Rational design of multifunctional polymeric micelles with stimuli-responsive for imaging-guided combination cancer therapy
Rational design of multifunctional polymeric micelles with stimuli-responsive for imaging-guided combination cancer therapy
Multidrug resistance (MDR) of tumor cells is one of the major obstacles for the failure chemotherapy. Currently, there is still unmet demand for innovative strategies to overcome MDR as well as effective imaging-guided therapy. Here, we developed a novel multifunctional doxorubicin (Dox)/Elacridar (Ela) co-loaded FA/Cy7-PEG-PCL nanomicelles [denoted as FA/Cy7-MCs(Dox/Ela)] to overcome MDR and imaging in breast cancer. The nanomicelles exhibited an average size of around 43 nm in diameter with well dispersed and a pH responsive drug release. The FA/Cy7-MCs(Dox/Ela) nanomicelles had also an evident effect on the inhibition of Ela-induced P-gp ATPase activity and exhibited good photostability. In vitro cell culture experiments, FA/Cy7-MCs(Dox/Ela), showed higher cellular uptake and more significant cytotoxicity effect against MCF-7/MDR cells than the free Dox due to FA-receptor mediated cell endocytosis and Ela mediated P-gp inhibition. The in vivo imaging study revealed FA/Cy7-MCs(Dox/Ela) nanomicelles exhibit longer retention time and higher fluorescence intensity in the tumor sites when compared to Cy7 alone. In vivo antitumor efficacy assay displayed in FA/Cy7-MCs(Dox/Ela) have significantly higher antitumor activity compared with free Dox at the same dosage in MCF-7/ ADR tumor bearing nude mice. In vitro and in vivo toxicity results indicated that the nanomicelles were of low cytotoxicity and also harmless to normal organs in mice. These findings suggest that these FA/Cy7-MCs(Dox/Ela) nanomicelles have great potential for effective therapy of resistant cancers by combining with chemotherapeutic agent and P-gp ATPase activity inhibitor. It may also serve as a targeted cancer theranostic for real-time monitored in vivo dynamic distribution with high spatial resolution.
Active Targeting, Co-Delivery Carrier, Fluorescence Imaging, Nanomicelles, PEG-PCL
1221-1234
Yang, Hong
19665776-8750-4077-97d9-1ac35e57f804
Zhang, Chengchen
abc47c06-4b99-4aed-be72-463f211e9dfa
Li, Tingting
22947025-5c93-42ac-8d15-adc06a68e316
Shen, Xue
b334d366-7a1c-43a6-aebe-6e0e2d5be9f6
Chen, Zhongyuan
97a392ea-867c-4516-98ec-c2f001da0df2
Xie, Xiaoxue
259f7a20-3e73-4cee-bbe8-660ec5b84824
Li, Shun
f462fe35-203f-4b2a-a81c-edf6dd11f126
Qin, Xiang
af7395df-ffd1-400f-aabe-a6f8fe32001d
Wu, Chunhui
72ab377b-a38d-47f0-9f5e-ddc02b4bb4b7
Liu, Yiyao
f7cc88be-e992-4b2b-b4d1-9ca42e4aaf60
10 October 2017
Yang, Hong
19665776-8750-4077-97d9-1ac35e57f804
Zhang, Chengchen
abc47c06-4b99-4aed-be72-463f211e9dfa
Li, Tingting
22947025-5c93-42ac-8d15-adc06a68e316
Shen, Xue
b334d366-7a1c-43a6-aebe-6e0e2d5be9f6
Chen, Zhongyuan
97a392ea-867c-4516-98ec-c2f001da0df2
Xie, Xiaoxue
259f7a20-3e73-4cee-bbe8-660ec5b84824
Li, Shun
f462fe35-203f-4b2a-a81c-edf6dd11f126
Qin, Xiang
af7395df-ffd1-400f-aabe-a6f8fe32001d
Wu, Chunhui
72ab377b-a38d-47f0-9f5e-ddc02b4bb4b7
Liu, Yiyao
f7cc88be-e992-4b2b-b4d1-9ca42e4aaf60
Yang, Hong, Zhang, Chengchen, Li, Tingting, Shen, Xue, Chen, Zhongyuan, Xie, Xiaoxue, Li, Shun, Qin, Xiang, Wu, Chunhui and Liu, Yiyao
(2017)
Rational design of multifunctional polymeric micelles with stimuli-responsive for imaging-guided combination cancer therapy.
Journal of Biomedical Nanotechnology, 13 (10), .
(doi:10.1166/jbn.2017.2444).
