Prevention of Margin Recurrence in Esophageal Cancer Using Biodegradable Sandwich-Structured Nanofibrous Cisplatin-Eluting Membranes---In vitro and in vivo Study

Thoracic squamous cell esophageal carcinoma is one of the most aggressive cancers and is characterized by a poor prognosis. Due to the anatomical proximity of thoracic esophagus to the surrounding vital organs, achieving adequate circumferential resection margin(CRM) during operation is not always feasible. According to our recent study, even after preoperative chemoradiotherapy, there were still 33.8% and 17.2% of ypT3 cases had close(＜1mm) and positive CRM. More importantly, the distance of CRM was identified as the most important predictor for locoregional recurrence. Despite postoperative adjuvant therapy was invariably given in these patients, survival remained suboptimal. The poor outcome in these patients could be attributed to three major reasons (1) Long postoperative recovery period after esophagectomy : patients lose the "golden time" for adjuvant therapy (2)Tumoricidal RT dose could not be delivered to the whole mediastinum due to the dose limitation of normal thoracic organ (3) Systemic cytotoxic drugs are extensively transported to the whole body and only a small fraction of the drugs reach the tumor site. And most of the drug content is released soon after administration, causing drug levels in the body to rise rapidly, peak and then decline sharply, leading to unacceptable side effects . Due to these obstacles, a delivery system loaded with chemotherapeutic agent at tumor site( i.e. localized chemotherapy) which provide a high local concentration of the drug detrimental to malignant cells might shown lots of potential in cancer treatment. However, most reported chemotherapeutic drug delivery systems had important limitations; either with "short" releasing period /hard to manipulate or might lead to unwanted local wound complications(ex: delayed healing, infection). The purpose of this study is to develop novel sandwich-structured nanofibrous membranes to provide sustained-release delivery of cisplatin of surgical margins. To prepare the biodegradable membranes, PLGA, collagen, and cisplatin were first dissolved in HFIP. They will be electrospinned into sandwich-structured membranes with PLGA/collagen as the surface layers and PLGA/cisplatin as the core. Theoretically, with the large surface area and microporous structure provided by the nanofibers, the membrane can deliver higher and sustained drug concentrations locally than any other implants. Furthermore, the collagen layer can promote wound healing as well. In our 2-year proposal, three phases of study will be performed: Membrane fabrication and in vivo evaluation, cytotoxic activity confirmation by xenograft animal model and long term safety evaluation on canine model.

Project ID:PC10207-0414
External Project ID:NSC102-2628-B182-007