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Double-Emulsion Copolyester Microcapsules for Sustained Intraperitoneal Release of Carboplatin

preprint
revised on 01.11.2019 and posted on 07.11.2019 by Aneta Cymbaluk-Płoska, Peter Sobolewski, Anita Chudecka-Głaz, Ewa Wiśniewska, Joanna Łapczuk, Marcin Frankowski, Marek Droździk, Miroslawa El Fray

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.

Funding

Polish National Science Centre (NCN): 2011/03/B/ST8/06353

History

Email Address of Submitting Author

psobolewski@zut.edu.pl

Institution

West Pomeranian University of Technology, Szczecin

Country

Poland

ORCID For Submitting Author

0000-0002-2097-0990

Declaration of Conflict of Interest

No conflicts

Version Notes

Added ECD to Fig 3 and changed inset to panel; added arrows to Fig. 10; expanded discussion.

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