Hyaluronic acid-based hydrogel for regional delivery of paclitaxel to intraperitoneal tumors

Abstract

Intraperitoneal (IP) chemotherapy is an effective way of treating local and regional malignancies confined in the peritoneal cavity such as ovarian cancer. However, a persistent major challenge in IP chemotherapy is the need to provide effective drug concentrations in the peritoneal cavity for an extended period of time. We hypothesized that hyaluronic acid (HA)-based in-situ crosslinkable hydrogel would serve as a carrier of paclitaxel (PTX) particles to improve their IP retention and therapeutic effects. In-vitro gel degradation and release kinetics studies demonstrated that HA gels could entrap microparticulate PTX (>100 μm) and release the drug over 10 days, gradually degraded by hyaluronidase, but had limited effect on retention of Taxol, a 14-nm micelle form of PTX. When administered IP to tumor-bearing nude mice, PTX was best retained in the peritoneal cavity as PTX-gel (microparticulate PTX entrapped in the HA gel), whereas Taxol-gel and other Taxol-based formulations left negligible amount of PTX in the cavity after 14 days. Despite the increase in IP retention of PTX, PTX-gel did not further decrease the tumor burdens than Taxol-based formulations, presumably due to the limited dissolution of PTX. This result indicates that spatial availability of a drug does not necessarily translate to the enhanced anti-tumor effect unless it is accompanied by the temporal availability.

Fig. 1

(A) In-vitro PTX release kinetics from HA-gel (40 mg/mL). % Cumulative PTX released = (PTX released in the medium by the specified time)/(PTX loaded in the gel). Results shown are averages of two independently and identically prepared samples. (B) Body weight changes after treatments. Body weights were measured every other day (2, 4, and 6 days) after each treatment (after initial treatment for the Taxol-multiple group) and normalized to the weight measured shortly prior to the treatment (indicated as a dotted line). *: p<0.05; **: p<0.01; ***: p<0.001, as compared to the no treatment group of each time point (Dunnett test). (C) PTX level in peritoneal lavage fluid after each treatment. **: p<0.01, as compared to Taxol-multiple (Mann-Whitney test). (D) Anti-tumor efficacy of each treatment. Data represent numbers and weights of tumor nodules observed in the peritoneal cavity, as normalized to those of untreated mice (indicated as a dotted line). Any PTX treatments were significantly different from PBS or Gel (p<0.001 Tukey test).