AACR: Nanoparticle delivers chemo+radio therapy in ovarian cancer
Folate-targeted nanoparticle Paclitaxel Y90 is a biologically-targeted chemoradiotherapy for ovarian cancer and represents a potential novel treatment for ovarian peritoneal metastases, according to a presentation at the annual meeting of the American Association for Cancer Research (AACR) last week in Orlando, Fla.
Approximately 15,000 women die of ovarian cancer in the U.S. each year. One of the most common causes of mortality in these patients is peritoneal metastases. While intraperitoneal chemotherapy and radioisotope therapy have shown favorable clinical results, both lead to significant toxicities.
Chemoradiotherapy has been shown to be superior to either therapy alone in many cancers, such as head and neck cancer, cervical cancer and rectal cancer. However, it has not been evaluated in ovarian cancer due to concerns of toxicity, according to Michael Werner, PhD, postdoctoral fellow at University of North Carolina in Chapel Hill, and colleagues.
Advances in nanotechnology have enabled the development of biologically-targeted nanoparticle therapeutic carriers. These nanoparticles allow preferential delivery of therapeutics to tumors, which, in turn, increases efficacy and minimizes toxicity.
In the study, Werner and colleagues hypothesized that a ChemoRad nanoparticle, which can deliver both chemotherapy and radiotherapy targeted against ovarian cancer cells, can be a novel and effective treatment for ovarian peritoneal metastases.
Werner and colleagues engineered a folate-targeted ChemoRad nanoparticle encapsulating Paclitaxel and Y90 for intraperitoneal chemoradiotherapy of ovarian cancer. The nanoparticle was evaluated using the SKOV-3 ovarian carcinoma cell line and a murine model of ovarian peritoneal metastases. Folate was utilized as a targeting ligand as most ovarian cancers overexpress the folate receptor. Paclitaxel, a first-line chemotherapy for ovarian cancer, was used as the model drug. Y90 was employed as the therapeutic radioisotope based on its high-energy emission and low toxicity.
The folate-targeted ChemoRad nanoparticle was formulated by a nanoprecipitation method. The resulting nanoparticles had a hydrophobic polymeric core where Paclitaxel was encapsulated. The nanoparticle surface was covered by a self-assembled monolayer of lipid and lipid-polymer. Metal chelators were incorporated into the sub-surface layer for the chelation of Y90.
Drug release study showed controlled release with more than 95 percent of Paclitaxel released at 24 hours. Werner and colleagues demonstrated that folate mediated cellular uptake of targeted nanoparticle Paclitaxel Y90 by SKOV-3 cells. An in vitro efficacy study showed the folate-targeted nanoparticle Paclitaxel Y90 was more effective than that of non-targeted nanoparticle Paclitaxel Y90.
The researchers then validated the folate nanoparticle containing Paclitaxel and Y90 in vivo. Peritoneal xenograft metastases were induced by injecting SKOV-3 cells intraperitoneal in nude mice. Therapeutics were given intraperitoneal at three weeks post tumor implantation.
"We were able to demonstrate that folate-targeted nanoparticle Paclitaxel Y90 is more effective than folate-targeted nanoparticle Paclitaxel, folate-targeted nanoparticle Y90 and non-targeted nanoparticles containing either or both therapeutic agents. In conclusion, we have demonstrated that folate-targeted nanoparticle Paclitaxel Y90 is a biologically-targeted chemoradiotherapy for ovarian cancer. It represents a potential novel treatment for ovarian peritoneal metastases,” noted Werner and colleagues.
Approximately 15,000 women die of ovarian cancer in the U.S. each year. One of the most common causes of mortality in these patients is peritoneal metastases. While intraperitoneal chemotherapy and radioisotope therapy have shown favorable clinical results, both lead to significant toxicities.
Chemoradiotherapy has been shown to be superior to either therapy alone in many cancers, such as head and neck cancer, cervical cancer and rectal cancer. However, it has not been evaluated in ovarian cancer due to concerns of toxicity, according to Michael Werner, PhD, postdoctoral fellow at University of North Carolina in Chapel Hill, and colleagues.
Advances in nanotechnology have enabled the development of biologically-targeted nanoparticle therapeutic carriers. These nanoparticles allow preferential delivery of therapeutics to tumors, which, in turn, increases efficacy and minimizes toxicity.
In the study, Werner and colleagues hypothesized that a ChemoRad nanoparticle, which can deliver both chemotherapy and radiotherapy targeted against ovarian cancer cells, can be a novel and effective treatment for ovarian peritoneal metastases.
Werner and colleagues engineered a folate-targeted ChemoRad nanoparticle encapsulating Paclitaxel and Y90 for intraperitoneal chemoradiotherapy of ovarian cancer. The nanoparticle was evaluated using the SKOV-3 ovarian carcinoma cell line and a murine model of ovarian peritoneal metastases. Folate was utilized as a targeting ligand as most ovarian cancers overexpress the folate receptor. Paclitaxel, a first-line chemotherapy for ovarian cancer, was used as the model drug. Y90 was employed as the therapeutic radioisotope based on its high-energy emission and low toxicity.
The folate-targeted ChemoRad nanoparticle was formulated by a nanoprecipitation method. The resulting nanoparticles had a hydrophobic polymeric core where Paclitaxel was encapsulated. The nanoparticle surface was covered by a self-assembled monolayer of lipid and lipid-polymer. Metal chelators were incorporated into the sub-surface layer for the chelation of Y90.
Drug release study showed controlled release with more than 95 percent of Paclitaxel released at 24 hours. Werner and colleagues demonstrated that folate mediated cellular uptake of targeted nanoparticle Paclitaxel Y90 by SKOV-3 cells. An in vitro efficacy study showed the folate-targeted nanoparticle Paclitaxel Y90 was more effective than that of non-targeted nanoparticle Paclitaxel Y90.
The researchers then validated the folate nanoparticle containing Paclitaxel and Y90 in vivo. Peritoneal xenograft metastases were induced by injecting SKOV-3 cells intraperitoneal in nude mice. Therapeutics were given intraperitoneal at three weeks post tumor implantation.
"We were able to demonstrate that folate-targeted nanoparticle Paclitaxel Y90 is more effective than folate-targeted nanoparticle Paclitaxel, folate-targeted nanoparticle Y90 and non-targeted nanoparticles containing either or both therapeutic agents. In conclusion, we have demonstrated that folate-targeted nanoparticle Paclitaxel Y90 is a biologically-targeted chemoradiotherapy for ovarian cancer. It represents a potential novel treatment for ovarian peritoneal metastases,” noted Werner and colleagues.