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.
Highlights
Metformin is the first-line treatment for type-2 diabetes[1], which recent epidemiological evidence identified as potential, still controversial, anti-tumor agent[2,3,4]
Aimed to potentiate the efficacy of metformin for cancer treatment, here we report the development of different sterile metformin-loaded formulations based on poloxamers P407 and P124, which are injectable at room temperature (r.t.) and jellify at body temperature; these formulations were prepared according to statistical Design of Experiments (DoE) and characterized for thermal, rheological and drug release properties, in order to find an optimal formulation
16% w/w P407 and P188 solutions were analyzed by photon correlation spectroscopy (PCS)
Summary
Metformin is the first-line treatment for type-2 diabetes[1], which recent epidemiological evidence identified as potential, still controversial, anti-tumor agent[2,3,4]. Large doses would need to be orally administered to obtain anticancer effects with the consequent risk of either adverse effects or possible drug interactions in patients receiving chemotherapy Based on these observations, a specific local delivery system could be useful to concentrate the drug at the tumor sites. We measured the absorption kinetics of the optimized metformin preparation, evaluating plasma and liver concentrations of the drug after subcutaneous (s.c.) administration, and investigated its antitumor efficacy after peritumoral inoculation on mouse pseudo-orthotopic human breast cancer cell xenografts The relevance of this new pharmacological tool resides in providing the proof of the in vivo metformin anticancer efficacy after continuous local exposition to low drug concentrations. The results of this study may be useful in the design of a long-releasing device for disease stabilization in inoperable cancer patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