Abstract
Multidrug resistance (MDR) of tumor cells is one of the major obstacles for the failure chemotherapy. Currently, there is still unmet demand for innovative strategies to overcome MDR as well as effective imaging-guided therapy. Here, we developed a novel multifunctional doxorubicin (Dox)/Elacridar (Ela) co-loaded FA/Cy7-PEG-PCL nanomicelles [denoted as FA/Cy7-MCs(Dox/Ela)] to overcome MDR and imaging in breast cancer. The nanomicelles exhibited an average size of around 43 nm in diameter with well dispersed and a pH responsive drug release. The FA/Cy7-MCs(Dox/Ela) nanomicelles had also an evident effect on the inhibition of Ela-induced P-gp ATPase activity and exhibited good photostability. In vitro cell culture experiments, FA/Cy7-MCs(Dox/Ela), showed higher cellular uptake and more significant cytotoxicity effect against MCF-7/MDR cells than the free Dox due to FA-receptor mediated cell endocytosis and Ela mediated P-gp inhibition. The in vivo imaging study revealed FA/Cy7-MCs(Dox/Ela) nanomicelles exhibit longer retention time and higher fluorescence intensity in the tumor sites when compared to Cy7 alone. In vivo antitumor efficacy assay displayed in FA/Cy7-MCs(Dox/Ela) have significantly higher antitumor activity compared with free Dox at the same dosage in MCF-7/ ADR tumor bearing nude mice. In vitro and in vivo toxicity results indicated that the nanomicelles were of low cytotoxicity and also harmless to normal organs in mice. These findings suggest that these FA/Cy7-MCs(Dox/Ela) nanomicelles have great potential for effective therapy of resistant cancers by combining with chemotherapeutic agent and P-gp ATPase activity inhibitor. It may also serve as a targeted cancer theranostic for real-time monitored in vivo dynamic distribution with high spatial resolution.
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Published date: 10 October 2017
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The in vivo antitumor efficacy of different therapeutic formulations was further explored on the MCF-7/ MDR tumor-bearing mice. As shown in Figure 9(D), FA/Cy7-MCs(Dox/Ela) group presented a great capable of suppressing the tumor growth (about 67% inhibition rate) than the groups of MCs(Dox/Ela) (about 10% inhibition rate) and free Dox (no inhibition), which was mainly attributed to the tumor-targeting capability of the micelles functionalized by FA. This result also was evidenced by the variations of tumor weight (Fig. 9(C)). The images of the tumor in the whole mice (Fig. 9(A)) or harvested from the mice (Fig. 9(B)) visually showed the greatest tumor shrinkage after treatment with FA/Cy7-MCs(Dox/Ela). Additionally, no remarkable change in body weight was observed during the treatment with FA/Cy7-MCs(Dox/Ela) (Fig. 9(E)). The obvious antitumor effect of FA/Cy7-MCs(Dox/Ela) also been demonstrated by H&E staining and TUNEL assay. The H&E results showed that most of the cells in FA/Cy7-MCs(Dox/Ela) group were seriously destroyed, indicating that treatment with FA/Cy7-MCs(Dox/Ela) has induced significant cell apoptosis and necrosis. Furthermore, TUNEL staining assay shows enhanced apoptosis and cell death by FA/Cy7-MCs(Dox/Ela) compared to other formulations (Fig. 6(F)). All the results indicated that Acknowledgments: We would like to thank the National Natural Science Foundation of China (81671821, 31470959, 81471785, 31470906, 11502049, 11772088, 31700811), the Basic Research Program of Sichuan Science and Technology (2017JY0019, 2017JY0217), the China Postdoctoral Science Foundation (2016M592657), and the Fundamental Research Funds for the Central Universities (ZYGX2016Z001, ZYGX2015J143) for financial supports.
Publisher Copyright:
© 2017 American Scientific Publishers.
Keywords:
Active Targeting, Co-Delivery Carrier, Fluorescence Imaging, Nanomicelles, PEG-PCL
Identifiers
Local EPrints ID: 482321
URI: http://eprints.soton.ac.uk/id/eprint/482321
ISSN: 1550-7033
PURE UUID: 7533c51f-4625-4886-9620-38dae38d89bc
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Date deposited: 26 Sep 2023 16:52
Last modified: 06 Jun 2024 02:19
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Author:
Hong Yang
Author:
Chengchen Zhang
Author:
Tingting Li
Author:
Xue Shen
Author:
Zhongyuan Chen
Author:
Xiaoxue Xie
Author:
Shun Li
Author:
Xiang Qin
Author:
Chunhui Wu
Author:
Yiyao Liu
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