Shrirang Karve

Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis

Peritoneal metastasis is a major cause of morbidity and mortality in ovarian cancer. While intraperitoneal chemotherapy and radiotherapy have shown favorable clinical results, both are limited by their non-targeted nature. We aimed to develop a biologically targeted nanoparticle therapeutic for the treatment of ovarian cancer peritoneal metastasis. Folate-targeted nanoparticles encapsulating chemotherapy and/or radiotherapy were engineered. Paclitaxel (Ptxl) was used as the chemotherapeutic and yittrium-90 ((90)Y) was employed as the therapeutic radioisotope. Folate was utilized as the targeting ligand as most ovarian cancers overexpress the folate receptor. Nanoparticle characterization studies showed monodispersed particles with controlled Ptxl release. Folate targeting ligand mediated the uptake of NPs into tumor cells. In vitro efficacy studies demonstrated folate-targeted NPs containing chemoradiotherapy was the most effective therapeutic compared to folate-targeted NPs containing a single therapeutic or any non-targeted NP therapeutics. In vivo efficacy studies using an ovarian peritoneal metastasis model showed that folate-targeted NP therapeutics were significantly more effective than non-targeted NP therapeutics. Among the folate-targeted therapeutics, the NP containing chemoradiotherapy appeared to be the most effective. Our results suggest that folate-targeted nanoparticles containing chemoradiotherapy have the potential as a treatment for ovarian peritoneal metastasis.

Folate-targeted Polymeric Nanoparticle Formulation of Docetaxel is an Effective Molecularly Targeted Radiosensitizer with Efficacy Dependent on the Timing of Radiotherapy

Nanoparticle (NP) chemotherapeutics hold great potential as radiosensitizers. Their unique properties, such as preferential accumulation in tumors and their ability to target tumors through molecular targeting ligands, are ideally suited for radiosensitization. We aimed to develop a molecularly targeted nanoparticle formulation of docetaxel (Dtxl) and evaluate its property as a radiosensitizer. Using a biodegradable and biocompatible lipid-polymer NP platform and folate as a molecular targeting ligand, we engineered a folate-targeted nanoparticle (FT-NP) formulation of Dtxl. These NPs have sizes of 72 ± 4 nm and surface charges of -42 ± 8 mV. Using folate receptor overexpressing KB cells and folate receptor low HTB-43 cells, we showed folate-mediated intracellular uptake of NPs. In vitro radiosensitization studies initially showed FT-NP is less effective than Dtxl as a radiosensitizer. However, the radiosensitization efficacy is dependent on the timing of radiotherapy. In vitro radiosensitization conducted with irradiation given at the optimal time (24 h) showed FT-NP Dtxl is as effective as Dtxl. When FT-NP Dtxl is compared to Dtxl and nontargeted nanoparticle (NT-NP) Dtxl in vivo, FT-NP was found to be significantly more effective than Dtxl or NT-NP Dtxl as a radiosensitizer. We also confirmed that radiosensitization is dependent on timing of irradiation in vivo. In summary, FT-NP Dtxl is an effective radiosensitizer in folate-receptor overexpressing tumor cells. Time of irradiation is critical in achieving maximal efficacy with this nanoparticle platform. To the best of our knowledge, our report is the first to demonstrate the potential of molecularly targeted NPs as a promising new class of radiosensitizers.

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3′ kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.

Abstract 382: Evaluation of folate-targeted ChemoRad nanoparticle as intraperitoneal chemoradiotherapy for ovarian cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL 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 (IP) chemotherapy and IP 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. Advances in nanotechnology have enabled the development of biologically targeted nanoparticle (NP) therapeutic carriers. These NPs allow preferential delivery of therapeutics to tumors, which in turn increases efficacy and minimizes toxicity. Our laboratory was the first to develop a nanoparticle platform, the ChemoRad NP, which can deliver both chemotherapy and radiotherapy. We hypothesized that a ChemoRad NP targeted against ovarian cancer cells can be a novel and effective treatment for ovarian peritoneal metastases. In this study, we engineered a folate-targeted ChemoRad NP encapsulating paclitaxel and Y90 for IP chemoradiotherapy of ovarian cancer. The NP 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 (Ptxl), 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 NP was formulated by a nanoprecipitation method. The resulting NPs have a hydrophobic polymeric core where Ptxl is encapsulated. The NP surface is 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. Characterization of the NPs showed particle size of 70+/−5 nm and 60% Ptxl encapsulation efficiency. Drug release study showed controlled release with more than 95% of Ptxl released at 24 hrs. We demonstrated folate mediated cellular uptake of targeted NP Ptxl Y90 by SKOV-3 cells. An in vitro efficacy study showed the folate-targeted NP Ptxl Y90 (T-NP Ptxl Y90) is more effective than that of non-targeted NP Ptxl Y90. We then validated our folate NP containing Ptxl and Y90 in vivo. Peritoneal xenograft metastases were induced by injecting SKOV-3 cells IP in nude mice. Therapeutics were given IP at 3 weeks post tumor implantation. We were able to demonstrate that T-NP Ptxl Y90 is more effective than T-NP Ptxl, T-NP Y90, and non-targeted NPs containing either or both therapeutic agents. In conclusion, we have demonstrated that folate-targeted NP Ptxl Y90 is a biologically targeted chemoradiotherapy for ovarian cancer. It represents a potential novel treatment for ovarian peritoneal metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 382. doi:10.1158/1538-7445.AM2011-382