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In vitro and in vivo evaluation of SN-38 nanocrystals with different particle sizes

Authors Chen M, Li W, Zhang X, Dong Y, Hua Y, Zhang H, Gao J, Zhao L, Li Y, Zheng A

Received 3 February 2017

Accepted for publication 7 June 2017

Published 1 August 2017 Volume 2017:12 Pages 5487—5500

DOI https://doi.org/10.2147/IJN.S133816

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Alexander Kharlamov

Peer reviewer comments 2

Editor who approved publication: Dr Linlin Sun


Min Chen,1,2 Wanqing Li,3 Xun Zhang,1 Ye Dong,1 Yabing Hua,1 Hui Zhang,1 Jing Gao,1 Liang Zhao,2 Ying Li,1 Aiping Zheng1

1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 2School of Pharmacy, Jinzhou Medical University, Jinzhou, 3School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China

Abstract: 7-Ethyl-10-hydroxycamptothecin (SN-38) is a potent broad-spectrum antitumor drug derived from irinotecan hydrochloride (CPT-11). Due to its poor solubility and instability of the active lactone ring, its clinical use is significantly limited. As one of the most promising formulations for poorly water-soluble drugs, nanocrystals have attracted increasing attention. In order to solve these problems and evaluate the antitumor effect of SN-38 in vitro and in vivo, two nanocrystals with markedly different particle sizes were prepared. Dynamic light scattering and transmission electron microscopy were used to investigate the two nanocrystals. The particle sizes of SN-38 nanocrystals A (SN-38/NCs-A) and SN-38 nanocrystals B (SN-38/NCs-B) were 229.5±1.99 and 799.2±14.44 nm, respectively. X-ray powder diffraction analysis showed that the crystalline state of SN-38 did not change in the size reduction process. An accelerated dissolution velocity of SN-38 was achieved by nanocrystals, and release rate of SN-38/NCs-A was significantly faster than that of SN-38/NCs-B. Cellular uptake, cellular cytotoxicity, pharmacokinetics, animal antitumor efficacy, and tissue distribution were subsequently examined. As a result, enhanced intracellular accumulation in HT1080 cells and cytotoxicity on different tumor cells were observed for SN-38/NCs-A compared to that for SN-38/NCs-B and solution. Besides, compared to the SN-38 solution, SN-38/NCs-A had a higher bioavailability after intravenous injection; while the bioavailability of SN-38/NCs-B was even lower than that of the SN-38 solution. SN-38/NCs-A exhibited a significant inhibition of tumor growth compared to SN-38 solution and SN-38/NCs-B in vivo. The antitumor effect of SN-38/NCs-B was stronger than SN-38 solution. The tissue distribution study in tumor-bearing mice showed that nanocrystals could markedly improve the drug accumulation in tumor tissue by the enhanced permeability and retention effect compared to SN-38 solution, and the amount of SN-38 in tumors of SN-38/NCs-A group was much more than that of SN-38/NCs-B group. In conclusion, nanocrystals dramatically enhanced the anticancer efficacy of SN-38 in vitro and in vivo, and the particle size had a significant influence on the dissolution behavior, pharmacokinetic properties, and tumor inhibition of nanocrystals.

Keywords: SN-38, nanocrystals, antitumor efficacy, cellular uptake, pharmacokinetics, tissue distribution

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