Transarterial chemoembolization with miriplatin-lipiodol emulsion for neuroendocrine metastases of the liver

Miriplatin,a cisplatin derivative with a high affinity for iodized oil,is a novel chemotherapeutic agent designed for use in the transarterial treatment of hepatocellular carcinoma.This case report describes our experience with transarterial chemoembolization(TACE) using miriplatin in 2 patients with neuroendocrine liver metastases.A 38-year-old man with multiple neuroendocrine liver metastases was treated by whole liver chemoembolization,and a 35-year-old woman with a single hepatic lesion was treated by superselective chemoembolization.No serious adverse events were noted during the interventional procedures,or during the observation period of 3 mo in either patient.Sufficient iodized oil uptake was observed in the hypervascular lesions on the unenhanced computed tomography(CT) at 7 d after the procedure.Contrast-enhanced CT obtained at 3 mo after chemoembolization revealed that all hepatic lesions were substantially reduced in size irrespective of tumor vascularity or degree of cystic degeneration,although iodized oil accumulation was only marginal for lesions with cystic degeneration.Thus,TACE with miriplatin can be a safe and effective therapeutic option for the treatment of neuroendocrine metastases of the liver.

Effects of Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma Using a Combination of Platinum Agents (Cisplatin plus Miriplatin): A Retrospective Comparison with Cisplatin Monotherapy

Background: Miriplatin is a slow-release, lipophilic platinum complex, developed to produce a superior antitumor effect for hepatocellular carcinoma (HCC). However, the miriplatin suspension is highly viscous and can form an embolism in the hepatic artery, which can result in insufficient antitumor effect. Thus, reducing the viscosity of the suspension compound by combining it with the less-viscous cisplatin suspension might reduce or even prevent vessel embolism, while providing the quick-release effects of cisplatin. Purpose: To compare the outcomes of therapy using miriplatin plus cisplatin and cisplatin monotherapy in transcatheter arterial chemoembolization (TACE) for HCC. Methods: We retrospectively evaluated a total of 87 patients with Barcelona Clinic Liver Cancer (BCLC) stage A or B HCC who received conventional TACE using a combination of platinum agents (cisplatin and miriplatin) (n = 50) or cisplatin alone (n = 37) for the first time from September 2006 to December 2012. Short term therapeutic effect was measured by dynamic computed tomography 1 - 3 months after TACE, in reference to the modified Response Evaluation Criteria in Solid Tumors. Treatment-related adverse effects were graded by the National Cancer Institute Common Terminology Criteria (ver. 4.0). 1-, 3-, and 5-year survival rates were calculated. Subgroup analyses were performed by Child-Pugh classification and BCLC criteria. Results: Median duration of follow-up was 35 months (range 7 - 90). Median overall survival was 38 months. Patients who had combination therapy had better 1-, 3-, and 5-year survival rates: 100%, 56.7%, and 26.2%, respectively, compared to monotherapy: 100%, 42.1%, and 9.0%, respectively (p = 0.034). No serious complication or treatment-related mortality was observed in both groups. Conclusion: TACE using miriplatin plus cisplatin was related to a prolonged survival, with comparable adverse effects of TACE using cisplatin alone.

Improved Synthesis of Miriplatin

Miriplatin, a novel lipophilic platinum complex has been developed to treat hepatocellular carcinoma. An improvd synthetic route was designed and used to prepare the target compound. The intermediate Pt(C6H14N2)(I) 2 was synthesized from K 2 PtCl 4 , KI and (1R,2R)-1,2-cyclohexanediamine, Pt(C 6 H 14 N 2 )(I) 2 was reacted with AgNO 3 to prepare Pt(C 6 H 14 N 2 )(H 2 O) 2 (NO 3 ) 2 solution then was subsequently reacted with CH 3 (CH 2 ) 12 COONa in n-butanol to give target compound with satisfied yield 81%(based on Pt(C 6 H 14 N 2 )I 2 ). The structure of the target compound was identified by elemental analysis, ESI-MS, FT-IR, 1H-NMR, thermal analysis, the structure was consistent with the target compound.

Nanomedicine integrating the lipidic derivative of 5-fluorouracil,miriplatin and PD-L1 si RNA for enhancing tumor therapy

Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied clinically.In this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for chemo-immunotherapy.In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages.Furthermore,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition.The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.

