Metcalf, Chet, Svenson, Sonke , Hwang, Jungyeon, Tripathi, Snehlata, Gangal, Geeti, Kabir, Sujan, Lazarus, Douglas, Cole, Roderic, Sweryda-Krawiec, Beata, Shum, Pochi, Brown, Donna, Case, Roy, van der Poll, Derek, Harlfinger, Stephanie, Teng, Chi-Hse, Rohde, Ellen and Eliasof, Scott (2019) 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. Journal of Medicinal Chemistry, 62 (21). pp. 9541-9559. ISSN 0022-26231520-4804

Abstract

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.

Item Type:	Article
Date Deposited:	28 Nov 2019 00:45
Last Modified:	28 Nov 2019 00:45
URI:	https://oak.novartis.com/id/eprint/34980