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

Authors:
Publisher website
Google Scholar
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 relationship (SAR). Improved in vivo pharmacokinetics (PK) for the cabazitaxel (CBTX) NDCs with glycinate- (1c) and hexanoate-containing linkers (2c) were demonstrated, along with high and sustained tumor levels (>168 hrs 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 an optimal and improved in vivo PK (plasma and tumor) and efficacy profile vs. parent drug, and the results support the potential therapeutic use of CRLX522 as a new anticancer agent.
Funding Information
  • Novartis

This publication has 64 references indexed in Scilit: