Journal Article
. 2015 Aug;7(34).
doi: 10.1021/acsami.5b05347.

Nanodrug Formed by Coassembly of Dual Anticancer Drugs to Inhibit Cancer Cell Drug Resistance

Yuanyuan Zhao 1 Fei Chen 1 Yuanming Pan 1 Zhipeng Li 1 Xiangdong Xue 1 Chukwunweike Ikechukwu Okeke 1 Yifeng Wang 1 Chan Li 1 Ling Peng 2 Paul C Wang 3 Xiaowei Ma 1 Xing-Jie Liang 1 
Affiliations
  • PMID: 26270258
  •     37 References
  •     13 citations

Abstract

Carrier-free pure nanodrugs (PNDs) that are composed entirely of pharmaceutically active molecules are regarded as promising candidates to be the next generation of drug formulations and are mainly formulated from supramolecular self-assembly of drug molecules. It benefits from the efficient use of drug compounds with poor aqueous solubility and takes advantage of nanoscale drug delivery systems. Here, a type of all-in-one nanoparticle consisting of multiple drugs with enhanced synergistic antiproliferation efficiency against drug-resistant cancer cells has been created. To nanoparticulate the anticancer drugs, 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) were chosen as a typical model. The resulting HD nanoparticles (HD NPs) were formulated by a "green" and convenient self-assembling method, and the water-solubility of 10-hydroxycamptothecin (HCPT) was improved 50-fold after nanosizing by coassembly with DOX. The formation process was studied by observing the morphological changes at various reaction times and molar ratios of DOX to HCPT. Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around HCPT molecules through intermolecular forces. With the advantage of nanosizing, HD NPs could improve the intracellular drug retention of DOX to as much as 2-fold in drug-resistant cancer cells (MCF-7R). As a dual-drug-loaded nanoformulation, HD NPs effectively enhanced drug cytotoxicity to drug-resistant cancer cells. The combination of HCPT and DOX exhibited a synergistic effect as the nanosized HD NPs improved drug retention in drug-resistant cancer cells against P-gp efflux in MCF-7R cells. Furthermore, colony forming assays were applied to evaluate long-term inhibition of cancer cell proliferation, and these assays confirmed the greatly improved cytotoxicity of HD NPs in drug-resistant cells compared to free drugs.

Keywords: assemble; carrier-free; drug resistance; insoluble drugs; pure nanodrug.

EPR-effect: utilizing size-dependent nanoparticle delivery to solid tumors.
Triantafyllos Stylianopoulos.
Ther Deliv, 2013 Apr 06; 4(4). PMID: 23557281
Nonproductive rearrangement of DNA topoisomerase I and II genes: correlation with resistance to topoisomerase inhibitors.
K B Tan, M R Mattern, +2 authors, R K Johnson.
J Natl Cancer Inst, 1989 Nov 15; 81(22). PMID: 2553992
Preparation and size control of sub-100 nm pure nanodrugs.
Jinfeng Zhang, Yanan Li, +3 authors, Chun-Sing Lee.
Nano Lett, 2014 Dec 17; 15(1). PMID: 25514014
Excited-state proton transfer reactions of 10-hydroxycamptothecin.
Kyril M Solntsev, Erica N Sullivan, +3 authors, Dan Huppert.
J Am Chem Soc, 2004 Sep 30; 126(39). PMID: 15453804
Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug.
Xiaoyang Xu, Kun Xie, +10 authors, Omid C Farokhzad.
Proc Natl Acad Sci U S A, 2013 Oct 30; 110(46). PMID: 24167294    Free PMC article.
Highly Cited.
RGD-modified apoferritin nanoparticles for efficient drug delivery to tumors.
Zipeng Zhen, Wei Tang, +6 authors, Jin Xie.
ACS Nano, 2013 May 31; 7(6). PMID: 23718215    Free PMC article.
