Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 545, Issue 1-2, Pages 306-317Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2018.04.016
Keywords
Gambogic acid; Antitumor; Layer-by-layer self-assembled micelles; Protamine; Hyaluronic acid
Categories
Funding
- National Nature Science Foundation of China [81573620, 81274088]
- key project of Anhui universities provincial natural science research [KJ2017A394, KJ2016A683]
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This study aimed to develop a novel type of multilayer micelle using protamine (PRM) and hyaluronic acid (HA) for the delivery of gambogic acid (GA). GA-loaded micelles (GA-M) were simply and rapidly prepared using lecithin/solutol HS15 using a film-dispersion method. PRM and HA were added in sequence to form layer-bylayer self-assembled micelles (HA-PRM-GA-M), in which particle size, zeta potential, particle morphology, drug loading, encapsulation efficiency, and in vitro release were investigated. Surface charge reversal demonstrated that rapid HA detachment exposed PRM, leading to activation of a proton sponge effect in the hyaluronidase (HAase)-rich tumor microenvironment. Compared with coumarin 6-loaded micelles (C6-M), more efficient intracellular trafficking was observed for HA-PRM-C6-M, which is associated with the endosomal/lysosomal escaping ability of the exposed PRM. In vivo imaging showed increased enrichment of near infrared fluorescent dye (DIR)-loaded HA-PRM-DIR-M at the tumor site, suggesting that HA enhanced the active tumor targeting of GA. Furthermore, HA-PRM-GA-M showed the stronger antitumor activity than GA and GA-M against human lung adenocarcinoma (A549) tumor xenografts in nude mice. In summary, our findings show the potential of HAPRM- GA-M as a novel intravenous drug carrier for the treatment of lung cancer.
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