Liposomal encapsulation enhances the antitumour efficacy of the vascular disrupting agent ZD6126 in murine B16.F10 melanoma

Abstract

Vascular disrupting agents (VDAs) are able to affect selectively tumour endothelial cell morphology resulting in vessel occlusion and widespread tumour cell necrosis. However, single-agent antitumour activity of VDAs is typically limited, as tumour regrowth occurs rapidly following drug treatment. To improve the therapeutic effectiveness of VDAs, we investigated liposomal targeting using ZD6126 as a model VDA. ZD6126 is a phosphate-prodrug of the tubulin-binding vascular disrupting agent ZD6126 phenol. ZD6126 was encapsulated into long circulating PEG-liposomes for passive targeting and PEG-liposomes conjugated with peptide ligands containing the RGD-motif for active targeting to a v -integrins on tumour endothelial cells. ZD6126 could be stably encapsulated, and liposomes displayed minimal leakage in vitro (o10% in 3 weeks). In vivo, upon intravenous injection, free ZD6126 was rapidly converted into ZD6126 phenol, which was cleared from the circulation within minutes. In contrast, ZD6126 encapsulated into either RGD-targeted or PEG liposomes showed prolonged blood circulation times (t 1/2 ¼ 10 h), and ZD6126 phenol exposure was also prolonged (t 1/2 ¼ 8 h). Both liposomal formulations displayed tumour accumulation plus hepatosplenic uptake by local macrophages. The altered pharmacokinetics and tissue distribution profiles of both liposomal ZD6126 formulations resulted both in single-dose and multiple-dose regimes, in improved therapeutic efficacy in established murine B16.F10 melanomas compared with free ZD6126. The passively and actively targeted liposomes showed equal antitumour efficacy, indicating that delivery of ZD6126 to the tumour tissue may suffice to disrupt tumour blood vessels without the need for specific targeting to the tumour endothelium.

Nanoformulations of a Potent copper-based Aquaporin Inhibitor With Cytotoxic Effect Against Cancer Cells

“…The slight increase in the observed IC 50 values suggests that Cuphen remains incorporated in liposomes and, as such, is not immediately available to exert cytotoxic effects. Similar observations have been reported for other antitumor drugs [60]. As previously observed for the free form of the metallodrug, the efficacy of Cuphen liposomes must not only consider the IC 50 value ( Table 2) but also the survival rates, reflecting the extension of the cytotoxic effect.…”

Integrin-Mediated Drug Delivery in Cancer and Cardiovascular Diseases with Peptide-Functionalized Nanoparticles

“…Importantly, these liposomes effectively prevented lung metastases induced with B16F10 melanoma cells. Schiffelers and co-workers [147] half-life and improved the therapeutic efficacy with respect of free ZD6126.…”

Combination drug delivery via multilamellar vesicles enables targeting of tumor cells and tumor vasculature

“…Recently, important advances have been made to employ nanotechnology for drug delivery, enhancing the therapeutic efficacy of several anticancer drugs (Cho, Wang, Nie, Chen, & Shin, ; Davis, Chen, & Shin, ; Ling et al, ; Sun et al, ; Xu et al, ). Compared to free drugs, drug‐loaded nanoparticles can successfully provide targeted delivery with better efficacy and fewer side‐effects by prolonging blood circulation time, controlling sustained drug release, reducing systemic toxicities, and increasing drug concentration in cancer tissue through the enhanced permeability and retention (EPR) effect (Cho et al, ; Davis et al, ; Fens et al, ; Hu, Aryal, & Zhang, ; Joo et al, ; Liu, Fang, Joo, Wong, & Wang, ; Liu, Fang, Kim, Wong, & Wang, ; Straubinger et al, ; Waite & Roth, ; Wu et al, ).…”