脂溶性铂复合物抗癌药——Miriplatin Hydrate

Miriplatin Hydrate是大日本住友制药株式会社开发的脂溶性铂复合物抗癌药,商品名：Miripla,化学名：（SP-4-2）-[（1R,2R）-1,2环己二氨-N,N′]二（十四酸-O）合铂,CAS登记号：141977-79-9,结构式见图1,分子式C34H68N2O4Pt·H2O，相对分子质量：782．01。用于肝细胞癌，将70mg本品溶于3．5mL本品专用混悬液中，

miR-34a和米铂共载阳离子脂质体的构建及抗肿瘤活性研究

目的 构建共载miR-34a和米铂阳离子脂质体,以协同增效,用于肿瘤的化疗。方法 采用薄膜分散法制备米铂阳离子脂质体(MCL),将MCL与miR-34a共孵育,构建共载miR-34a和米铂的阳离子脂质体(MCL/miR-34a)。以粒径及多分散系数、电位、米铂含量和抗肿瘤活性为指标,对辅助磷脂(DOPE、DOPC、DMPC、DSPC、PC-98T)的种类、阳离子磷脂DOTAP/DOPE比、N/P、DSPE-mPEG2000及胆固醇用量进行筛选;选用磺酰罗丹明B染色法在细胞(人乳腺癌细胞系MDA-MB-231、人肝癌细胞系HepG2、人口腔表皮样癌细胞系KB和人胰腺癌细胞系As PC-1)水平评价MCL/miR-34a的抗肿瘤活性。结果 构建的MCL/miR-34a粒径均匀[(200±23)nm]且分布窄(PDI=0.242±0.01)、电位适宜[(45±8)m V]、包封率高(miR-34a的包封率99.2%,米铂的包封率99.8%),细胞水平上抗肿瘤活性显著优于单药米铂或mi R-34a。结论 成功构建的MCL/miR-34a可显著提高miR-34a和米铂的体外抗肿瘤活性,为核酸药物与小分子化疗药物共同递送提供新策略。

尺寸排阻色谱-电感耦合等离子体质谱联用研究比格犬血浆中米铂及铂代谢物形态

建立了基于尺寸排阻色谱-电感耦合等离子体质谱联用(SEC-ICP-MS)分析比格犬血浆中米铂及其铂代谢物形态的方法。半定量测得的血浆中总铂的含量与传统ICP-MS直接测定方法基本相同。采用BioSep-s2000型色谱柱在25 mmol/L磷酸盐缓冲液(pH 7.2)的色谱条件下与ICP-MS联用检测同位素Pt-195发现,血浆中有米铂原型和4种铂代谢物;将不同时间点采集的血浆进行铂形态分析发现,与蛋白结合的铂代谢物m2含量最高;米铂不与血浆蛋白结合。对比米铂与m2的相对含量发现,米铂原型与m2的比例在给药初期迅速下降,后缓慢上升,再随血药浓度的下降而缓慢下降。

HPLC法测定米铂白蛋白结合型纳米制剂中米铂的含量

目的建立米铂白蛋白结合型纳米制剂中米铂含量测定的高效液相色谱(HPLC)法。方法采用HPLC测定米铂白蛋白结合型纳米制剂中米铂的含量。色谱条件:辛烷基硅烷键合硅胶色谱柱(250 mm×4.6 mm,5μm),甲醇-乙腈-水(91:1:8)洗脱,流速1.0 ml/min,检测波长210 nm,柱温30℃,进样量20μl。结果建立了简便可行的米铂白蛋白结合型纳米制剂样品前处理方法;建立并验证了HPLC方法,线性范围3.63~130.80μg/ml(r=0.9995);低、中、高3个浓度的平均回收率(n=3)分别为(99.46±0.24)%、(99.20±1.38)%、(98.30±0.26)%;日内、间精密度RSD分别为1.62%(n=6)和1.32%(n=6);流速在0.99~1.01 ml/min范围内变化时米铂峰面积的RSD为1.01%(n=9),柱温在28~32℃之间变化时米铂峰面积的RSD为1.14%(n=9)。结论本文建立的含量测定方法简便易行,专属性强,灵敏度高,耐用性好;可定量检测米铂白蛋白结合型纳米制剂中米铂的含量。

铂抗肿瘤药米铂的热稳定性与晶型研究

对铂类抗肿瘤药物米铂的热稳定性和晶型进行了分析与研究.通过热分析(DSC-TG)法测定药物的熔点及结晶水的含量,并结合X射线粉末衍射仪(XPRD)及其原位高温(in-situ high temperature)附件测定了样品米铂的晶型结构及在加热过程中的晶型热稳定性.结果表明,试样米铂含有一个结晶水,加热到51.64℃时开始失去结晶水,在74.18℃发生微小的晶相转变,从亚稳态晶型转变为稳态晶型,210℃时转变为非晶态,221.81℃发生熔融变化,开始分解.

