Pharmacokinetics and pharmacodynamic evaluation of hyaluronic acid-modified imatinib-loaded PEGylated liposomes in CD44-positive Gist882 tumor-bearing mice

Abstract

To develop a PEGylated and CD44-targeted liposomes, enabled by surface coating with hyaluronic acid (HA) via amide bond to improve the efficacy of imatinib mesylate (IM), for tumor-targeted cytoplasmic drug delivery. HA was covalently grafted on DSPE-PEG2000-NH2 polymer. HA-modified or unmodified PEGylated liposomes were prepared with ethanol injection method, and the stability, drug release, and cytotoxicity of these liposomes were studied. Meanwhile, intracellular drug delivery efficiency, antitumor efficacy, and pharmacokinetics were also investigated. Ex vivo fluorescence biodistribution was also detected by small animal imaging. In addition, endocytosis mechanism was also explored HA-coated PEGylated liposomes (137.5 nm ± 10.24) had a negative zeta potential (−29.3 mV ± 5.44) and high drug loading (27.8%, w/w). The liposomes were stable with cumulative drug leakage (<60%) under physiological conditions. Blank liposomes were nontoxic to Gist882 cells, and IM-loaded liposomes had higher cytotoxicity to Gist882 cells. HA-modified PEGylated liposomes were internalized more effectively than non-HA coating via CD44-mediated endocytosis. Besides, the cellular uptake of HA-modified liposomes also partly depends on caveolin-medicated endocytosis and micropinocytosis. In rats, both liposomes produced a prolonged half-life of IM (HA/Lp/IM: 14.97h; Lp/IM: 11.15h) by 3- to 4.5-folds compared with the IM solution (3.61h). HA-decorated PEGylated liposomes encapsulated IM exhibited strong inhibitory effect on tumor growth in Gist882 cell-bearing nude mice and formation of 2D/3D tumor spheroids. The Ki67 immunohistochemistry result was consistent with the above results. IM-loaded PEGylated liposomes modified with HA exerted the excellent anti-tumor effect on tumor-bearing mice and more drugs accumulated into the tumor site.

GRAPHICAL ABSTRACT

Keywords:

• Hyaluronic acid
• imatinib mesylate
• Gist882
• long circulation

Author contributions

All authors contributed to conceptualization. Ju Huang was involved in material preparation investigation and methodology, project administration and resources, the writing of original draft. Jian Chen was responsible for software, data curation and formal analysis, and revision of the manuscript. All authors read and approved the final manuscript. Each author should have participated sufficiently in the work to take public responsibility for appropriate portions of the content.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data that support the findings of this study are not publicly available due to confidentiality but are available from the corresponding author.

Additional information

Funding

This study was financially supported by National Natural Science Foundation of China (No.81870453) and Transverse Connection Research project of Shandong university (No.1520020012).