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Fabrication of pH/Reduction Sensitive Polyethylene Glycol-Based Micelles for Enhanced Intracellular Drug Release.

ABSTRACT: At present, the drug is still difficult to release completely and quickly only with single stimulation. In order to promote the rapid release of polymeric micelles at tumor site, pH/reduction sensitive polymers (PCT) containing disulfide bonds and orthoester groups were synthesized. The PCT polymers can self-assemble in water and entrap doxorubicin to form drug-loaded micelles (DOX/PCT). In an in vitro drug release experiment, the cumulative release of DOX/PCT micelles in the simulated tumor microenvironment (pH 5.0 with GSH) reached (89.7 ± 11.7)% at 72 h, while it was only (16.7 ± 6.1)% in the normal physiological environment (pH 7.4 without GSH). In addition, pH sensitive DOX loaded micellar system (DOX/PAT) was prepared as a control. Furthermore, compared with DOX/PAT micelles, DOX/PCT micelles showed the stronger cytotoxicity against tumor cells to achieve an effective antitumor effect. After being internalized by clathrin/caveolin-mediated endocytosis and macropinocytosis, DOX/PCT micelles were depolymerized in intercellular acidic and a reductive environment to release DOX rapidly to kill tumor cells. Additionally, DOX/PCT micelles had a better inhibitory effect on tumor growth than DOX/PAT micelles in in vivo antitumor activity studies. Therefore, pH/reduction dual sensitive PCT polymers have great potential to be used as repaid release nanocarriers for intercellular delivery of antitumor drugs.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8470983 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBiofilm formation is one of the main reasons for persistent bacterial infections. Recently, pH-sensitive copolymers have fascinated incredible attention to tackle biofilm-related infections. However, the proper incorporation of pH-sensitive segments in the polymer chains, which could significantly affect the biofilms targeting ability, has not been particularly investigated. Herein, we synthesized three types of pH-sensitive copolymers based on poly (β-amino ester) (PAE), poly (lactic-co-glycolic acid) (PLA) and polyethylene glycol (PEG), PAE-PLA-mPEG (A-L-E), PLA-PAE-mPEG (L-A-E) and PLA-PEG-PAE (L-E-A) to address this issue.ResultsThe three copolymers could self-assemble into micelles (MA-L-E, ML-A-E and ML-E-A) in aqueous medium. Compared with MA-L-E and ML-A-E, placing the PAE at the distal PEG end of PLA-PEG to yield PLA-PEG-PAE (ML-E-A) was characterized with proper triggering pH, fully biofilm penetration, and high cell membrane binding affinity. Further loaded with Triclosan (TCS), ML-E-A/TCS could efficiently kill the bacteria either in planktonic or biofilm mode. We reasoned that PAE segments would be preferentially placed near the surface and distant from the hydrophobic PLA segments. This would increase the magnitude of surface charge-switching capability, as the cationic PAE+ would easily disassociate from the inner core without conquering the additional hydrophobic force arising from covalent linkage with PLA segments, and rapidly rise to the outermost layer of the micellar surface due to the relative hydrophilicity. This was significant in that it could enable the micelles immediately change its surface charge where localized acidity occurred, and efficiently bind themselves to the bacterial surface where they became hydrolyzed by bacterial lipases to stimulate release of encapsulated TCS even a relatively short residence time to prevent rapid wash-out. In vivo therapeutic performance of ML-E-A/TCS was evaluated on a classical biofilm infection model, implant-related biofilm infection. The result suggested that ML-E-A/TCS was effective for the treatment of implant-related biofilm infection, which was proved by the efficient clearance of biofilm-contaminated catheters and the recovery of surrounding infected tissues.ConclusionsIn summary, elaboration on the architecture of pH-sensitive copolymers was the first step to target biofilm. The ML-E-A structure may represent an interesting future direction in the treatment of biofilm-relevant infections associated with acidity.

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Fabrication of pH/Reduction Sensitive Polyethylene Glycol-Based Micelles for Enhanced Intracellular Drug Release.

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