Tumor priming microparticles for intraperitoneal therapy of ovarian cancer. Free

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Intraperitoneal (IP) therapy has been used to deliver high drug concentrations to tumors located in the peritoneal cavity for more than 30 years. Multiple randomized clinical trials have demonstrated the survival benefits of IP chemotherapy in stage III, optimally surgically debulked ovarian cancer patients. In the most recent NCI Cooperative Group trial (GOG 172), patients receiving the combination of intravenous plus IP chemotherapy showed a significantly longer progression-free and overall survival shown over the intravenous only arm (65.6 vs. 49.7 months). The utility and efficacy of IP therapy are limited by the toxicity associated with the use of indwelling catheter and local chemotherapy-induced toxicity, and by the limited drug penetration into larger tumors. The present study describes a two-component, biocompatible, biodegradable, controlled-release polymeric paclitaxel-loaded microparticles (referred to as tumor priming microparticles or TPM). The first component released a small fraction of the dose to induce apoptosis, reduce the tumor cell density, disrupt the tumor structure and expand the interstitial space, and thereby facilitates the penetration of drug/particles into tumors. The second component provided sustained drug delivery. The in vivo tumor penetration and spatial distribution of ³H-paclitaxel, formulated in either TPM or Cremphor/ethanol, were evaluated in IP metastatic, human ovarian SKOV3 xenograft model, using autoradiographic techniques. The levels of paclitaxel as a function of distance from the tumor surface was measured. The results showed higher maximum drug concentration (C_max) and AUC (area under the drug concentration versus distance curve) in tumors in the the TPM group compared to the Cremophor group (130 vs. 6.2 μg/g, p<0.05; 36 vs. 3.7 μg/g*mm, p<0.05), and longer drug retention (14% increase vs 32% decrease from 72 hr to 168 hr). In summary, formulating paclitaxel in a 2-component tumor priming microparticles significantly improved the targeting, penetration and retention in IP ovarian tumors, compared to the Cremophor/ethanol formulation. Supported in part by R43CA103133 and R44CA103133, NCI, DHHS.