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Abstract
Purpose
When designing liposome formulas for treatment and diagnostic purposes, two of the most common challenges are 1) the lack of a specific release mechanism for the encapsulated contents and 2) a short circulation time due to poor resistance to biological fluids. This study aimed to create a liposome formula with prolonged in vivo longevity and pH-sensitivity for cytoplasmic drug delivery.
Materials and methods
Liposomal particles were generated using hydrogenated soy (HS) phosphatidylcholine, cholesteryl hemisuccinate (CHEM), polyethylene glycol (PEG) and diethylenetriaminepentaacetic acid-modified phosphatidylethanolamine with film hydration and extrusion methods. The physicochemical properties of the different formulas were characterized. pH-sensitivity was evaluated through monitoring release of encapsulated calcein. Stability of the radiolabeled liposomes was assessed in vitro through incubation with human serum. The best formula was selected and injected into healthy rats to assess tissue uptake and pharmacokinetics.
Results
Liposomal particles were between 88 and 102 nm in diameter and negatively charged on the surface. Radiolabeling of all formulas with indium-111 was successful with good efficiency. 1%PEG-HS-CHEM not only responded to acidification very quickly but also underwent heavy degradation with serum. The 4%PEG-HS-CHEM, which exhibited both comparatively good pH-sensitivity (up to 20% release) and satisfactory stability (stability >70% after 24 h), was considered the best candidate for in vivo evaluation. Tissue distribution of 4%PEG-HS-CHEM was comparable to that of 4%PEG-HS-Chol, a long-circulating but pH-insensitive control, showing major accumulation in liver, spleen, intestine and kidneys. Analysis of blood clearance showed favorable half-life values: 0.6 and 14 h in fast and slow clearance phases, respectively.
Conclusion
4%PEG-HS-CHEM showed promising results in pH-sensitivity, serum stability, tissue uptake and kinetics and is a novel liposome formulation for multifunctional theranostic applications.
Acknowledgments
The authors would like to thank Dr Shubing (Steve) Zhao and Professor Warren C W Chan for conducting the characterization of our liposome samples. We would also be grateful to Dr Eric Rentschler and Hashimoto Electronic Industry Co., Ltd, for kindly providing us liposome automaker and liposome auto-extruder.
Disclosure
Yin Duan was an employee of Nordion Inc. during this study, but he is no longer with the organization; Lihui Wei is an employee of Nordion Inc. The authors report no other conflicts of interest in this work.