电感耦合等离子体放射光谱法测定抗癌药物米铂中微量金属杂质及其安全性评价

目的建立测定抗癌药物米铂中微量金属杂质的电感耦合等离子体放射光谱(ICP-AES)法,为评价米铂的金属残留对人体的影响提供方法。方法试样于600℃灼烧后经HCl-HNO3溶解,用ICP-AES法直接测定抗癌药物米铂中的微量金属杂质。结果对分析方法进行了验证,线性相关系数(r)为0.99 91~1.000 0,方法精密度为1.1%~5.3%,准确度为85.22%~109.60%,均符合药典要求;通过测定,计算出了钯(Pd)、铑(Rh)、铱(Ir)、钌(Ru)、镍(Ni)、铬(Cr)、铜(Cu)、锰(Mn)、铁(Fe)、锌(Zn)的实际日接触量,远小于允许日接触量(PDE)。结论 ICP-AES法简便、快速、准确,米铂中的金属残留物被充分除去,该药进入人体后,金属杂质的微量残留不会影响人体健康,无安全隐患。

顺式-碘氯[(1R,2R)-(-)-1,2-环己二胺]合铂(Ⅱ)的合成及结构表征

为了合成新型铂抗癌药物米铂的代谢产物之一顺式-碘氯[(1R,2R)-(-)-1,2-环己二胺]合铂(Ⅱ),以K2PtCl4为起始原料先后与二甲基亚砜、(1R,2R)-(-)-1,2-环己二胺、AgNO3、KI和KCl反应合成目标化合物。采用元素分析、质谱、核磁共振氢谱、红外光谱和热分析方法分析其组成和结构,结果显示合成的化合物结构与标题化合物一致。

HPLC测定注射用米铂的含量

目的建立HPLC法测定注射用米铂的含量。方法采用ThermoBDSHYPERSIL—C18（4．6mm×250mm，5μm）色谱柱；以乙腈-0．1mol／L磷酸氢二钠溶液（磷酸溶液调节pH值至5．0）（75：25）为流动相；流速为1．0mL／min；检测波长为220nm。结果米铂在60．02-240．08μg／mL浓度范围内线性较好（r=0．9999），平均回收率为99．85％，RSD为0．33％。结论本方法准确、可靠、操作性强，可用于注射用米铂含量的测定。

RP-HPLC法测定米铂的含量

目的建立以反相高效液相色谱法测定米铂含量的方法。方法色谱柱为十八烷基硅烷键合硅胶柱(C_(18),4.6 mm×150 mm,5μm),流动相为叔丁醇-乙腈(9∶1),流速:1.0 m L·min^(-1),柱温:30℃,紫外检测波长:220 nm,进样量:20μL。结果米铂在40.68~305.10μg·m L^(-1)的检测浓度内呈良好的线性关系,R^2=1;平均回收率为100.13%(n=9),RSD为0.15%。结论本方法简便、快速、准确,回收率好,可用于米铂的含量测定。

注射用米铂的制备及表征

目的:制备和表征注射用米铂。方法:快速冷冻法制备注射用米铂;以热分析(DSCTG)法测定药物的熔点及水分含量,采用动态光散射法考察药物的粒径分布,采用扫描电镜观察其微观形态。结果:注射用米铂在182.60℃发生微小的晶相转变,从亚稳态晶型转变为稳态晶型,219.41℃发生熔融变化,开始分解;粒度分布特征值(d0.15.353μm,d0.59.601μm,d0.917.332μm);扫描电镜观察其微观形态呈类球形。结论:成功制备注射用米铂微粒,便于工业化生产。

