Camptothecin (CPT), a potent inhibitor of topoisomerase I and HIF-1α, failed to demonstrate utility as an anti-cancer agent in early clinical trial investigations, primarily due to limited clinical activity and significant toxicity attributable to unfavorable physicochemical properties (e.g. low plasma solubility, pH-labile lactone ring). NLG207 (formerly CRLX101), a nanoparticle-drug conjugate (NDC) of CPT designed to optimize plasma pharmacokinetics and facilitate drug delivery to tumors, is included as part of combination treatment in two Phase II clinical trials ongoing at the National Cancer Institute (NCT02769962 and NCT03531827). To better understand the potential for drug-drug interactions and to correlate drug exposure to clinical outcomes and pharmacodynamic biomarkers, a robust analytical method was developed to measure CPT in human plasma. Two sample processing methods were developed to quantify both NDC-bound CPT and free CPT, primarily via alteration of pH conditions. A solid-phase extraction recovered >79 % of CPT prior to quantitative analysis by ultra HPLC-MS/MS. Dynamic calibration ranges of 10 to 10,000 ng/mL and 1 to 1000 ng/mL for total and free CPT, respectively were utilized to capture clinical ranges. NLG207 NDCs demonstrated significant rates of CPT release in human plasma at room temperature after 2 h but were shown to be stable at 4 °C for 24 h and through 4 freeze/thaw cycles. This assay was used to quantitate CPT plasma concentrations in clinical samples to confirm clinical utility following NLG207 treatment in subjects with advanced prostate cancer.

中文翻译：

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NLG207（以前称为CRLX101）纳米粒子结合和释放的喜树碱在人体血浆中的测量。

喜树碱（CPT）是拓扑异构酶I和HIF-1α的有效抑制剂，未能在早期临床试验研究中证明其作为抗癌药的效用，这主要是由于有限的理化性质（例如低血浆）引起的临床活性有限和明显的毒性溶解度，pH不稳定的内酯环）。NLG207（以前称为CRLX101）是CPT的一种纳米颗粒-药物结合物（NDC），旨在优化血浆药代动力学并促进药物向肿瘤的递送，被纳入美国国家癌症研究所正在进行的两项II期临床试验的联合治疗（NCT02769962和NCT03531827）。为了更好地了解药物相互作用的潜力，并将药物暴露与临床结果和药效生物标志物相关联，开发了一种强大的分析方法来测量人血浆中的CPT。主要通过改变pH条件，开发了两种样品处理方法来定量结合NDC的CPT和游离的CPT。在通过超高效液相色谱-质谱/质谱法进行定量分析之前，固相萃取回收了> 79％的CPT。总和游离CPT的动态校准范围分别为10到10,000 ng / mL和1到1000 ng / mL，以捕获临床范围。NLG207 NDCs在室温下2小时后在人血浆中显示出显着的CPT释放速率，但在4°C下保持24 h并经过4次冷冻/解冻循环后显示稳定。该测定法用于定量临床样品中的CPT血浆浓度，以确认NLG207治疗后在晚期前列腺癌患者中的临床实用性。主要通过改变pH条件，开发了两种样品处理方法来定量结合NDC的CPT和游离的CPT。在通过超高效液相色谱-质谱/质谱法进行定量分析之前，固相萃取回收了> 79％的CPT。总和游离CPT的动态校准范围分别为10到10,000 ng / mL和1到1000 ng / mL，以捕获临床范围。NLG207 NDCs在室温下2小时后在人血浆中显示出显着的CPT释放速率，但在4°C下保持24 h并经过4次冷冻/解冻循环后显示稳定。该测定法用于定量临床样品中的CPT血浆浓度，以确认NLG207治疗后在晚期前列腺癌患者中的临床实用性。主要通过改变pH条件，开发了两种样品处理方法来定量结合NDC的CPT和游离的CPT。在通过超高效液相色谱-质谱/质谱法进行定量分析之前，固相萃取回收了> 79％的CPT。总和游离CPT的动态校准范围分别为10到10,000 ng / mL和1到1000 ng / mL，以捕获临床范围。NLG207 NDCs在室温下2小时后在人血浆中显示出显着的CPT释放速率，但在4°C下保持24 h并经过4次冷冻/解冻循环后显示稳定。该测定法用于定量临床样品中的CPT血浆浓度，以确认NLG207治疗后在晚期前列腺癌患者中的临床实用性。在通过超高效液相色谱-质谱/质谱法进行定量分析之前，固相萃取回收了> 79％的CPT。总和游离CPT的动态校准范围分别为10到10,000 ng / mL和1到1000 ng / mL，以捕获临床范围。NLG207 NDCs在室温下2小时后在人血浆中显示出显着的CPT释放速率，但在4°C下保持24 h并经过4次冷冻/解冻循环后显示稳定。该测定法用于定量临床样品中的CPT血浆浓度，以确认NLG207治疗后在晚期前列腺癌患者中的临床实用性。在通过超高效液相色谱-质谱/质谱法进行定量分析之前，固相萃取回收了> 79％的CPT。总和游离CPT的动态校准范围分别为10到10,000 ng / mL和1到1000 ng / mL，以捕获临床范围。NLG207 NDCs在室温下2小时后在人血浆中显示出显着的CPT释放速率，但在4°C下保持24 h并经过4次冷冻/解冻循环后显示稳定。该测定法用于定量临床样品中的CPT血浆浓度，以确认NLG207治疗后在晚期前列腺癌患者中的临床实用性。NLG207 NDCs在室温下2小时后在人血浆中显示出显着的CPT释放速率，但在4°C下保持24 h并经过4次冷冻/解冻循环后显示稳定。该测定法用于定量临床样品中的CPT血浆浓度，以确认NLG207治疗后在晚期前列腺癌患者中的临床实用性。NLG207 NDCs在室温下2小时后在人血浆中显示出显着的CPT释放速率，但在4°C下保持24 h并经过4次冷冻/解冻循环后显示稳定。该测定法用于定量临床样品中的CPT血浆浓度，以确认NLG207治疗后在晚期前列腺癌患者中的临床实用性。