Development and In Vitro Evaluation of Long Circulating Liposomes for Targeted Delivery of Gemcitabine and Irinotecan in
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Research Article Development and In Vitro Evaluation of Long Circulating Liposomes for Targeted Delivery of Gemcitabine and Irinotecan in Pancreatic Ductal Adenocarcinoma S. Deodhar,1 A. K. Dash,1,3 E. J. North,1 and M. Hulce2
Received 7 April 2020; accepted 5 July 2020 Abstract. The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawback of suboptimal drug delivery at the target site and the systemic side effects produced by the unfettered exposure of the drug to healthy tissue. This study has the objective of developing novel poly(2-ethyl-2-oxazoline) (PETOX)–based long circulating liposomes loaded with gemcitabine and irinotecan for the treatment of pancreatic ductal adenocarcinoma, with a juxtaposition to PEGylated and uncoated liposomes. A PETOX −cholesteryl chloroformate lipopolymer conjugate (PETOX–ChC) with a carbonate linkage was prepared and characterized by 1H NMR, FTIR, and DSC. Liposomes were prepared using the thin film hydration technique followed by freeze–thaw and membrane extrusion methods. Liposome characterization includes particle size determination, zeta potential determination using a zetameter, and structural elucidation using 31P NMR and cryo-TEM. The PETOXylated liposomes showed a particle size of 180.1 ± 2.2 nm and a zeta potential of − 33.63 ± 1.23 mV. The liposomal combination therapy of gemcitabine and irinotecan was found to have an IC50 value 39 times lower in comparison to the drug combination in solution, while the PEGylated and PETOXylated liposomes showed IC50 values 1.6 times lower and 2 times lower than that of uncoated liposomes, respectively, against Mia PaCa II pancreatic cancer cell line. The PEGylated and PETOXylated liposomes showed 4.1 and 5.4 times slower macrophagial uptake in vitro in comparison to the uncoated liposomes respectively. The PEGylated liposomes showed 11% higher in vitro macrophagial uptake in comparison to PETOXylated liposomes. KEY WORDS: pancreatic cancer; long circulating liposome; polyethylene glycol; polyoxazoline; gemcitabine; irinotecan.
INTRODUCTION
1
Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, USA. 2 Department of Chemistry, Creighton University, Omaha, Nebraska, USA. 3 To whom correspondence should be addressed. (e–mail: [email protected]) Abbreviations: ABC, Accelerated blood clearance; ChC, Cholesteryl chloroformate; Cryo-TEM, Transmission electron cryomicroscopy; DCC, N,N′-Dicyclohexylcarbodiimide; DCM, Dichloromethane; DMAP, 4-Dimethylaminopyridine; DSC, Differential scanning calorimetry; DSPE, 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine; FTIR, Fourier transform infrared spectroscopy; HPLC, High-performance liquid chromatography; MTT, (3-(4,5-Dimethyl-2-thiazolyl)2,5-diphenyl-2H-tetrazolium bromide); NMR, Nuclear magnetic resonance; PDAC, Pancreatic ductal adenocarcinoma; PE, Phosphatidyl ethanolamine; PEG, Polyethylene glycol; PETOX, Poly(2-ethyl-2oxazoline); RES, Reticuloendothelial system.
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