肝癌介入治疗新药米铂的药理与临床研究

米铂是第三代铂类抗肿瘤药物,其与碘化油亲和性高,且肝动脉内给药后滞留于肿瘤部位,混悬液中的铂成分可长时间缓慢释放进入血液或组织中。其与DNA结合,通过阻止DNA合成而产生细胞毒效应。临床研究结果表明,米铂治疗肝细胞癌具有良好的疗效和安全性。现对其药理学、药动学、临床研究及安全性评价等作一综述。

米铂原料中光学异构体杂质研究

目的：建立米铂原料药中光学异构体杂质的定性及定量研究。方法：利用高效液相色谱法,采用主成分自身对照法对光学异构体杂质进行定量分析。结果：米铂在浓度0.2066～41.32μg·m L^-1,S,S异构体（杂质A）在浓度0.199 2～39.84μg·m L^-1范围内,R,S异构体（杂质B）在浓度0.195 8～39.16μg·m L^-1,浓度与峰面积线性关系良好,并且米铂,R,S异构体和S,S异构体的定量限（S/N=10）分别为10.33,9.79,9.96 ng;检测限（S/N=3）分别为5.16,4.90,4.98 ng。结论：本研究建立的主成分自身对照法灵敏度高,重复性好,适用于米铂原料中光学异构体杂质的定性定量分析。

铂类抗肿瘤药物米铂的合成及结构表征

目的:合成抗肿瘤新药米铂。方法:以顺式-(1R,2R)-1,2-环己二胺-二碘合铂(环铂)、硝酸银、正十四碳酸、氢氧化钠为原料合成米铂,采用元素分析、质谱、红外光谱、核磁共振氢谱和热分析对其结构进行表征。结果:合成的化合物结构与标题化合物一致,产率约73%。结论:该方法便于操作,产率高,适合进一步研究。

HPLC法测定米铂脂质体中米铂的含量

目的:建立米铂脂质体中米铂的含量测定方法。方法:采用HPLC法测定米铂脂质体中米铂的含量。色谱条件:采用Agilent C_8色谱柱(250 mm×4.6 mm,5μm),以甲醇-水(92∶8)为流动相,流速1.0m L·min^(-1),检测波长210 nm,柱温30℃,进样量20μL。结果:色谱分离度R=2.91,阴性对照无干扰;米铂在3.37~115.11μg·m L^(-1)范围内线性关系良好(r=0.999 9);低、中、高3种浓度的平均回收率分别为97.1%(RSD=0.90%,n=3)、97.0%(RSD=0.10%,n=3)和98.7%(RSD=0.59%,n=3);日内精密度RSD=0.75%(n=6),日间精密RSD=1.0%(n=6);流速在0.99~1.01 m L·min^(-1)范围内变化时RSD=0.49%(n=9),柱温在28~32℃之间变化时RSD=1.7%(n=9)。结论:本文建立的方法简便易行,稳定,准确,专属性强,耐用性好;可定量检测米铂脂质体中米铂的含量。

抗肿瘤药米铂的一种新合成方法及结构表征

目的合成抗肿瘤新药米铂。方法以顺式-(1R,2R)-1,2-环己二胺-二碘合铂(Ⅱ)为起始原料,先将顺式-(1R2,R)-12,-环己二胺-二碘合铂(Ⅱ)与硫酸银水解成含有硫酸根的水合物溶液,然后与八水氢氧化钡反应生成顺式-(1R2,R)-12,-环己二胺-二羟基合铂(Ⅱ)的水溶液,最后与正十四碳酸的正丁醇溶液反应合成米铂。采用元素分析、质谱、红外光谱、核磁共振氢谱和热分析对其结构进行表征。结果与结论合成的化合物结构与标题化合物一致,收率约68%。该方法便于操作,收率高,可做进一步研究。

抗肿瘤药米铂的合成工艺改进

目的改进抗肿瘤药米铂的合成工艺。方法以顺式-二碘-(1R,2R)-1,2-环己二胺合铂(Ⅱ)为起始原料,将顺式-二碘-(1R,2R)-1,2-环己二胺合铂(Ⅱ)与硝酸银水解合成含有硝酸根的水合物溶液,然后与阴离子树脂交换生成顺式-二羟基-(1R,2R)-1,2-环己二胺合铂(Ⅱ)的水溶液,再与正十四碳酸的正丁醇溶液反应合成米铂。采用元素分析、质谱、红外光谱、核磁共振氢谱、热分析和比旋光度对其结构进行表征。结果与结论合成的化合物结构与标题化合物一致,收率约75%。该方法便于操作,收率高。