Elacridar

• CAS: 143664-11-3
• Catalog Number: ACM143664113
• Category: Main Products
• Molecular Weight: 563.6
• Molecular Formula: C34H33N3O5
• Synonyms: N-[4-[2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)ethyl]phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-acridinecarboxamide
• Appearance: Solid

Case Study

Elacridar as an ABCB1/P-glycoprotein Inhibitor to Improve Tissue Distribution in Cabazitaxel Therapy

Loos NHC, et al. International Journal of Pharmaceutics, 2024, 650, 123708.

Elacridar, an ABCB1/P-glycoprotein inhibitor, demonstrates significant potential to optimize tissue distribution in orally administered chemotherapeutics like cabazitaxel, particularly when combined with the CYP3A inhibitor ritonavir. This approach is crucial for enhancing cabazitaxel's therapeutic efficacy, as oral availability is generally hindered by CYP3A-mediated first-pass metabolism and restricted tissue exposure due to ABCB1-mediated efflux.
In a controlled study, coadministration of ritonavir and elacridar effectively improved cabazitaxel's tissue distribution in mice. While ritonavir alone increased the plasma AUC0-2h of cabazitaxel by nearly 2-fold, its effect on tissue penetration, notably the brain, was markedly limited. Introducing elacridar, however, facilitated substantial tissue exposure: in wild-type mice, the brain-to-plasma ratio of cabazitaxel increased 7.3-fold with elacridar alone and 13.4-fold when combined with ritonavir. This synergy between ritonavir and elacridar was further highlighted in CYP3A4-humanized mice, where brain penetration improved up to 4.6-fold, underscoring elacridar's capability to overcome ABCB1 efflux barriers in cabazitaxel therapy.
Notably, while elacridar enhanced tissue penetration, it did not affect the systemic plasma concentration of cabazitaxel, suggesting selective augmentation of drug disposition at targeted sites. Furthermore, elacridar also reversed ABCB1's restrictive effect on ritonavir, improving its oral bioavailability and brain penetration by factors of 3.3 and 10.6, respectively. This study underscores elacridar's critical role as an efflux inhibitor, which, when combined with ritonavir, could significantly broaden the therapeutic index of cabazitaxel in treating solid tumors.

Elacridar-Enhanced Folate-Targeted Nanomicelles for Multidrug Resistance Reversal and Tumor Imaging

Zhang C, et al. Nanomedicine: Nanotechnology, Biology and Medicine, 2018, 14(5), 1847-1848.

Elacridar, a potent P-glycoprotein (P-gp) inhibitor, has shown remarkable efficacy in addressing the critical challenge of multidrug resistance (MDR) in tumor cells, a primary impediment in cancer chemotherapy. MDR often arises from the overexpression of drug efflux transporters, notably P-gp, which actively pump chemotherapeutic agents out of cells, reducing intracellular drug accumulation and thereby diminishing therapeutic efficacy. Early P-gp inhibitors like cyclosporin-A and verapamil were limited by suboptimal MDR reversal and notable cellular toxicity. In contrast, elacridar not only exhibits enhanced binding affinity for P-gp but also offers a safer toxicity profile, making it a prime candidate for overcoming MDR.
A recent study explored the integration of elacridar and doxorubicin (Dox) in folate-targeted, fluorescent PEG-PCL nanomicelles (FA/Cy7-Dox/Ela-micelles) to potentiate drug delivery to resistant tumor cells. These nanomicelles demonstrated a stable size of ~35 nm, confirmed via DLS and TEM, and exhibited superior intracellular accumulation of Dox in resistant MCF-7/ADR tumor cells. The folate targeting allowed receptor-mediated internalization, while elacridar's P-gp inhibition facilitated Dox retention, resulting in elevated cytotoxicity against MDR cells in vitro. In vivo, FA/Cy7-Dox/Ela-micelles further showcased their theranostic potential by providing both enhanced antitumor activity and real-time tumor imaging. The elacridar-mediated approach significantly boosted Dox's therapeutic impact by circumventing MDR, suggesting a robust application for folate-targeted micellar drug delivery systems as a dual-function platform in MDR tumor therapy and imaging.

Elacridar-Enabled Polymer-Lipid Nanoparticles for Enhanced Chemotherapeutic Delivery

Wong HL, et al. J Control Release, 2006, 116(3), 275-284.

Elacridar (GG918) has proven instrumental in reversing multidrug resistance (MDR) within cancer cells, which is often driven by the overexpression of efflux transporters like P-glycoprotein (P-gp). This study presents an advanced polymer-lipid nanoparticle (PLN) formulation co-loaded with the cytotoxic agent doxorubicin (Dox) and the chemosensitizer elacridar, designed to optimize intracellular drug delivery and potentiate Dox efficacy against resistant cancer cells.
The synthesis of the elacridar-Dox nanoparticles (DG)n begins with an ethanol solution of elacridar combined with a lipid mixture, typically triglyceride distearate and stearic acid. After removing solvents in a vacuum, the lipid-elacridar complex is mixed with a heated aqueous solution containing Dox, Pluronic-F68, and hydroxypropyl-starch ethoxylate (HPESO), followed by ultrasonication to achieve submicron-sized lipid emulsions. The emulsion is then diluted in cold water, forming stable PLN encapsulating both Dox and elacridar. Parallel methods were employed to produce nanoparticles containing only Dox or elacridar, serving as comparative controls.
These elacridar-Dox nanoparticles demonstrated a significant increase in Dox retention within MDR cells. By inhibiting P-gp-mediated drug efflux, elacridar enhances intracellular accumulation, thereby amplifying Dox's cytotoxic effects. The (DG)n formulation outperformed Dox-only nanoparticles in cytotoxicity assays, underscoring elacridar's vital role in overcoming MDR mechanisms. This elacridar-enabled PLN system highlights the potential of dual-loading nanoparticles for MDR cancers, where elacridar functions as an effective chemosensitizer within a robust drug delivery platform.