Introduction

Fenretinide (4-hydroxyphenylretinamide) is a synthetic derivative of retinoic acid with antitumor, anti-inflammatory, antiviral activity with minimal systemic toxicity and excellent tolerability. Currently, its activity has been demonstrated in liver diseases such as hepatoblastoma, hepatocellular carcinoma, hepatic fibrosis, and cirrhosis. Despite its excellent pharmacological characteristics, this drug has not entered clinical use due to its poor aqueous solubility and consequent low bioavailability which prevents the achievement of plasma levels adequate for therapeutic activity. In liver diseases, a further obstacle is represented by the extensive hepatic metabolization of fenretinide which prevents the achievement of therapeutic concentrations in this organ even at high administration doses.

 

Technical features

The invention concerns a new pharmaceutical nanoformulation of fenretinide capable of increasing the systemic bioavailability of this drug so as to deliver high drug concentrations to the liver and offer a valuable therapeutic option for hepatic diseases. In fact, following intravenous administration, the nanomicelles accumulate in the liver by extravasation through the discontinuities of the hepatic sinusoids. The accumulation provides high levels of fenretinide in the hepatic compartment and counterbalance the concentration decrease due to the hepatic metabolization of the drug. This way it is possible to obtain drug levels suitable to elicit therapeutic effects in liver diseases. Furthermore, the controlled distribution prevents the onset of side effects even following protracted therapies.

Possible Applications

• Pharmaceutical applications in liver diseases such as hepatoblastoma, hepatocellular carcinoma, hepatic fibrosis, and cirrhosis;
• Possible treatment of hepatic and extrahepatic solid tumors by accumulation of the nanomicelles in the solid tumors by extravasation through the discontinuities of the tumor capillaries formed by angiogenesis.

Advantages

• Possibility of obtaining therapeutic effects in liver diseases for which there are currently no valid therapeutic options using a drug with low toxicity such as fenretinide;
• Possibility of obtaining high levels of drug in the liver with increased therapeutic efficacy, avoiding uncontrolled distribution to other parts of the body, even in the presence of hepatic metabolization;
• Nanomicelles allow the incorporation of other drugs, in combination with fenretinide, allowing the realization of organ-targeted therapies with increased therapeutic efficiency and no off-target effects.