Mechanism-Based Targeting of Sickle Cell Pathobiology and Pain with Novel Transdermal Curcumin

Pain is a debilitating consequence of sickle cell disease (SCD). We examined the potential of novel topical transdermal curcumin (TDC) gel with transdermal systemic delivery to target pain and SCD pathobiology. Curcumin is an antioxidant and anti-inflammatory polyphenol with therapeutic potential but has poor oral bioavailability. TDC gel (Vasceptor TM, Vascarta Inc.), containing 0.1 M of curcuminoids (derived from Curcugen, Dolcas-Biotech, LLC), or vehicle were applied (0.1 mL) topically by gentle rubbing to the abdomen on alternating days for 3 weeks followed by analysis of blood, organ pathology and skin secretome. Using high-performance liquid chromatography, we found that curcumin levels peaked in the plasma (7.87 µg/mL) and blood cells (6.78 µg/mL) 60 min following administration in C57BL/6 mice, thus, showing efficient bioavailability. Next, we used humanized ‘ sickle‘, homozygous transgenic mice ( HbSS-BERK) expressing >99% human sickle hemoglobin (HbSS) without mouse α- and β-globins. These mice mimic the pathobiology and features of pain observed in persons with SCD. We observed that TDC application in male and female HbSS led to a significant decrease in hyperalgesia over the 21 days (D) of treatment. Mechanical hyperalgesia significantly decreased after 14D of treatment in males and after 21D in females (p