Nanoparticle depot for intraperitoneal chemotherapy of ovarian cancer

Intraperitoneal (IP) chemotherapy is a promising post-surgical therapy of ovarian cancer, with the full potential yet to be proven. To facilitate IP chemotherapy of ovarian cancer, we have developed a nanoparticle depot for IP chemotherapy consisted of paclitaxel (PTX) nanocrystals (PNC) and hyaluronic acid-based hydrogel (HA gel). PNC with a size of ∼310 nm was produced by nonsolvent and temperature-induced crystallization. Dissolution kinetics of PNC could be determined by the light scattering method rather than the dialysis method due to drug reprecipitation caused by diffusion barrier. PTX release profiles from PNC-gel and PTX precipitate-gel (PPT-gel) were estimated in both sink- and non-sink conditions, where the latter simulated the peritoneal environment. In-vitro release kinetics studies did not reveal any difference between PNC-gel and PPT-gel, partly due to the centrifugation-related artifacts. In cellular toxicity test and maximum tolerated dose assessment, PNC-gel provided more efficient killing effect and greater toxicity than PPT-gel, which contained larger PTX particles, indicating a greater dissolution rate of PNC due to the small size. A single IP administration of PNC-gel extended the survival of mice with IP tumors significantly better than the same dose Taxol, due to the local depot effect, whereas PPT-gel was not superior to Taxol in survival extension. While the cell toxicity test and in-vivo results consistently point to the beneficial effect of particle size reduction, in-vitro drug release kinetics did not predict the difference between PPT- and PNC-gels, suggesting the limitation of current release study methods. For PNC-gel to serve the cancer patients to its full potential, the compatibility between PNC and HA gel could be optimized by incorporating hydrophobic domains in the hydrogel and introducing surface stabilizer on PNC to achieve a well-controlled release. Aminoethyl 5β-cholanoamide (EtCA) was conjugated to one of the gel precursors, and the in-vitro PTX release was enhanced by the inclusion of EtCA. However, it was not pursued in the subsequent studies due to the unexpected toxicity of EtCA. Albumin-stabilized PNC with a sub-200 nm particle size were prepared using a method involving incipient crystallization in polymer matrix and subsequent surface stabilization with albumin. The function and quantitation of surface stabilizers need further investigation. In-vitro dissolution test and bioactivity evaluation of Cim-alb remains to be performed to test the contribution of small size to enhancing local availability of PTX