A novel platinum（Ⅳ） complex [Ph3PEt]2[PtCl6] 1 obtained from the reaction of H2PtCl6 and [Ph3PEt]I （Ph3PEt^＋ = ethyl-triphenylphosphenonium） has been structurally characterized. It crystallizes in triclinic, spa...A novel platinum（Ⅳ） complex [Ph3PEt]2[PtCl6] 1 obtained from the reaction of H2PtCl6 and [Ph3PEt]I （Ph3PEt^＋ = ethyl-triphenylphosphenonium） has been structurally characterized. It crystallizes in triclinic, space group P1 with a = 10.20850（10）, b = 10.33870（10）, c = 10.814 .A a = 79.453（12）, β = 66.879（ 11 ）, γ = 72.461 （10）°, V = 998.14（9） A^3, Z = 1, Dc = 1.648 g/cm^3, μ（MoKa） = 4.025 mm^-1, F（000） = 490, C40H40Cl6P2Pt, Mr = 990.44, the final R = 0.0270 and wR = 0.0617 for 5787 observed reflections with 1 〉 2σ（Ⅰ）. Structure analysis indicates that the platinum atom almost has the ideal octahedral coordination geometry of PtCl6. The quaternary phosphate cations （Ph3PEt^＋） acting as counter ions are in combination with PtCl6 anions by static attracting forces and H-bonds. Upon the hydrogen bonds existing between cations and anions, the whole structure represents a chain-like construction. Based on the crystal data, quantum chemistry calculation at the DFT/B3LPY level was carded out to reveal the electronic structure of 1.展开更多
Anticancer platinum prodrugs that can be controllably activated are highly desired for personalized precision medicine and patient compliance in cancer therapy.However,the clinical application of platinum(Ⅳ)prodrugs(...Anticancer platinum prodrugs that can be controllably activated are highly desired for personalized precision medicine and patient compliance in cancer therapy.However,the clinical application of platinum(Ⅳ)prodrugs(Pt(Ⅳ))is restricted by tissue penetration of external irradiation.Here,we report a novel Pt(Ⅳ)activation strategy based on endogenous luminescence of tumor microenvironment responsiveness,which completely circumvents the limitation of external irradiation.The designed Pt(Ⅳ)–Lu,a mixture of trans,trans,trans-[Pt(N_(3))_(2)(OH)_(2)(py)_(2)]and luminol(Lu),has controllable activation property:it remains inert in reductant environment and normal tissues,but under tumor microenvironment,Lu will be oxidized to produce blue luminescence,which rapidly reduce Pt(Ⅳ)to Pt(Ⅱ)without the need of any external activator.Pt(Ⅳ)–Lu shows excellent responsive antitumor ability both in vitro and in vivo.Compared to cisplatin,the median lethal dose in BALB/c mice increased by an order of magnitude.Our results suggest that Pt(Ⅳ)–Lu exhibits highly controllable activation property,superior antitumor activity,and good biosafety,which may provide a novel strategy for the design of platinum prodrugs.展开更多
Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and ...Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.展开更多
Chemotherapy is the first-line treatment for cancer, but its systemic toxicity can be severe. Tumorselective prodrug activation offers promising opportunities to reduce systemic toxicity. Here, we present a strategy f...Chemotherapy is the first-line treatment for cancer, but its systemic toxicity can be severe. Tumorselective prodrug activation offers promising opportunities to reduce systemic toxicity. Here, we present a strategy for activating prodrugs using radiopharmaceuticals. This strategy enables the targeted release of chemotherapeutic agents due to the high tumor-targeting capability of radiopharmaceuticals. [^(18)F]FDG(2-[^(18)F]-fluoro-2-deoxy-D-glucose), one of the most widely used radiopharmaceuticals in clinics, can trigger Pt(IV) complex for controlled release of axial ligands in tumors, it might be mediated by hydrated electrons generated by water radiolysis resulting from the decay of radionuclide18F. Its application offers the controlled release of fluorogenic probes and prodrugs in living cells and tumor-bearing mice. Of note,an OxaliPt(IV) linker is designed to construct an [^(18)F]FDG-activated antibody-drug conjugate(Pt-ADC).Sequential injection of Pt-ADC and [^(18)F]FDG efficiently releases the toxin in the tumor and remarkably suppresses the tumor growth. Radiotherapy is booming as a perturbing tool for prodrug activation,and we find that [^(18)F]FDG is capable of deprotecting various radiotherapy-removable protecting groups(RPGs). Our results suggest that tumor-selective radiopharmaceutical may function as a trigger, for developing innovative prodrug activation strategies with enhanced tumor selectivity.展开更多
基金This work was supported by the Foundation of Education Committee of Fujian Province (JB03052, JB04016, JB04017) and the Student Research Training Program (SRTP) (04075)
文摘A novel platinum（Ⅳ） complex [Ph3PEt]2[PtCl6] 1 obtained from the reaction of H2PtCl6 and [Ph3PEt]I （Ph3PEt^＋ = ethyl-triphenylphosphenonium） has been structurally characterized. It crystallizes in triclinic, space group P1 with a = 10.20850（10）, b = 10.33870（10）, c = 10.814 .A a = 79.453（12）, β = 66.879（ 11 ）, γ = 72.461 （10）°, V = 998.14（9） A^3, Z = 1, Dc = 1.648 g/cm^3, μ（MoKa） = 4.025 mm^-1, F（000） = 490, C40H40Cl6P2Pt, Mr = 990.44, the final R = 0.0270 and wR = 0.0617 for 5787 observed reflections with 1 〉 2σ（Ⅰ）. Structure analysis indicates that the platinum atom almost has the ideal octahedral coordination geometry of PtCl6. The quaternary phosphate cations （Ph3PEt^＋） acting as counter ions are in combination with PtCl6 anions by static attracting forces and H-bonds. Upon the hydrogen bonds existing between cations and anions, the whole structure represents a chain-like construction. Based on the crystal data, quantum chemistry calculation at the DFT/B3LPY level was carded out to reveal the electronic structure of 1.
