209. Stem Cell/Nanoparticle Constructs for Targeted Ovarian Cancer Therapy

Intro. Targeted drug delivery is a critical goal for effective cancer therapy. Nanoparticles (NPs) have shown promise as platforms for targeting drugs to tumors, but major challenges remain for controlling the distribution and retention of NPs within tumors. In general, NPs predominantly accumulate in the liver and spleen and have difficulty penetrating poorly vascularized and hypoxic tumor regions. Neural Stem Cells (NSCs) are ideal candidates for use as carriers for NPs in order to overcome these biodistribution challenges. NSCs have demonstrated inherent tumor tropic properties in preclinical invasive and metastatic tumor models, migrating selectively to invasive tumor foci, penetrating hypoxic tumor regions, and even traversing through the blood-brain barrier to access intracranial tumor foci following intravenous administration. We have been pioneers in genetically modifying NSCs to express prodrug activating enzymes for gene therapy, completing a first-in-human safety clinical trial for recurrent glioma in 2013, and demonstrating proof of concept for localized drug delivery (Phase I ongoing).As NSC-based therapies move into the clinic, there is an opportunity to develop complementary NSC-mediated treatment strategies for tumor elimination. We have shown that these clinically relevant NSCs maintain their tumor tropism when transporting either surface-bound or internalized NPs. NSC-NPs selectively penetrate tumor foci (Figure 1Figure 1 shows NSC-NPs, orange, at tumor foci, green, near liver). The combination of NSCs and NPs offers the potential to realize a modular and general drug targeting system. We now demonstrate that the cisplatin-loaded NPs carried by NSCs is a viable approach for the treatment of Stage III ovarian cancer, where tumors have metastasized to the abdominal cavity. We show that encapsulating cisplatin within silica NPs allows for delayed drug release for 24 hours with minimal leakage, allowing sufficient time for the NSCs to effectively penetrate and distribute through tumor foci.Figure 1View Large Image | Download PowerPoint SlideMethods. Ten million NSCs carrying cisplatin-loaded silica NPs (Figure 2Figure 2) were injected intraperitoneally (IP) into nude mice containing established human ovarian (OVCAR8) peritoneal metastases. Control groups included equivalent levels of free cisplatin or cisplatin-loaded NPs.Figure 2View Large Image | Download PowerPoint SlideResults. IP delivery these NSC-NP constructs showed significantly increased concentrations of cisplatin at multiple tumor sites, regardless of size, throughout the peritoneum, as compared to free drug alone or drug-loaded NPs alone. At all timepoints tested, only tumors treated with the NSC-NP constructs had therapeutically significant levels of drug present (Figure 3 shows 6h and 24h timepointsFigure 3 shows 6h and 24h timepoints). This allows for concentration of drug at tumor sites, while minimizing toxicities. Long-term efficacy studies are in progress. Our present goal is to generate the efficacy and safety data needed to move toward clinical trials.Figure 3View Large Image | Download PowerPoint Slide