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Combinatorial and sequential delivery of gemcitabine and oseltamivir phosphate from implantable poly(D,L-lactic-co-glycolic acid) cylinders disables human pancreatic cancer cell survival

Authors Allison Logan S, Brissenden AJ, Szewczuk MR, Neufeld RJ

Received 24 March 2017

Accepted for publication 23 June 2017

Published 31 July 2017 Volume 2017:11 Pages 2239—2250


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Georgios D. Panos

Stephanie Allison Logan,1 Amanda J Brissenden,1 Myron R Szewczuk,2 Ronald J Neufeld1

1Department of Chemical Engineering, 2Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

Abstract: Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre-existing resistance in heterogeneous cancer cells in tumors due to selective pressure from the single agent. Gemcitabine (GEM), a chemotherapeutic agent, is the current standard of care for patients with pancreatic cancer. Patients with pancreatic cancer receiving GEM have a low progression-free survival. Given the poor response rate to GEM, cancer cells are known to develop rapid resistance to this drug. Metronomic chemotherapy using combinatorial and sequential delivery systems are novel developmental approaches to disrupt tumor neovascularization, reduce systemic drug toxicity, and increase the sensitivity of chemotherapeutics in cancer. Here, implantable double-layered poly(D,L-lactic-co-glycolic acid) (PLGA) cylinders were engineered to sequentially release GEM in combination with oseltamivir phosphate (OP) over an extended time. Double-layered PLGA cylindrical implants loaded with these active hydrophilic drugs were fabricated with minimal loss of drugs during the formulation, enabling extensive control of drug loading and establishing uniform drug distribution throughout the polymer matrix. OP is used in the formulation because of its anticancer drug properties targeting mammalian neuraminidase 1 (Neu1) involved in multistage tumorigenesis. OP and GEM encapsulated in inner/outer GEMin/OPout or OPin/GEMout implantable PLGA double-layered cylinders displayed sustained near linear release over 30 days. OP and GEM released from the double-layered cylinders effectively reduced cell viability in pancreatic cancer cell line PANC1 and its GEM-resistant variant for up to 15 days.

Keywords: pancreatic cancer, oseltamivir phosphate, gemcitabine, PLGA, chemoresistance

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