基金supported by the National Natural Science Foundation of China(Nos.32201171 and 82372115)the Science and Technology Program of Guangzhou(No.202102021266)。
文摘Anticancer platinum prodrugs that can be controllably activated are highly desired for personalized precision medicine and patient compliance in cancer therapy.However,the clinical application of platinum(Ⅳ)prodrugs(Pt(Ⅳ))is restricted by tissue penetration of external irradiation.Here,we report a novel Pt(Ⅳ)activation strategy based on endogenous luminescence of tumor microenvironment responsiveness,which completely circumvents the limitation of external irradiation.The designed Pt(Ⅳ)–Lu,a mixture of trans,trans,trans-[Pt(N_(3))_(2)(OH)_(2)(py)_(2)]and luminol(Lu),has controllable activation property:it remains inert in reductant environment and normal tissues,but under tumor microenvironment,Lu will be oxidized to produce blue luminescence,which rapidly reduce Pt(Ⅳ)to Pt(Ⅱ)without the need of any external activator.Pt(Ⅳ)–Lu shows excellent responsive antitumor ability both in vitro and in vivo.Compared to cisplatin,the median lethal dose in BALB/c mice increased by an order of magnitude.Our results suggest that Pt(Ⅳ)–Lu exhibits highly controllable activation property,superior antitumor activity,and good biosafety,which may provide a novel strategy for the design of platinum prodrugs.
基金financially supported by the National Natural Science Foundation of China (Nos.82020108029, 82073398)supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University (No.SKLNMZZ202021)+4 种基金the"111"Project from the Ministry of Education of Chinathe State Administration of Foreign Experts Affairs of China (No.B16046)Double First-Rate construction plan of China Pharmaceutical University (Nos.CPU2018GY06,CPU2022QZ18)China Postdoctoral Science Foundation (Nos.2021M703598, 2022M720173)Jiangsu Funding Program for Excellent Postdoctoral Talent and International Postdoctoral Exchange Fellowship Program 2022。
文摘Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.
基金was Beijing Municipal Natural Science Foundation (Z200018)National Natural Science Foundation of China (22225603)+2 种基金Ministry of Science and Technology of the People’s Republic of China (2021YFA1601400)Program of the Local Science and Technology Development (Gansu Province) Guided by Central Government (YDZX20216200001201)Changping Laboratory, and the Central Guidance for Local Science and Technology Development Projects (202138-03)。
文摘Chemotherapy is the first-line treatment for cancer, but its systemic toxicity can be severe. Tumorselective prodrug activation offers promising opportunities to reduce systemic toxicity. Here, we present a strategy for activating prodrugs using radiopharmaceuticals. This strategy enables the targeted release of chemotherapeutic agents due to the high tumor-targeting capability of radiopharmaceuticals. [^(18)F]FDG(2-[^(18)F]-fluoro-2-deoxy-D-glucose), one of the most widely used radiopharmaceuticals in clinics, can trigger Pt(IV) complex for controlled release of axial ligands in tumors, it might be mediated by hydrated electrons generated by water radiolysis resulting from the decay of radionuclide18F. Its application offers the controlled release of fluorogenic probes and prodrugs in living cells and tumor-bearing mice. Of note,an OxaliPt(IV) linker is designed to construct an [^(18)F]FDG-activated antibody-drug conjugate(Pt-ADC).Sequential injection of Pt-ADC and [^(18)F]FDG efficiently releases the toxin in the tumor and remarkably suppresses the tumor growth. Radiotherapy is booming as a perturbing tool for prodrug activation,and we find that [^(18)F]FDG is capable of deprotecting various radiotherapy-removable protecting groups(RPGs). Our results suggest that tumor-selective radiopharmaceutical may function as a trigger, for developing innovative prodrug activation strategies with enhanced tumor selectivity.
