A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells

• Published in: Journal of experimental & clinical cancer research 2019-08, Vol.38 (1), p.373-17, Article 373
• Main Authors: Orienti, Isabella, Salvati, Valentina, Sette, Giovanni, Zucchetti, Massimo, Bongiorno-Borbone, Lucilla, Peschiaroli, Angelo, Zolla, Lello, Francescangeli, Federica, Ferrari, Mariella, Matteo, Cristina, Bello, Ezia, Di Virgilio, Antonio, Falchi, Mario, De Angelis, Maria Laura, Baiocchi, Marta, Melino, Gerry, De Maria, Ruggero, Zeuner, Ann, Eramo, Adriana
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analysis; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antitumour activity; Apoptosis; Bioavailability; Biological Availability; Cancer; Cancer cells; Cancer stem cells; Cancer treatment; Care and treatment; Cell Proliferation; Clinical trials; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Drug delivery systems; Female; Fenretinide; Fenretinide - administration & dosage; Fenretinide - chemistry; Fenretinide - pharmacokinetics; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical research; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Micelles; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Patient compliance; Recurrence (Disease); Solid tumours; Solubility; Stem cell transplantation; Stem cells; Tissue Distribution; Toxicity; Treatment outcome; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-019-1383-9

An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.