A water soluble prodrug of a novel camptothecin analog is efficacious against breast cancer resistance protein-expressing tumor xenografts.
Mika Endo, Masanori Miwa, +14 authors, Hisafumi Yamada-Okabe.
Cancer Chemother Pharmacol, 2009 Jun 06; 65(2). PMID: 19495753
10-Hydroxycamptothecin loaded nanoparticles: preparation and antitumor activity in mice.
Leyang Zhang, Mi Yang, +5 authors, Baorui Liu.
J Control Release, 2007 Apr 03; 119(2). PMID: 17400320
Carrier-free functionalized multidrug nanorods for synergistic cancer therapy.
Mengjiao Zhou, Xiujuan Zhang, +4 authors, Xiaohong Zhang.
Biomaterials, 2013 Aug 21; 34(35). PMID: 23958027
Nanocrystal technology, drug delivery and clinical applications.
Jens-Uwe A H Junghanns, Rainer H Müller.
Int J Nanomedicine, 2008 Nov 11; 3(3). PMID: 18990939    Free PMC article.
Highly Cited. Review.
New developments in chemotherapy of advanced breast cancer.
D E Lebwohl, R Canetta.
Ann Oncol, 2000 Feb 17; 10 Suppl 6. PMID: 10676565
Review.
A novel multifunctional poly(amidoamine) dendrimeric delivery system with superior encapsulation capacity for targeted delivery of the chemotherapy drug 10-hydroxycamptothecin.
Xiuqi Kong, Kui Yu, +10 authors, Zhangyong Hong.
Int J Pharm, 2014 Feb 18; 465(1-2). PMID: 24530519
Drug resistance in cancer: principles of emergence and prevention.
Natalia L Komarova, Dominik Wodarz.
Proc Natl Acad Sci U S A, 2005 Jun 28; 102(27). PMID: 15980154    Free PMC article.
Highly Cited.
Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line.
S H Kaufmann.
Cancer Res, 1991 Feb 15; 51(4). PMID: 1705167
PEGylated nanographene oxide for delivery of water-insoluble cancer drugs.
Zhuang Liu, Joshua T Robinson, Xiaoming Sun, Hongjie Dai.
J Am Chem Soc, 2008 Jul 30; 130(33). PMID: 18661992    Free PMC article.
Highly Cited.
The state of nanoparticle-based nanoscience and biotechnology: progress, promises, and challenges.
Beatriz Pelaz, Sarah Jaber, +16 authors, Wolfgang J Parak.
ACS Nano, 2012 Sep 29; 6(10). PMID: 23016700
Synthesis of water-soluble camptothecin-polyoxetane conjugates via click chemistry.
Olga Yu Zolotarskaya, Alison F Wagner, +3 authors, Hu Yang.
Mol Pharm, 2012 Oct 12; 9(11). PMID: 23051100    Free PMC article.
The predictive value of PgR and HER-2 for response to primary systemic chemotherapy in inflammatory breast cancer.
Hiroko Nogi, Tadashi Kobayashi, +5 authors, Ken Uchida.
Int J Clin Oncol, 2008 Aug 16; 13(4). PMID: 18704635
Chemotherapy in early breast cancer: when, how and which one?
Marcus Schmidt.
Breast Care (Basel), 2014 Sep 02; 9(3). PMID: 25177256    Free PMC article.
Review.
Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers.
Hwan-Woo Park, Haeli Park, +8 authors, Jun Hee Lee.
Nat Commun, 2014 Sep 06; 5. PMID: 25189398    Free PMC article.
Highly Cited.
Creation of pure nanodrugs and their anticancer properties.
Hitoshi Kasai, Tatsuya Murakami, +9 authors, Mitsuru Hashida.
Angew Chem Int Ed Engl, 2012 Sep 13; 51(41). PMID: 22969010
Targeted therapeutic nanotubes influence the viscoelasticity of cancer cells to overcome drug resistance.
