Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer

Meng-Xue Zhou; Jia-Yu Zhang; Xiao-Meng Cai; Rui Dou; Li-Fo Ruan; Wen-Jiang Yang; Wen-Chu Lin; Jun Chen; Yi Hu

doi:10.1007/s10118-022-2775-4

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Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer

RESEARCH ARTICLE | Updated：2023-03-07

- Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer
- Chinese Journal of Polymer Science Vol. 41, Issue 4, Pages: 525-537(2023)
- Affiliations：
  
  a.CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and University of Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Beijing 100049, China
  b.Key Laboratory of Tea Biology and Resource Utilization of Ministry of Agriculture, Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China
  c.Division of Nuclear Technology and Applications, Institute of High Energy Physics, Chinese Academy of Sciences (CAS), Beijing 100049, China
  d.High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China, University of Science and Technology of China, Hefei 230026, China
- Author bio：
  
  chenjun@ihep.ac.cn (J.C.)
  huyi@ihep.ac.cn (Y.H.)
- Funds：
- DOI：10.1007/s10118-022-2775-4
  CLC：
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Meng-Xue Zhou, Jia-Yu Zhang, Xiao-Meng Cai, et al. Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer. [J]. Chinese Journal of Polymer Science 41(4):525-537(2023)
DOI：

Meng-Xue Zhou, Jia-Yu Zhang, Xiao-Meng Cai, et al. Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer. [J]. Chinese Journal of Polymer Science 41(4):525-537(2023) DOI： 10.1007/s10118-022-2775-4.

摘要

We design a near-infrared (NIR) light- and acidity-activated micellar nanoparticle (iPUTDN) for mitochondrial-targeted doxorubicin (DOX) delivery to combat DOX resistance in small-cell lung cancer. NIR irradiation at the tumor region can peel off the PEG shell from the PEGylated iPUTDN nanoparticles to expose iRGD for deep tumor penetration and subsequently release the triphenylphosphonium(TPP)-conjugated DOX (TDOX) for reduction of both the mitochondrial membrane potential and the content of ATP.

Abstract

As one of the major challenges in tumor chemotherapy, multidrug resistance typically correlates with the poor drug penetration within tumor tissues and drug efflux by the ATP-driven efflux pumps in tumor cells. Herein, we design a kind of near-infrared (NIR) light- and acidity-activated micellar iPUTDN nanoparticle for mitochondria-targeting doxorubicin (DOX) delivery to combat DOX resistance in small-cell lung cancer. While the PEGylated iPUTDN nanoparticles can keep stealth in blood circulation, NIR irradiation at the tumor region can peel off the PEG shell from the nanoparticles, and the exposed iRGD can facilitate deep tumor penetration of the nanoparticles. After being internalized by DOX-resistant H69AR cells, the poly(,β,-aminoester)s (PAE)-based nanoparticles can release the triphenylphosphonium (TPP)-conjugated DOX (TDOX) into the cytosol, which can further accumulate in mitochondria with the aid of TPP. Consequently, the mitochondrial membrane potential and ATP content are both reduced in DOX-resistant H69AR cells. The ,in vivo, therapeutic results show that TDOX-loaded nanoparticles with the aid of NIR light irradiation can effectively suppress the DOX-resistant small-cell lung cancer without noticeable adverse effects.

关键词

Keywords

DoxorubicinNIR/pH-dual sensitive nanoparticlesTumor penetrationMitochondriaDrug resistance

references

Wang, H.; Gao, Z.; Liu, X.; Agarwal, P.; Zhao, S.; Conroy, D. W.; Ji, G.; Yu, J.; Jaroniec, C . P.; Liu, Z.; Lu, X.; Li, X.; He, X. Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance . Nat. Commun. , 2018 . 9 562 DOI:10.1038/s41467-018-02915-8http://doi.org/10.1038/s41467-018-02915-8 .

Zeng, X.; Sun, J.; Li, S.; Shi, J.; Gao, H.; Sun Leong, W.; Wu, Y.; Li, M.; Liu, C.; Li, P.; Kong, J.; Wu, Y . Z.; Nie, G.; Fu, Y.; Zhang, G. Blood-triggered generation of platinum nanoparticle functions as an anti-cancer agent . Nat. Commun. , 2020 . 11 567 DOI:10.1038/s41467-019-14131-zhttp://doi.org/10.1038/s41467-019-14131-z .

Jiao, D.; Yang, S . Overcoming resistance to drugs targeting KRAS(G12C) mutation . The Innovation , 2020 . 1 100035 .

Du, X.; Yang, B.; An, Q.; Assaraf, Y . G.; Cao, X.; Xia, J. Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors . The Innovation , 2021 . 2 100103 .

Wang, H.; Liang, Y.; Yin, Y.; Zhang, J.; Su, W.; White, A . M.; Bin, J.; Xu, J.; Zhang, Y.; Stewart, S.; Lu, X.; He, X. Carbon nano-onion-mediated dual targeting of P-selectin and P-glycoprotein to overcome cancer drug resistance . Nat. Commun. , 2021 . 12 312 DOI:10.1038/s41467-020-20588-0http://doi.org/10.1038/s41467-020-20588-0 .

Christie, E. L.; Pattnaik, S.; Beach, J.; Copeland, A.; Rashoo, N.; Fereday, S.; Hendley, J.; Alsop, K.; Brady, S. L.; Lamb, G.; Pandey, A.; deFazio, A.; Thorne, H.; Bild, A.; Bowtell, D. D. L . Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer . Nat. Commun. , 2019 . 10 1295 DOI:10.1038/s41467-019-09312-9http://doi.org/10.1038/s41467-019-09312-9 .

