Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 10, Issue 26, Pages 21836-21846Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.8b04192
Keywords
micelles; hepatotoxicity; self-assembly; prodrug; oleanolic acid; methotrexate
Funding
- National Basic Research Program of China [2015CB856500]
- National Natural Science Foundation of China [21650110447]
- State Key Laboratory of Medicinal Chemical Biology (Nankai University) [2017030]
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Nanocarriers have been extensively utilized to enhance the anti-tumor performance of chemotherapy, but it is very challenging to eliminate the associated hepatotoxicity. This was due to the significant liver accumulation of cytotoxic drug-loaded nanocarriers as a consequence of systemic biodistribution. To address this, we report a novel type of nanocarrier that was made of hepatoprotective compound (oleanolic acid/OA) with a model drug (methotrexate/MTX) being physically encapsulated. OA was covalently connected with methoxy poly(ethylene glycol) (mPEG) via a hydrazone linker, generating amphiphilic mPEG-OA prodrug conjugate that could self-assemble into pH-responsive micelles (ca. 100 nm), wherein the MTX loading was ca. 5.1% (w/w). The micelles were stable at pH 7.4 with a critical micelle concentration of 10.5 mu M. At the acidic endosome/lysosome microenvironment, the breakdown of hydrazone induced the micelle collapse and fast release of payloads (OA and MTX). OA also showed adjunctive anti-tumor effect with a low potency, which was proved in 4T1 cells. In the mouse 4T1 breasttumor model, MTX-loaded mPEG-OA micelles demonstrated superior capability regarding in vivo tumorgrowth inhibition because of the passive tumor targeting of nanocarriers. Unsurprisingly, MTX induced significant liver toxicity, which was evidenced by the increased liver mass and increased levels of alanine transaminase, aspartate transaminase, and lactate dehydrogenase in serum as well as in liver homogenate. MTX-induced hepatotoxicity was also accompanied with augmented oxidative stress, for example, the increase of the malondialdehyde level and the reduction of glutathione peroxidase and superoxide dismutase concentration in the liver. As expected, mPEG-OA micelles significantly reduced the liver toxicity induced by MTX because of the hepatoprotective action of OA, which was supported by the reversal of all the above biomarkers and qualitative histological analysis of liver tissue. This work offers an efficient approach for reducing the liver toxicity associated with chemotherapy, which can be applied to various antitumor drugs and hepatoprotective materials.
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