Discovery of a Novel Cabazitaxel Nanoparticle–Drug Conjugate (CRLX522) with Improved Pharmacokinetic Properties and Anticancer Effects Using a β‑Cyclodextrin–PEG Copolymer Based Delivery Platform

Novel
nanoparticle–drug conjugates (NDCs) containing diverse,
clinically relevant anticancer drug payloads (docetaxel, cabazitaxel,
and gemcitabine) were successfully generated and tested in drug discovery
studies. The NDCs utilized structurally varied linkers that attached
the drug payloads to a β-cyclodextrin–PEG copolymer to
form self-assembled nanoparticles. In vitro release studies revealed
a diversity of release rates driven by linker structure–activity
relationships (SARs). Improved in vivo pharmacokinetics (PK) for the
cabazitaxel (CBTX) NDCs with glycinate-containing (1c) and hexanoate-containing linkers (2c) were demonstrated,
along with high and sustained tumor levels (>168 h of released
drug
in tumor tissues). This led to potent efficacy and survival in both
taxane- and docetaxel-resistant in vivo anticancer mouse efficacy
models. Overall, the CBTX-hexanoate NDC 2c (CRLX522),
demonstrated optimal and improved in vivo PK (plasma and tumor) and
efficacy profile versus those of the parent drug, and the results
support the potential therapeutic use of CRLX522 as a new anticancer
agent.

本研究成功制备并在药物发现研究中测试了一系列搭载多种临床相关抗癌有效载荷（多西他赛、卡巴他赛与吉西他滨）的新型纳米颗粒-药物偶联物（nanoparticle–drug conjugates, NDCs）。该类NDCs采用结构各异的连接子，将药物有效载荷偶联至β-环糊精-聚乙二醇共聚物上，进而形成自组装纳米颗粒。体外释放研究表明，连接子的构效关系（structure–activity relationships, SARs）介导了多样化的药物释放速率。研究证实，搭载含甘氨酸酯连接子（1c）与含己酸酯连接子（2c）的卡巴他赛（cabazitaxel, CBTX）NDCs具有更优的体内药代动力学（pharmacokinetics, PK）特性，同时可在肿瘤组织中使释放的药物维持高浓度，持续时长超过168小时。该特性使其在紫杉烷类与多西他赛耐药的体内抗癌小鼠药效模型中展现出强效的抗肿瘤活性与生存获益。综上，含己酸酯连接子的卡巴他赛NDC 2c（CRLX522）相较其母药展现出更优异的体内药代动力学（血浆与肿瘤组织）特性与药效谱，研究结果支持CRLX522作为新型抗癌药物的潜在临床治疗应用价值。