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The Delivery of a Wnt Pathway Inhibitor Toward CSCs Requires Stable Liposome Encapsulation and Delayed Drug Release in Tumor Tissues.

ABSTRACT: The Wnt signaling pathway is involved in tumorigenesis and various stages of tumor progression, including the epithelial-mesenchymal transition, metastasis, and drug resistance. Many efforts have been made to develop drugs targeting this pathway. CGX1321 is a porcupine inhibitor that can effectively block Wnt ligand synthesis and is currently undergoing clinical trials. However, drugs targeting the Wnt pathway may frequently cause adverse events in normal tissues, such as the intestine and skin. Formulation of the drug inside liposomes could enable preferential drug delivery to solid tumor tissues and limit drug exposure in normal organs. We developed a strategy to stably encapsulate CGX1321 inside liposomes with minimal drug releases in circulation. The liposomal drugs were shown to interfere with the aberrant Wnt signaling specifically in tumor tissues, resulting in focused effects on LGR5+ CSCs (cancer stem cells), while sparing other cells from significant cytotoxicity. We showed it is feasible to use such a CSC elimination approach to treat malignant cancers prone to rapid progression using a LoVo tumor model as well as a GA007 patient derived xenograft (PDX) model. Nano drug delivery systems may be required for precision medicine in cancer therapy.

SUBMITTER: Li C

PROVIDER: S-EPMC6732336 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The Delivery of a Wnt Pathway Inhibitor Toward CSCs Requires Stable Liposome Encapsulation and Delayed Drug Release in Tumor Tissues.

Li Chong C Liang Yaoyao Y Cao Jing J Zhang Ning N Wei Xiaohui X Tu Meiqing M Xu Fengwei F Xu Yuhong Y

Molecular therapy : the journal of the American Society of Gene Therapy 20190705 9

The Wnt signaling pathway is involved in tumorigenesis and various stages of tumor progression, including the epithelial-mesenchymal transition, metastasis, and drug resistance. Many efforts have been made to develop drugs targeting this pathway. CGX1321 is a porcupine inhibitor that can effectively block Wnt ligand synthesis and is currently undergoing clinical trials. However, drugs targeting the Wnt pathway may frequently cause adverse events in normal tissues, such as the intestine and skin. ...[more]

PMID: 31350188

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Project description:Aim: Co-encapsulation of anti-cancer agents in pegylated liposomes may provide an effective tool to maximize efficacy of combined drug therapy by taking advantage of the long circulation time, passive targeting, and reduced toxicity of liposome formulations. Methods: We have developed several liposome formulations of co-encapsulated drugs using various permutations of three active agents: doxorubicin (Dox), mitomycin-C lipidic prodrug (MLP), and alendronate (Ald). Dox and MLP are available in single drug liposomal formulations: pegylated liposomal Dox (PLD, Doxil®), clinically approved, and pegylated liposomal MLP (PL-MLP, Promitil®), in phase 1-2 clinical testing. We have previously shown that co-encapsulation of Dox and Ald in pegylated liposomes (PLAD) results in a formulation with valuable immuno-pharmacologic properties and superior antitumor properties over PLD in immunocompetent animal models. Building on the PLAD and PL-MLP platforms, we developed a new pegylated liposomal formulation of co-entrapped Dox and MLP (PLAD-MLP), with the former localized in the liposome water phase via remote loading with an ammonium alendronate and the latter passively loaded into the liposome lipid bilayer. An alternative formulation of co-entrapped MLP and Dox in which ammonium Ald was replaced with ammonium sulfate (PLD-MLP) was also tested for comparative purposes. Results: PLAD-MLP displays high loading efficiency of Dox and MLP nearing 100%, and a mean vesicle diameter of 110 nm. Cryo-transmission electron microscopy (cryo-TEM) of PLAD-MLP reveals round vesicles with an intra-vesicle Dox-alendronate precipitate. PLAD-MLP was tested in an in vitro MLP activation assay with the reducing agent dithiothreitol and found to be significantly less susceptible to thiolytic activation than PL-MLP. Alongside thiolytic activation of MLP, a significant fraction of encapsulated Dox was released from liposomes. PLAD-MLP is stable upon in vitro incubation in human plasma with nearly 100% drug retention. In mouse pharmacokinetic studies, PLAD-MLP extended MLP half-life in circulation when compared to that of MLP delivered as PL-MLP. In addition, the MLP levels in tissues were greater than those obtained with PL-MLP, indicating that PLAD-MLP slows down the cleavage of the prodrug MLP to MMC, thus resulting in a more sustained and prolonged exposure. The circulation half-life of Dox in PLAD-MLP was similar to the PLD Dox half-life. The pattern of tissue distribution was similar for the co-encapsulated drugs, although Dox levels were generally higher than those of MLP, as expected from cleavage of MLP to its active metabolite MMC. In mouse tumor models, the therapeutic activity of PLAD-MLP was superior to PL-MLP and PLD with a convenient safety dose window. The Ald-free formulation, PLD-MLP, displayed similar pharmacokinetic properties to PLAD-MLP, but its therapeutic activity was lower. Conclusion: PLAD-MLP is a novel multi-drug liposome formulation with attractive pharmacological properties and powerful antitumor activity and is a promising therapeutic tool for combination cancer chemotherapy.

Dataset Information

The Delivery of a Wnt Pathway Inhibitor Toward CSCs Requires Stable Liposome Encapsulation and Delayed Drug Release in Tumor Tissues.

Publications

The Delivery of a Wnt Pathway Inhibitor Toward CSCs Requires Stable Liposome Encapsulation and Delayed Drug Release in Tumor Tissues.

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