Ashwinkumar A Bhirde, Bhaskara V Chikkaveeraiah, +11 authors, Xiaoyuan Chen.
ACS Nano, 2014 Apr 09; 8(5). PMID: 24708375    Free PMC article.
Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells.
K Yusa, T Tsuruo.
Cancer Res, 1989 Sep 15; 49(18). PMID: 2569930
Highly Cited.
The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo.
Hiroshi Maeda, Hideaki Nakamura, Jun Fang.
Adv Drug Deliv Rev, 2012 Oct 24; 65(1). PMID: 23088862
Highly Cited. Review.
Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery.
Ronnie H Fang, Che-Ming J Hu, +5 authors, Liangfang Zhang.
Nano Lett, 2014 Mar 29; 14(4). PMID: 24673373    Free PMC article.
Highly Cited.
Applications and potential toxicity of magnetic iron oxide nanoparticles.
Gang Liu, Jinhao Gao, Hua Ai, Xiaoyuan Chen.
Small, 2012 Sep 29; 9(9-10). PMID: 23019129
Review.
A review of stimuli-responsive nanocarriers for drug and gene delivery.
Srinivas Ganta, Harikrishna Devalapally, Aliasgar Shahiwala, Mansoor Amiji.
J Control Release, 2008 Feb 12; 126(3). PMID: 18261822
Highly Cited. Review.
Dendrimer-encapsulated camptothecins: increased solubility, cellular uptake, and cellular retention affords enhanced anticancer activity in vitro.
Meredith T Morgan, Yuka Nakanishi, +7 authors, Mark W Grinstaff.
Cancer Res, 2006 Dec 21; 66(24). PMID: 17178889
Functionalized nanoscale micelles improve drug delivery for cancer therapy in vitro and in vivo.
Tuo Wei, Juan Liu, +7 authors, Xing-Jie Liang.
Nano Lett, 2013 May 03; 13(6). PMID: 23634882
Spatiotemporal drug release visualized through a drug delivery system with tunable aggregation-induced emission.
Xiangdong Xue, Yuanyuan Zhao, +10 authors, Xing-Jie Liang.
Adv Mater, 2013 Oct 17; 26(5). PMID: 24129910
Primary systemic chemotherapy for inflammatory breast cancer.
Sarah Sinclair, Sandra M Swain.
Cancer, 2010 Jun 22; 116(11 Suppl). PMID: 20503414
Review.
Polymer-coated nanoparticles interacting with proteins and cells: focusing on the sign of the net charge.
Dominik Hühn, Karsten Kantner, +10 authors, Wolfgang J Parak.
ACS Nano, 2013 Apr 10; 7(4). PMID: 23566380
Highly Cited.
Controlled antibody/(bio-) conjugation of inorganic nanoparticles for targeted delivery.
Jose-Maria Montenegro, Valeria Grazu, +5 authors, Wolfgang J Parak.
Adv Drug Deliv Rev, 2013 Jan 03; 65(5). PMID: 23280372
Review.
Longitudinal bioluminescence imaging of the dynamics of Doxorubicin induced apoptosis.
Gang Niu, Lei Zhu, +7 authors, Xiaoyuan Chen.
Theranostics, 2013 Mar 09; 3(3). PMID: 23471295    Free PMC article.
Elevated expression of DNA topoisomerase II in camptothecin-resistant human tumor cell lines.
Y Sugimoto, S Tsukahara, +2 authors, T Tsuruo.
Cancer Res, 1990 Dec 15; 50(24). PMID: 2174738
Liposome-encapsulated doxorubicin reverses drug resistance by inhibiting P-glycoprotein in human cancer cells.
Chiara Riganti, Claudia Voena, +7 authors, Amalia Bosia.
Mol Pharm, 2011 Apr 16; 8(3). PMID: 21491921
Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin.
C A Frederick, L D Williams, +4 authors, A H Wang.
