Re(I) and Tc(I) Complexes for Targeting Nitric Oxide Synthase: Influence of the Chelator in the Affinity for the Enzyme

Aiming to design ^99mTc complexes for probing nitric oxide synthase (NOS) by SPECT, we synthesized conjugates ( L4 – L6 ) comprising a NOS‐recognizing moiety connected to a diamino‐propionic acid (dap) chelating unit. The conjugates led to complexes of the type fac‐[M(CO)₃(?³‐L)] (M = Re/^99mTc; Re4 / Tc4 : L =  L4 ; Re5 / Tc5 : L =  L5 ; Re6 / Tc6 : L =  L6 ). Enzymatic studies showed that L4 and L5 , but not L6 , gave complexes ( Re4 and Re5 ) that are less potent than the conjugates. To rationalize these results, we performed docking and molecular dynamics simulations. The high affinity of L4 and L5 is due to the strong interactions between the dap chelator and polar residues of the binding cavity. These interactions are hampered by metallation resulting in complexes with lower affinity. The higher potency of Re5 compared to Re4 was assigned to the increased bulkiness of Re5 and the presence of additional anchoring groups that better fit the active site and provide more extensive contacts. In turn, Re6 is too bulky and its organometallic tail is oriented toward the peripheral pocket of iNOS, leading to loss of contacts and a lower affinity. These results were compared with our previous results obtained with analogue complexes stabilized by a pyrazolyl‐diamine chelating unit.     

Enhanced Cytotoxicity through Conjugation of a “Clickable” Luminescent Re(I) Complex to a Cell-Penetrating Lipopeptide

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Luminescent Copolymer‐Rhenium(I) Hybrid Materials via Picolylamine‐Modified Poly(pentafluorophenyl acrylate)

The synthesis and photophysical properties of well‐defined polymer‐rhenium(I) hybrid materials is described. Reversible addition‐fragmentation chain transfer polymerization of pentafluorophenyl acrylate yields a parent homopolymer that serves as a reactive scaffold for the preparation of a series of new statistical copolymers containing pendent pyridyl functional groups in conjunction with various other repeat unit species. Attachment of [Re(CO)₃(phen)]⁺ fragments via coordination through the pendent pyridyl groups yields the hybrid metal‐copolymer materials. Photophysical studies confirm successful rhenium coordination as judged from the absorption and emission profiles of the hybrid materials and further verify that the polymeric scaffold has no discernable effect on the luminescent properties of the coordinated rhenium species.     

血管内照射对兔血管平滑肌细胞增殖和凋亡的影响

目的:探讨188铼(188Re)血管内照射对血管平滑肌细胞增殖和凋亡的影响.方法:40只新西兰白兔随机分为对照组(n=20只)和照射组(n=20只),均行腹主动脉球囊内皮拉伤术.照射组内皮拉伤后行188Re血管内照射治疗,管腔下0.5 mm处累计吸收剂量为15 Gy;对照组则不行血管内照射.分别于术后1、3周处死动物,取病理组织学标本进行增殖细胞核抗原(PCNA)和凋亡细胞分析.结果:照射组第1、3周PCNA细胞阳性率分别为(27.69±7.04)%与(20.88±4.55)%,明显低于对照组(42.71±6.11)%、(29.48±10.13)%(P均＜0.05);照射组第3周平滑肌细胞凋亡细胞百分比为(40.16±7.93)%,明显高于对照组(28.50±9.39)%(P=0.018).结论:188Re血管内照射能抑制血管平滑肌细胞增殖,促进血管平滑肌细胞凋亡,从而抑制新生内膜增生,减少PTCA术后再狭窄的发生.     

