Pharmacokinetic/pharmacodynamic correlation and biodistribution of paclitaxel and cyclopamine from M-CPA/PTX in HCC mice following multiple dosing

Hepatocellular Carcinoma (HCC) is the most common form of liver cancer, highly aggressive and heterogenous. Due to lack of effective diagnostic techniques, HCC is often detected when surgical and chemotherapeutic interventions are inadequate. To address this, we developed a polymeric micelle containing Paclitaxel (PTX), a microtubule-stabilizer, and Cyclopamine (CPA), a Hedgehog pathway inhibitor, termed M-CPA/PTX. The M-CPA/PTX contained 2.5 mg each of PTX and CPA, with size of 70.6 ± 3.4 nm, PDI of 0.12 ± 0.04 (n = 3), and encapsulation efficiency of ≥ 80% for both agents. The biodistribution (BD) of PTX and CPA in tumor, liver, lung, spleen and kidney were characterized following IV dosing of 5 mg/kg M-CPA/PTX in C-MYC expressing transgenic mice which were randomized into four groups: vehicle (n = 10), 1 dose (n = 8), 2 doses (n = 7), and 3 doses (n = 9). ANOVA with Tukey's post hoc test was for statistical analysis with p-value < 0.05 for significance. The BD data were compiled in Table 1. The blood concentrations for each agent were substantially lower than those in tumor and organs at 24 hours post the last dose. The BD patterns were distinct between PTX and CPA. The PTX concentrations were the highest in tumor, 369-443 ng/g, followed by liver >> lungs> kidney >> spleen, 11-15 ng/g. The CPA concentrations were high in lungs, 537-751 ng/g, and kidney, 305-339 ng/g, followed by tumor, 218-300 ng/g, and liver, 206-328 ng/g. The BD levels were not significantly altered among the dosing groups. The 3D PK/PD correlation was established for tumor growth inhibition (%), with tumor concentrations of PTX and CPA in individual mice. In conclusion, the biodistributions of PTX and CPA following multiple IV dosing in an HCC mouse model were characterized, and a 3D PK/PD correlation was established with PX and CPA uptakes in tumor, potentially enabling future efficacy projection.Table 1: Biodistribution of PTX and CPA from M-CPA/PTX