The effect of RGD-targeted and non-targeted liposomal Galbanic acid on the therapeutic efficacy of pegylated liposomal doxorubicin: From liposomal preparation to in-vivo studies

Maryam Ebrahimi Nik,Mahmoud Reza Jaafari,Mohammad Mashreghi,Sara Nikoofal-Sahlabadi,Mohamadreza Amin,Hamid Reza Sadeghnia,Mehrdad Iranshahi,Jamshid Gholizadeh Navashenaq,Bizhan Malaekeh-Nikouei

doi:10.1016/j.ijpharm.2021.120710

Abstract

The anti-cancer therapeutic application of Galbanic acid (Gba) as a strong antiangiogenic sesquiterpene coumarin has been limited due to its low water solubility. This issue necessitates developing new liposomal formulations for the efficient delivery of Gba in vivo. In this study, various liposomal formulations were prepared by a thin-film hydration method, and Gba was incorporated into the liposomal bilayers, which consequently increased its release profile compared to formulations in our previous study prepared by remote loading methods. The most stable formulation with desired properties was selected and decorated with RGD peptide (cyclo [Arg-Gly-Asp-D-Tyr-Cys]) to target tumor vasculature actively. The fluorescently-labeled model liposomes showed that the targeting could improve the receptor-mediated endocytosis of the liposomes higher than those prepared in our previous study in vitro in human umbilical vein endothelial cells (HUVECs), which was confirmed by chicken chorioallantoic membrane angiogenesis (CAM) model in vivo. Although not significant, it also could increase the accumulation of liposomes in colon tumors. In BALB/c mice bearing colon cancer, not only non-targeted Gba liposomes but also even RGD-targeted ones combinatorial therapy with pegylated liposomal doxorubicin could improve the anti-tumor efficacy as compared to their monotherapy. These outcomes have strong consequences for cancer therapy.

Highlights

Since its emergence in late 2019, SARS-CoV-2 has rapidly spread across the globe, resulting in more than 160 million confirmed COVID-19 cases and more than 3 million confirmed casualties as of May 15th, 2021
We experimentally analyze the effects of different combinations of these receptor binding domain (RBD) mutations on hACE2 receptor binding affinities
Our results show that receptor binding domains from rapidly spreading variants of SARS-CoV-2 bind with increased affinity to the hACE2 receptor and that this is predominantly caused by the N501Y mutation

Summary

Introduction

Since its emergence in late 2019, SARS-CoV-2 has rapidly spread across the globe, resulting in more than 160 million confirmed COVID-19 cases and more than 3 million confirmed casualties as of May 15th, 2021 (coronavirus.jhu.edu). As revealed by the GISAID initiative (gisaid.org), SARS-CoV-2 slowly but continuously mutates, resulting in some instances in variants that become dominant in the population due to increased transmission and/or immune evasion. A number of these variants carry mutations in the spike protein, which is located on the viral surface and interacts with the angiotensin-converting enzyme (ACE2) on host cells, resulting in membrane fusion and viral entry One such mutation is D614G, which confers increased infectivity and transmissibility and has rapidly become the dominant global variant.[1,2] Another common mutation is N439K, which is located in the receptor binding domain and enhances affinity for the hACE2 receptor by creating a new salt-bridge across the binding interface.[3] SARS-CoV-2 N439K retains fitness and causes infections with similar clinical outcome, and shows immune evasion

Methods

Results

Conclusion