Abstract
Despite on-going medical advances, ovarian cancer survival rates have stagnated. In order to improve IP delivery of platinum-based antineoplastics, we aimed to develop a sustained drug delivery system for carboplatin (CPt). Toward this aim, we pursued a double emulsion process for obtaining CPt-loaded microcapsules composed of poly(ethylene terephthalate-ethylene dilinoleate) (PET-DLA) copolymer. We were able to obtain PET-DLA microspheres in the targeted size range of 10–25 µm (median: 18.5 µm), to reduce intraperitoneal clearance by phagocytosis and lymphoid transit. Empty microspheres showed the lack of toxicity in vitro. The double emulsion process yielded 2.5% w/w CPt loading and obtained microcapsules exhibited sustained (>20 day) zero-order release. The encapsulated CPt was confirmed to be bioavailable, as the microcapsules demonstrated efficacy against human ovarian adenocarcinoma (SK-OV-3) cells in vitro. Following intraperitoneal injection in mice, we did not observe adhesions, only mild, clinically-insignificant, local inflammatory response. Tissue platinum levels, monitored over 14 days using atomic absorption spectroscopy, revealed low burst and reduced systemic uptake (plasma, kidney), as compared to neat carboplatin injection. Overall, the results demonstrate the potential of the developed microencapsulation system for long-term intraperitoneal sustained release of carboplatin for the treatment of ovarian cancer.
Highlights
Ovarian cancer accounted for >180,000 deaths worldwide in 2018, representing 4.4% of cancer related deaths in females [1]
As well as its dissemination and recurrence are localized in the peritoneal cavity, local intraperitoneal (IP) delivery has long been explored as a means of improving outcomes and a recent meta-analysis [5] has demonstrated that IP delivery of platinum-based antineoplastics increases overall survival, but at the cost of more serious gastrointestinal (GI) complications, along with catheter-related complications
In our previous work [28], we demonstrated the use of a double emulsion process to encapsulate carboplatin
Summary
Ovarian cancer accounted for >180,000 deaths worldwide in 2018, representing 4.4% of cancer related deaths in females [1]. The 5-year survival worldwide ranges from 20–49%, depending on the country, and has remained largely flat since 1995, despite on-going medical advances [2]. This is likely due to the very high rate of recurrence: approx. As well as its dissemination and recurrence are localized in the peritoneal cavity, local intraperitoneal (IP) delivery has long been explored as a means of improving outcomes and a recent meta-analysis [5] has demonstrated that IP delivery of platinum-based antineoplastics (platins: cisplatin, carboplatin) increases overall survival (hazard ratio of 0.81), but at the cost of more serious gastrointestinal (GI) complications, along with catheter-related complications. As a result, developing drug delivery systems (DDS) for ovarian cancer therapy is an attractive strategy towards improving outcomes, while reducing complications
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