Investigation of Eutectic Mixtures of Fatty Acids as a Novel Construct for Temperature-Responsive Drug Delivery

Abstract

Farzana Parveen,1– 3 Asadullah Madni,2 Vladimir P Torchilin,1 Mubashar Rehman,4 Talha Jamshaid,2 Nina Filipczak,1 Nadia Rai,2,5 Muhammad Muzamil Khan,2,3 Muhammad Imran Khan6 1Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, 02115, USA; 2Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Punjab, 63100, Pakistan; 3Primary and Secondary Healthcare Department, Government of Punjab, Lahore, 54000, Pakistan; 4Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan; 5Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, 92618, USA; 6Riphah Institute of Pharmaceutical Sciences, Riphah International University Lahore Campus, Lahore, 54000, PakistanCorrespondence: Asadullah Madni, Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Punjab, 63100, Pakistan, Tel [phone], Fax [phone], Email [email protected]: Most of the traditional nanocarriers of cancer therapeutic moieties present dose-related toxicities due to the uptake of chemotherapeutic agents in normal body cells. The severe life-threatening effects of systemic chemotherapy are well documented. Doxorubicin, DOX is the most effective antineoplastic agent but with the least specific action that is responsible for severe cardiotoxicity and myelosuppression that necessitates careful monitoring while administering. Stimuli-sensitive/intelligent drug delivery systems, specifically those utilizing temperature as an external stimulus to activate the release of encapsulated drugs, have become a subject of recent research. Thus, it would be ideal to have a nanocarrier comprising safe excipients and controllable drug release capacity to deliver the drug at a particular site to minimize unwanted and toxic effects of chemotherapeutics. We have developed a simple temperature-responsive nanocarrier based on eutectic mixture of fatty acids. This study aimed to develop, physicochemically characterize and investigate the biological safety of eutectic mixture of fatty acids as a novel construct for temperature-responsive drug release potential.Methods: We have developed phase change material, PCM, based on a series of eutectic mixtures of fatty acids due to their unique and attractive physicochemical characteristics such as safety, stability, cost-effectiveness, and ease of availability. The reversible solid-liquid phase transition of PCM is responsible to hold firm or actively release the encapsulated drug. The eutectic mixtures of fatty acids (stearic acid and myristic acid) along with liquid lipid (oleic acid) were prepared to exhibit a tunable thermoresponsive platform. Doxorubicin-loaded lipid nanocarriers were successfully developed with combined hot melt encapsulation (HME) and sonication method and characterized to achieve enhanced permeability and retention (EPR) effect-based solid tumor targeting in response to exogenous temperature stimulus. The cytotoxicity against melanoma cell lines and in vivo safety studies in albino rats was also carried out.Results: Doxorubicin-loaded lipid nanocarriers have a narrow size distribution (94.59– 219.3 nm), and a PDI (0.160– 0.479) as demonstrated by photon correlation microscopy and excellent colloidal stability (Z.P value: − 22.7 to − 32.0) was developed. Transmission electron microscopy revealed their spherical morphology and characteristics of a monodispersed system. A biphasic drug release pattern with a triggered drug release at 41°C and 43°C and a sustained drug release was observed at 37°C. The thermoresponsive cytotoxic potential was demonstrated in B16F10 cancer cell lines. Hemolysis assay and acute toxicity studies with drug-free and doxorubicin lipid nanocarrier formulations provided evidence for their non-toxic nature.Conclusion: We have successfully developed a temperature-responsive tunable platform with excellent biocompatibility and intelligent drug release potential. The formulation components being from natural sources present superior characteristics in terms of cost, compatibility with normal body cells, and adaptability to preparation methods. The reported preparation method is adapted to avoid complex chemical processes and the use of organic solvents. The lipid nanocarriers with tunable thermoresponsive characteristics are promising biocompatible drug delivery systems for improved localized delivery of chemotherapeutic agents.Graphical Abstract: Keywords: nanostructured lipid carriers, lipid nanocarriers, thermoresponsive, eutectic mixtures, fatty acids, phase change materials, doxorubicin, acute toxicity studies, hemolysis assay

Keywords

• nanostructured lipid carriers
• lipid nanocarriers
• thermoresponsive
• phase change materials
• doxorubicin
• acute toxicity studies
• hemolysis assay