owing to the effective shielding of the nanoparticles, the stability of AQ4N is well preserved, highlighting the vital function of the nano-carriers. By virtue of strain-promoted azide–alkyne cycloaddition, the nanocarriers are further decorated with a dense PEG layer to enhance their dispersion in the physiological environment and improve their therapeutic performance. Both in vitro and in vivo studies reveal that the O2-depleting PDT process indeed aggravates intracellular/tumor hypoxia that activates the cytotoxicity of AQ4N through a cascade process, consequently achieving PDT-induced and hypoxia-activated synergistic therapy. Benefiting from the localized therapeutic effect of PDT and hypoxia-activated cytotoxicity of AQ4N, this hybrid nanomedicine exhibits enhanced therapeutic efficacy with negligible systemic toxicity, making it a promising candidate for cancer therapy.
关键词： hypoxia-activated prodrugs,cascade therapy,nanoscale metal–organic frameworks,banoxantrone,photodynamic therapy
更新于2025-09-04 15:30:14
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Modulating the cellular uptake of fluorescently tagged substrates of prostate-specific antigen before and after enzymatic activation
摘要： A series of peptides based on the prostate-specific antigen (PSA) specific sequence histidine-serine-serine-lysine-leucine-glutamine were functionalised with an anthraquinone fluorophore at the C-terminal residue side chain using the copper(I) catalyzed azide-alkyne cycloaddition reaction. The effect of incorporating a negatively charged N-terminal tetra-glutamic acid group to the substrate and the effect of masking the negatively charged C-terminal carboxylic acid functionality of the substrate was investigated using confocal fluorescence microscopy in two cell lines (DLD-1 and LnCaP). The addition of a tetra-glutamic acid group to the N-terminus of the intact sequence was shown to reduce cellular uptake of the intact substrate prior to activation by PSA. In contrast, masking the C-terminal carboxylic acid group of the substrate as a methyl ester was shown to improve cellular uptake of the peptide fragment after activation by PSA. The synthesized C-terminal methyl ester substrates with the anthraquinone attached to the side chain were confirmed to be cleaved by PSA in LC-MS analysis, and the cytotoxicity of the substrates was shown to increase in the presence of PSA, consistent with cleavage and uptake of the C-terminal fragment. The results indicate that C- and N- terminal functionalisation of peptide substrates targeting PSA can be used to modulate the cellular uptake of peptides before and after enzymatic activation, and may thus be an important consideration in the design of tumour activated prodrugs.
关键词： peptide substrates,cellular uptake,tumour activated prodrugs,prostate-specific antigen,anthraquinone fluorophore
更新于2025-09-04 15:30:14