Cristal Therapeutics, Maastricht, the Netherlands.
Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany.
Adv Drug Deliv Rev. 2022 Dec;191:114613. doi: 10.1016/j.addr.2022.114613. Epub 2022 Nov 4.
Nanomedicines are used to improve the efficacy and safety of pharmacotherapeutic interventions. Unraveling the biological behavior of nanomedicines, including their biodistribution and target site accumulation, is essential to establish design criteria that contribute to superior performance. CriPec® technology is based on amphiphilic methoxy-poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide lactate] (mPEG-b-pHPMAmLac) block copolymers, which are designed to upon self-assembly covalently entrap active pharmaceutical ingredients (API) in core-crosslinked polymeric micelles (CCPM). Key features of CCPM are a prolonged circulation time, high concentrations at pathological sites, and low levels of accumulation in the majority of healthy tissues. Proprietary hydrolysable linkers allow for tunable and sustained release of entrapped API, including hydrophobic and hydrophilic small molecules, as well as peptides and oligonucleotides. Preclinical imaging experiments provided valuable information on their tumor and tissue accumulation and distribution, as well as on uptake by cancer, healthy and immune cells. The frontrunner formulation CPC634, which refers to 65 nm-sized CCPM entrapping the chemotherapeutic drug docetaxel, showed excellent pharmacokinetic properties, safety, tumor accumulation and antitumor efficacy in multiple animal models. In the clinic, CPC634 also demonstrated favorable pharmacokinetics, good tolerability, signs of efficacy, and enhanced localization in tumor tissue as compared to conventional docetaxel. PET imaging of radiolabeled CPC634 showed quantifiable accumulation in ∼50 % of tumors and metastases in advanced-stage cancer patients, and demonstrated potential for use in a theranostic setting even when applied at a companion diagnostic dose. Altogether, the preclinical and clinical results obtained to date demonstrate that mPEG-b-pHPMAmLac CCPM based on CriPec® technology are a potent, tunable, broadly applicable and well-tolerable platform for targeted drug delivery and improved anticancer therapy.
纳米药物被用于提高药物治疗干预的疗效和安全性。揭示纳米药物的生物学行为，包括它们的生物分布和靶部位积累，对于建立有助于卓越性能的设计标准至关重要。CriPec®技术基于两亲性甲氧基聚（乙二醇）-b-聚[N-（2-羟丙基）甲基丙烯酰胺乳酸酯]（mPEG-b-pHPMAmLac）嵌段共聚物，旨在自组装时将活性药物成分（API）共价包埋在核交联聚合物胶束（CCPM）中。CCPM 的主要特点是延长循环时间、在病变部位高浓度聚集，以及在大多数健康组织中低积累。专有可水解键允许包埋的 API 进行可调且持续的释放，包括疏水性和亲水性小分子、肽和寡核苷酸。临床前成像实验提供了有关其肿瘤和组织积累和分布以及癌症、健康和免疫细胞摄取的宝贵信息。先导制剂 CPC634 是指 65nm 大小的 CCPM 包埋化疗药物多西他赛，在多种动物模型中表现出优异的药代动力学特性、安全性、肿瘤积累和抗肿瘤疗效。在临床中，与传统多西他赛相比，CPC634 也表现出良好的药代动力学特性、良好的耐受性、疗效迹象和增强的肿瘤组织定位。放射性标记的 CPC634 的 PET 成像显示，在晚期癌症患者中，约 50%的肿瘤和转移部位可定量积累，并且即使在伴随诊断剂量下应用，也具有用于治疗诊断的潜力。总之，迄今为止获得的临床前和临床结果表明，基于 CriPec®技术的 mPEG-b-pHPMAmLac CCPM 是一种强大、可调、广泛适用且耐受性良好的靶向药物递送和改善抗癌治疗的平台。
