Ovarian cancer spheroid shrinkage following continuous exposure to cisplatin is a function of spheroid diameter.

OBJECTIVE: Most ovarian cancer patients present with advanced-stage disease, disseminated in the peritoneal cavity. Standard treatment involves surgical resection of all visible tumor, followed by delivery of systemic therapy. Patients with advanced-stage disease may be candidates for intraperitoneal (IP) chemotherapy following surgical debulking. Recent clinical trials have created controversy regarding the benefits of this approach. Previous clinical trials report that patients with microscopic residual disease respond best to IP therapy. The goal of this study was to determine the relationship between tumor size and the efficacy of continuous chemotherapy. METHODS: Small and large ovarian cancer spheroids (derived from UCI101 and A2780 cell lines) were exposed to short-term high (modeling an IP injection, "IP") or prolonged, low cisplatin concentrations (modeling an implanted device, "device"), which have been previously shown to be less toxic. Spheroid diameter was measured at various time points via image analysis and used to quantify tumor shrinkage over the course of treatment. RESULTS: We show that "IP" doses more effectively shrink large spheroids when the same cumulative dose is administered with both treatments, but that both regimens similarly treat small spheroids. We also demonstrate that higher cumulative "device" doses are most effective at shrinking large spheroids. CONCLUSIONS: These results support the hypothesis that intratumoral drug distribution following IP treatment is diffusion-controlled. An implanted device that continuously delivers low doses of IP chemotherapy would, therefore, be maximally effective against microscopic tumors.

A course in prosthetics for the developing world: Merging education, research, and industry to teach biomedical design for social impact.

Under the auspices of the MIT D-Lab, a team of graduate students has instructed a course since 2008 that centers around teaching low-cost prosthetic design for resource-constrained environments. Recently, the course has evolved into a fully immersive design experience that pairs student teams with real-life international stakeholders and industry partners. Following this structure, projects initiated as part of the course have been tested at field sites around the world, stimulated further research, advanced student careers, raised additional grant money, and generated peer-reviewed publications and intellectual property.

Sustained, low-dose intraperitoneal cisplatin improves treatment outcome in ovarian cancer mouse models.

Intraperitoneal (IP) chemotherapy for ovarian cancer treatment prolongs overall survival by 16 months compared to intravenous chemotherapy but is not widely practiced due to catheter-related complications and complexity of administration. An implantable, nonresorbable IP microdevice was used to release chemotherapeutic agent at a constant rate of approximately 1.3 µg/h in vitro and 1.0 µg/h in vivo. Studies conducted in two orthotopic murine models bearing human xenografts (SKOV3 and UCI101) demonstrate that continuous dosing reduces tumor burden to the same extent as weekly IP bolus drug injections. Treatment-induced toxicity was quantified via body weight loss and complete blood count. The microdevice resulted in significantly less toxicity than IP bolus injections, despite administration of higher cumulative doses (total area under the concentration-time curve of 3049 ng day/mL with the microdevice vs. 2118 ng-day/mL with IP bolus injections). This preclinical study supports the concept that reduced toxicity with similar efficacy outcomes can be achieved by continuous dosing in ovarian cancer patients currently treated with IP therapy.

Single compartment drug delivery.

Drug design is built on the concept that key molecular targets of disease are isolated in the diseased tissue. Systemic drug administration would be sufficient for targeting in such a case. It is, however, common for enzymes or receptors that are integral to disease to be structurally similar or identical to those that play important biological roles in normal tissues of the body. Additionally, systemic administration may not lead to local drug concentrations high enough to yield disease modification because of rapid systemic metabolism or lack of sufficient partitioning into the diseased tissue compartment. This review focuses on drug delivery methods that physically target drugs to individual compartments of the body. Compartments such as the bladder, peritoneum, brain, eye and skin are often sites of disease and can sometimes be viewed as "privileged," since they intrinsically hinder partitioning of systemically administered agents. These compartments have become the focus of a wide array of procedures and devices for direct administration of drugs. We discuss the rationale behind single compartment drug delivery for each of these compartments, and give an overview of examples at different development stages, from the lab bench to phase III clinical trials to clinical practice. We approach single compartment drug delivery from both a translational and a technological perspective.