Pulmonary Delivery of Fenretinide: A Possible Adjuvant Treatment In COVID-19

Abstract

At present, there is no vaccine or effective standard treatment for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (or coronavirus disease-19 (COVID-19)), which frequently leads to lethal pulmonary inflammatory responses. COVID-19 pathology is characterized by extreme inflammation and amplified immune response with activation of a cytokine storm. A subsequent progression to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) can take place, which is often followed by death. The causes of these strong inflammatory responses in SARS-CoV-2 infection are still unknown. As uncontrolled pulmonary inflammation is likely the main cause of death in SARS-CoV-2 infection, anti-inflammatory therapeutic interventions are particularly important. Fenretinide N-(4-hydroxyphenyl) retinamide is a bioactive molecule characterized by poly-pharmacological properties and a low toxicity profile. Fenretinide is endowed with antitumor, anti-inflammatory, antiviral, and immunomodulating properties other than efficacy in obesity/diabetic pathologies. Its anti-inflammatory and antiviral activities, in particular, could likely have utility in multimodal therapies for the treatment of ALI/ARDS in COVID-19 patients. Moreover, fenretinide administration by pulmonary delivery systems could further increase its therapeutic value by carrying high drug concentrations to the lungs and triggering a rapid onset of activity. This is particularly important in SARS-CoV-2 infection, where only a narrow time window exists for therapeutic intervention.

Keywords: COVID-19; adjuvant treatment; anti-inflammatory; antiviral environment; fenretinide; pulmonary delivery.

Figure 1

Schematic representation of the progression of coronavirus disease-19 (COVID-19). After an incubation period, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) starts a rapid replication in the lung airway and alveolar epithelial cells. This triggers an immune response with cytokine production, excessive inflammation, and further amplification of the immune response that triggers the cytokine storm. Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) may arise with dire consequences.

Figure 2

Inhalation of pulmonary formulations and size-dependent distribution of aerosol particles in the respiratory tract.

Figure 3

The potential use of fenretinide in COVID-19 by pulmonary delivery. SARS-CoV-2 lung infection triggers excessive inflammation and activation of the cytokine storm. Pulmonary delivery of fenretinide can provide high drug concentrations in the lung airway and alveolar epithelia, thus inducing a rapid onset of anti-inflammatory activity and an “antiviral environment”. This generates a supportive adjuvant localized therapy useful in multimodal treatments.