Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 600, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2021.120532
Keywords
Triple-negative breast cancer; Guanabenz acetate; Repurposing; Polymersomes; PEG-PCL; Nanoprecipitation; Process variables; Biodistribution; Anti-cancer activity
Categories
Ask authors/readers for more resources
The study successfully developed a novel cancer therapeutic by repurposing guanabenz acetate (GA), leading to the formulation of GA-loaded PS nanoparticles. In vitro tests on cellular uptake, anti-cancer, and anti-metastatic activity of GA-loaded PS showed promising results, indicating enhanced efficacy compared to free GA in both breast cancer cell lines.
Poor patient response and limited treatment modalities are the major challenges against combating triple-negative breast cancer (TNBC). The high related mortality urges for novel cancer therapeutics. Guanabenz acetate (GA) is an orphan antihypertensive drug with a short half-life. Re-purposing (GA) by developing a poly-mersome (PS)-based cancer nanomedicine is an innovative approach in treating TNBC. Formulation and optimization of GA-loaded PEGylated Polycaprolactone PS through different process variables (solvent selection, the order of addition, pH of the aqueous phase, and drug to polymer ratio) were achieved by the nanoprecipitation method. The in vitro cellular uptake, anti-cancer, and anti-metastatic activity of GA and GA-loaded PS were tested in MDA-MB 231(TNBC cell line) and MCF-7 cell line. Western blot analysis was performed to elucidate the molecular anti-cancer mechanism. The in vivo biodistribution study and antitumor activity were investigated in the TNBC-xenograft model implanted in mice. Under optimized formulation conditions, GA-loaded PS had a nanosize of 90.5 nm with PDI < 0.2, a zeta potential -9.11 mV, drug encapsulation efficiency of 92.11% and sustained drug release for 6-days. GA-loaded PS exhibited enhanced cellular uptake and achieved a significantly lower IC50 in both breast cancer cell lines compared to free GA. Treatment with GA-loaded PS (60 mu M) showed a significant reduction of 60.5 and 78.1% in cancer migration and metastasis in the case of MDA-MB 231 and MCF-7, respectively. Besides, drug-loaded PS increased phosphorylation of translational regulator eIF2 alpha and decreased expression of Rac1 which were essential for decreasing cancer cell survival and metastasis. In vivo biodistribution study of GA-loaded PS showed long-circulating PS with high passively targeted tumor accumulation. Treatment with GA-loaded PS resulted in a significant decrease in tumor size and weight compared to free GA. In conclusion, GA-loaded PS is a new promising cancer therapeutics for the treatment of TNBC.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available