Biochemistry, 1990 Mar 13; 29(10). PMID: 2334681
Highly Cited.
A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy.
Leiqiang Han, Tianqi Wang, +3 authors, Na Zhang.
Int J Nanomedicine, 2016 Dec 14; 11. PMID: 27956831    Free PMC article.
Nanocrystals of a new camptothecin derivative WCN-21 enhance its solubility and efficacy.
Jia You, Yuyuan Chen, +6 authors, Chuanrui Xu.
Oncotarget, 2017 Apr 21; 8(18). PMID: 28423733    Free PMC article.
Inhibition of glioblastoma growth and invasion by 125I brachytherapy in rat glioma model.
Feihong Chen, Dan Wang.
Am J Transl Res, 2017 Jun 01; 9(5). PMID: 28559975    Free PMC article.
Nanoformulations for combination or cascade anticancer therapy.
Lei Miao, Shutao Guo, +2 authors, Leaf Huang.
Adv Drug Deliv Rev, 2017 Jun 19; 115. PMID: 28624477    Free PMC article.
Review.
Preclinical Evaluation and Monitoring of the Therapeutic Response of a Dual Targeted Hyaluronic Acid Nanodrug.
Minglong Chen, Wenqi Zhang, +6 authors, Shi Gao.
Contrast Media Mol Imaging, 2017 Nov 04; 2017. PMID: 29097925    Free PMC article.
Camptothecin-based nanodrug delivery systems.
Yan Wen, Yingze Wang, +4 authors, Xingjie Liang.
Cancer Biol Med, 2018 Jan 27; 14(4). PMID: 29372102    Free PMC article.
Facile Fabrication of Reduction-Responsive Supramolecular Nanoassemblies for Co-delivery of Doxorubicin and Sorafenib toward Hepatoma Cells.
Qingqing Xiong, Mangmang Cui, +2 authors, Tianqiang Song.
Front Pharmacol, 2018 Mar 01; 9. PMID: 29487523    Free PMC article.
Nanotechnology for Cancer Therapy Based on Chemotherapy.
Chen-Yang Zhao, Rui Cheng, Zhe Yang, Zhong-Min Tian.
Molecules, 2018 Apr 05; 23(4). PMID: 29617302    Free PMC article.
Review.
Carrier-Free, Dual-Functional Nanorods Via Self-Assembly Of Pure Drug Molecules For Synergistic Chemo-Photodynamic Therapy.
Yuping Zhao, Yanna Zhao, +8 authors, Jun Han.
Int J Nanomedicine, 2019 Dec 07; 14. PMID: 31806963    Free PMC article.
Tangeretin-Assisted Platinum Nanoparticles Enhance the Apoptotic Properties of Doxorubicin: Combination Therapy for Osteosarcoma Treatment.
Sangiliyandi Gurunathan, Muniyandi Jeyaraj, Min-Hee Kang, Jin-Hoi Kim.
Nanomaterials (Basel), 2019 Aug 01; 9(8). PMID: 31362420    Free PMC article.
Self-assembled natural phytochemicals for synergistically antibacterial application from the enlightenment of traditional Chinese medicine combination.
Xuehao Tian, Penglong Wang, +12 authors, Haimin Lei.
Acta Pharm Sin B, 2020 Oct 23; 10(9). PMID: 33088696    Free PMC article.
A smart dual-drug nanosystem based on co-assembly of plant and food-derived natural products for synergistic HCC immunotherapy.
Bingchen Zhang, Jiali Jiang, +8 authors, Jingwei Shao.
Acta Pharm Sin B, 2021 Feb 04; 11(1). PMID: 33532190    Free PMC article.
Quantitative self-assembly of pure drug cocktails as injectable nanomedicines for synergistic drug delivery and cancer therapy.
Xiaona Chen, Binbin Xie, +6 authors, Hangxiang Wang.
Theranostics, 2021 Apr 27; 11(12). PMID: 33897877    Free PMC article.