MCF-7乳腺癌细胞摄取188Re-DTPA-DG的实验研究

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姜黄素固体分散体的制备及体外溶出特性

目的制备姜黄素固体分散体，改善姜黄素的溶出度。方法以泊洛沙姆188为载体，用溶剂熔融法制备固体分散体，以差示扫描量热法、X射线粉末衍射进行物相鉴定，并对所得样品进行体外溶出度研究。结果姜黄素固体分散体中药物部分以分子状态分散，部分以微晶分散．药物的累积溶出速率随载体比例增加而增加，以1：9的比例效果最好。结论采用泊洛沙姆188制备的固体分散体能显著提高姜黄素的体外溶出度。     

抗人膀胱癌单克隆抗体188Re标记及荷瘤裸鼠体内放射性分布

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In vivo evaluation of 188Re-labeled alpha-melanocyte stimulating hormone peptide analogs for melanoma therapy

The purpose of our study was to optimize melanoma tumor uptake of 188Re-CCMSH and reduce its nonspecific kidney retention. Nephrotoxicity is often a serious problem associated with targeted radiotherapy, therefore, increasing the tumor/kidney uptake ratio of 188Re-CCMSH is crucial for optimizing its therapeutic efficacy. Structural modification of the peptide and amino acid co-infusion were investigated as strategies to improve the tumor/kidney uptake ratio of 188Re-CCMSH. The substitution of Lys11 with Arg11 was examined to determine if removal of lysine from the peptide would improve kidney clearance without sacrificing tumor uptake. The pharmacokinetics of 188Re-CCMSH and 188Re-(Arg(11))CCMSH were determined in B16/F1 murine melanoma-bearing C57 mice. Tumor uptake values of (188)Re-CCMSH and 188Re-(Arg(11))CCMSH were 15.03 +/- 5.20% ID/g and 20.44 +/- 1.91% ID/g at 1 hr postinjection and 1.94 +/- 0.47% ID/g and 3.50 +/- 2.32% ID/g at 24 hr postinjection. Renal retention of 188Re-(Arg(11))CCMSH was 11.79 +/- 1.29 ID/g and 3.67 +/- 0.51 ID/g at 1 hr and 4 hr postinjection, which was a greater than 50% reduction compared to 188Re-CCMSH. The Arg for Lys substitution in 188Re-(Arg(11))CCMSH resulted in improved tumor uptake and reduced kidney retention. Renal retention of both 188Re-CCMSH and 188Re-(Arg(11))CCMSH were significantly reduced by co-injection of 20 mg of L-lysine, L-arginine and a combination of L-lysine:L-arginine. Tumor/kidney uptake values for 188Re-CCMSH and 188Re-(Arg(11))CCMSH were maximally reduced by 52.9% and 46.3%, respectively. However, even with amino acid co-injection, the tumor/kidney ratio of 188Re-CCMSH was lower than that of 188Re-(Arg(11))CCMSH. Improved tumor uptake and reduced kidney retention of 188Re-(Arg(11))CCMSH will facilitate targeted irradiation of melanoma tumors while minimizing the dose to the kidneys.     

188Re-TPA-DG内照射吸收剂量的估算

目的:估算188Re-DTPA-DG(二乙三胺五乙酸-脱氧葡萄糖)肿瘤治疗中肿瘤和主要器官内照射吸收剂量.方法:荷MCF-7乳腺癌裸鼠尾静脉注射后,在3、12、24h处死动物,测定小鼠体内各脏器放射性分布,换算至标准人体内分布数据,按MIRD法计算188Re-DTPA-DG全身、肿瘤和各主要器官的平均总吸收剂量.结果:肿瘤辐射剂量为255.32mSv/MBq,其他脏器内照射吸收剂量在0.002～6.850 mGy/MBq之间,有效剂量为1.420±0.043 mSv/MBq.结论:188Re-DTPA-DG可以作为临床上肿瘤治疗和诊断药物的可能.     

188Re-HEDP治疗转移性骨肿瘤疼痛的临床价值

目的 探讨^188Re—HEDP(^188铼-1-羟基亚乙基二瞵酸盐)治疗转移性骨肿瘤疼痛的临床价值。方法 用^188W-^188Re发生器淋洗的^188Re示踪剂制备^188Re—HEDP，38例癌骨转移患者用^188Re—HEDP治疗，观察其疗效。结果 38例经^188Re—HEDP治疗后骨痛消失12例(31．6％)，骨痛明显减轻19例(50％)，止痛总有效率为83．7％；治疗后骨转移灶完全消失1例(2．6％)，转移灶减少或缩小在50％以上3例(7．9％)，减少或缩小在25％以上5例(13．2％)，转移灶消失或缩小的总有效率为23．7％。结论 ^188Re—HEDP对恶性肿瘤多发性骨转移所致疼痛有明显疗效，且安全无副作用。