Development of an Injectable Slow-Release Metformin Formulation and Evaluation of Its Potential Antitumor Effects

Abstract

Metformin is an antidiabetic drug which possesses antiproliferative activity in cancer cells when administered at high doses, due to its unfavorable pharmacokinetics. The aim of this work was to develop a pharmacological tool for the release of metformin in proximity of the tumor, allowing high local concentrations, and to demonstrate the in vivo antitumor efficacy after a prolonged metformin exposition. A 1.2% w/w metformin thermoresponsive parenteral formulation based on poloxamers P407 and P124, injectable at room temperature and undergoing a sol-gel transition at body temperature, has been developed and optimized for rheological, thermal and release control properties; the formulation is easily scalable, and proved to be stable during a 1-month storage at 5 °C. Using NOD/SCID mice pseudo-orthotopically grafted with MDA-MB-231/luc+ human breast cancer cells, we report that multiple administrations of 100 mg of the optimized metformin formulation close to the tumor site cause tissue accumulation of the drug at levels significantly higher than those observed in plasma, and enough to exert antiproliferative and pro-apoptotic activities. Our results demonstrate that this formulation is endowed with good stability, tolerability, thermal and rheological properties, representing a novel tool to be pursued in further investigations for adjuvant cancer treatment.

Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability

“…Starting from epidemiologic studies, a potential chemopreventive effect of metformin was identified in diabetic patients, demonstrating a significant lower incidence of several solid tumors ( Evans et al, 2005 ). Following this evidence, numerous preclinical studies demonstrated that metformin significantly reduce cell proliferation in different in vitro and in vivo cancer models, including breast ( Hirsch et al, 2009 ; Barbieri et al, 2015 ; Baldassari et al, 2018 ), prostate ( Ben Sahra et al, 2011 ; Kato et al, 2015 ), colon ( Zaafar et al, 2014 ), neuroblastoma ( Costa et al, 2014 ), osteosarcoma ( Gatti et al, 2016 , 2018 ; Xu et al, 2017 ; Paiva-Oliveira et al, 2018 ), and, relevant to this study, GBM ( Sato et al, 2012 ; Wurth et al, 2013 ; Yang et al, 2016 ; Kim et al, 2017 ). Notably, while displaying toxic effects in several tumor cells, metformin is basically harmless for normal stem cells ( Wurth et al, 2013 ; Gritti et al, 2014 ), confirming the safety profile of this drug as observed after chronic use in diabetic patients.…”

“…However, important issues and concerns about this off-label activity are still unsolved. In particular, extremely high drug concentrations (within the mM range) are required to induce antitumor effects in in vitro studies, although in vivo metformin intratumoral concentrations were reported to be several fold higher than in plasma ( Nguyen et al, 2017 ; Baldassari et al, 2018 ). It was therefore proposed that protracted in vivo treatment using clinically reachable doses, can possibly induce antitumor effects ( Gritti et al, 2014 ).…”

Experimental Evidence and Clinical Implications of Pituitary Adenoma Stem Cells

“…One of the most relevant information that can be obtained by identification of CSC from different tumors, is the possibility to analyze, with good translational potential, the sensitivity of this subpopulation to traditional or innovative pharmacological treatments. For example, studies on CSC from glioblastoma, breast cancer or osteosarcoma (119,(121)(122)(123), demonstrated a higher sensitivity of this subpopulation to metformin, as compared to "differentiated" tumor cells, determining the development of a drug repositioning approach (124,125). In particular, while it is well-accepted that stem-like cells are particularly resistant to classical cytotoxic drugs due to the overexpression of drug-extruding pumps and DNA-repairing enzymes (110), in CSC cultures from different tumors the sensitivity to molecular-targeted drugs, in particular to tyrosine kinase inhibitors, is retained (114,126).…”

Bioengineered Scaffolds for Thermo-responsive Drug Delivery in Wound Healing

“…thermo-responsive polymer is mixed with the API at room temperature for subsequent injection into the body. After that, the body's temperature increase above polymer LCST induces a phase transition that forms a physical gel, favoring the release of the drug from the scaffold [141][142][143].…”