Mitoxantrone-preloaded water-responsive phospholipid-amorphous calcium carbonate hybrid nanoparticles for targeted and effective cancer therapy

International Journal of Nanomedicine Dovepress open access to scientific and medical research O r i g in a l R e s e a r c h International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 88.198.20.149 on 23-Jul-2019 For personal use only. Open Access Full Text Article Mitoxantrone-preloaded water-responsive phospholipid-amorphous calcium carbonate hybrid nanoparticles for targeted and effective cancer therapy This article was published in the following Dove Medical Press journal: International Journal of Nanomedicine Cheng Wang 1,* Min Han 1,2,* Xuerong Liu 1 Shaoqing Chen 1 Fuqiang Hu 1 Jihong Sun 3 Hong Yuan 1 Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; 2Hangzhou Zhongmei Huadong Pharmaceutical Co, Ltd, Hangzhou 310011, China; 3Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China 1 *These authors contributed equally to this work Introduction Correspondence: Jihong Sun Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No 3 Qingchun East Road, Hangzhou 310016, China Tel +86 571 8609 0073 Email Hong Yuan Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China Tel +86 571 8820 6742 Email Currently, cancer remains one of the most lethal diseases around the world requiring unremitting efforts.1 Among the most widely adopted antitumor drugs, mitoxantrone (MIT) is a chemotherapeutic agent that can intercalate into DNA or RNA through hydrogen bonding to induce cross-links and strand breaks. Furthermore, MIT can also facilitate topoisomerase II inhibition as well as mitochondrial pathway inhibition.2 However, nonspecific cell death or apoptosis induced by MIT can injure both healthy and cancer cells. As a result, despite the utilization of MIT for the treatment of a wide range of cancers,3 inadvertent side effects, especially cardiotoxicity, limit its further clinical application in cancer therapy.4 The generally recognized approach to minimize the side effects of chemotherapy is to introduce drug delivery systems (DDSs).5 Although selective accumulation of DDSs in the neoplastic area can be easily satisfied by tumor homing or in situ injection technologies,6,7 insufficient drug release within targeted sites remains a pending issue 1503 submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2019:14 1503–1517 Dovepress © 2019 Wang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/IJN.S193976 Powered by TCPDF (www.tcpdf.org) Background: The application of mitoxantrone (MIT) in cancer therapy has been severely limited by its inherent drawbacks. In addition, effective cancer therapy calls for drug release systems capable of enforcing drug release within cancer cells in response to infinite stimulant with enhanced drug penetration capability. Methods: MIT-preloaded phospholipid-amorphous calcium carbonate hybrid nanoparticles (PL/ACC-MIT) that surface modified with PL shell (containing shielding polymer polyethylene glycol and targeting moiety folic acid) were prepared by a facile solvent-diffusion method. Results: It has been proven that the resulting PL/ACC-MIT nanoparticles demonstrated satisfactory stability against various aqueous environments with minimal drug leakage and exerted strong targeting capability but selective preference to the folate receptor-overexpressing cell line. In contrast, once exposed to the enzyme-abundant and acidic environments of cancer cells, the PL/ACC-MIT nanoparticles can readily decompose to facilitate quick drug release and enhanced drug penetration to yield preferable antitumor effect both in vitro and in vivo. Conclusion: In this study, MIT-preloaded water-responsive hybrid nanoparticles with increased stability, targetability, controlled drug release, and enhanced drug penetration were successfully developed, which might be a candidate for targeted and effective cancer therapy. Keywords: mitoxantrone, water responsive, hybrid nanoparticles, amorphous calcium carbonate, cancer therapy Dovepress International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 88.198.20.149 on 23-Jul-2019 For personal use only. Wang et al that requires additional efforts.8,9 Many currently available DDSs usually suffer from ineffective drug release whereby high local drug levels cannot translate into sufficiently available drug levels.10 For some responsive ones, drug release might be impaired due to the consumption of corresponding stimulants (such as H+ and glutathione)11,12 during the release process. This calls for a new and effective approach that enforces drug release in the cancer cells in response to some infinite stimulants. Moreover, it has been found that normal DDSs are predominantly located near the blood vessels and only delivered to the cells on the tumor periphery, which is primarily attributed to the physiological barriers of the solid tumor that impedes the uniform distribution of anticancer drugs throughout the tumor in a therapeutic concentration.13 Calcium carbonate as a naturally nontoxic inorganic biomaterial has multiple intrinsic advantages that are suitable for broad biomedical applications.14 It can be divided into crystallized and amorphous categories based on its polymorph. Unlike crystallized calcium carbonate which usually is in the micrometer range, nanosized amorphous calcium carbonate (ACC) can be more readily obtained by various simple methods.15,16 The phenomenon that ACC will dissolve and/or transfer polymorph in water has generally been recognized as the major obstacle for its extended application in nanomedicine.16 However, in our view, if this characteristic can be preserved and yet be realized specifically within targeted sites, it would be beneficial to enforce drug release within cells in a water-responsive manner. The use of organic-inorganic hybrid nanocarriers for controlled release of antitumor drugs has gained great interest, in particular to improve the selectivity and efficacy of drugs.17–19 Compared with single carriers, hybrid nanocarriers built upon the success of traditional platforms with further optimizations in material, size, and structural properties could greatly improve t (...truncated)