Johnson, Z. L.; Chen, J . ATP binding enables substrate release from multidrug resistance protein 1 . Cell , 2018 . 172 81 -89 . DOI:10.1016/j.cell.2017.12.005http://doi.org/10.1016/j.cell.2017.12.005 .

Knudsen, J. G.; Hamilton, A.; Ramracheya, R.; Tarasov, A. I.; Brereton, M.; Haythorne, E.; Chibalina, M. V.; Spégel, P.; Mulder, H.; Zhang, Q.; Ashcroft, F . M.; Adam, J.; Rorsman, P. Dysregulation of glucagon secretion by hyperglycemia-induced sodium-dependent reduction of ATP production . Cell Metab. , 2019 . 29 430 -442 . DOI:10.1016/j.cmet.2018.10.003http://doi.org/10.1016/j.cmet.2018.10.003 .

Zhang, J.; Song, X.; Xia, M.; Xue, Y.; Zhou, M.; Ruan, L.; Lu, H.; Chen, J.; Wang, D.; Chai, Z.; Hu, Y . The proximity of the G-quadruplex to hemin impacts the intrinsic DNAzyme activity in mitochondria . Chem. Commun. , 2021 . 57 3038 -3041 . DOI:10.1039/D0CC08316Jhttp://doi.org/10.1039/D0CC08316J .

Ruan, L.; Zhou, M.; Chen, J.; Huang, H.; Zhang, J.; Sun, H.; Chai, Z.; Hu, Y. Thermoresponsive drug delivery to mitochondria in vivo. Chem. Commun. 2019, 55, 14645-14648.

Wang, D.; Huang, H.; Zhou, M.; Lu, H.; Chen, J.; Chang, Y . T.; Gao, J.; Chai, Z.; Hu, Y. A thermoresponsive nanocarrier for mitochondria-targeted drug delivery . Chem. Commun. , 2019 . 55 4051 -4054 . DOI:10.1039/C9CC00603Fhttp://doi.org/10.1039/C9CC00603F .

Zheng, Y.; Ji, X.; Yu, B.; Ji, K.; Gallo, D.; Csizmadia, E.; Zhu, M.; Choudhury, M. R.; De La Cruz, L. K. C.; Chittavong, V.; Pan, Z.; Yuan, Z.; Otterbein, L. E.; Wang, B . Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide . Nat. Chem. , 2018 . 10 787 -794 . DOI:10.1038/s41557-018-0055-2http://doi.org/10.1038/s41557-018-0055-2 .

Wolfram, J.; Ferrari, M . Clinical cancer nanomedicine . Nano today , 2019 . 25 85 -98 . DOI:10.1016/j.nantod.2019.02.005http://doi.org/10.1016/j.nantod.2019.02.005 .

Yamada, Y.; Satrialdi; Hibino, M.; Sasaki, D.; Abe, J.; Harashima, H. Power of mitochondrial drug delivery systems to produce innovative nanomedicines. Adv. Drug Deliv. Rev. 2020, 154-155, 187-209.

Wallace, K. B.; Sardão, V. A.; Oliveira, P. J . Mitochondrial determinants of doxorubicin-induced cardiomyopathy . Circ. Res. , 2020 . 126 926 -941 . DOI:10.1161/CIRCRESAHA.119.314681http://doi.org/10.1161/CIRCRESAHA.119.314681 .

Dong, X.; Sun, Y.; Li, Y.; Ma, X.; Zhang, S.; Yuan, Y.; Kohn, J.; Liu, C.; Qian, J . Synergistic combination of bioactive hydroxyapatite nanoparticles and the chemotherapeutic doxorubicin to overcome tumor multidrug resistance . Small , 2021 . 17 e2007672 DOI:10.1002/smll.202007672http://doi.org/10.1002/smll.202007672 .

Keckesova, Z.; Donaher, J. L.; De Cock, J.; Freinkman, E.; Lingrell, S.; Bachovchin, D. A.; Bierie, B.; Tischler, V.; Noske, A.; Okondo, M. C.; Reinhardt, F.; Thiru, P.; Golub, T. R.; Vance, J. E.; Weinberg, R. A . LACTB is a tumour suppressor that modulates lipid metabolism and cell state . Nature , 2017 . 543 681 -686 . DOI:10.1038/nature21408http://doi.org/10.1038/nature21408 .

van den Bogert, C.; Holtrop, M.; Melis, T. E.; Roefsema, P. R.; Kroon, A. M . Different effects of oxytetracycline and doxycycline on mitochondrial protein synthesis in rat liver after long-term treatment . Biochem. Pharmacol. , 1987 . 36 1555 -1559 . DOI:10.1016/0006-2952(87)90126-2http://doi.org/10.1016/0006-2952(87)90126-2 .

Wang, M.; Ruan, L.; Zheng, T.; Wang, D.; Zhou, M.; Lu, H.; Gao, J.; Chen, J.; Hu, Y . A surface convertible nanoplatform with enhanced mitochondrial targeting for tumor photothermal therapy . Colloid Surf. B , 2020 . 189 110854 DOI:10.1016/j.colsurfb.2020.110854http://doi.org/10.1016/j.colsurfb.2020.110854 .

Liu, Y.; Li, H.; Xie, J.; Zhou, M.; Huang, H.; Lu, H.; Chai, Z.; Chen, J.; Hu, Y . Facile construction of mitochondria-targeting nanoparticles for enhanced phototherapeutic effects . Biomater. Sci. , 2017 . 5 1022 -1031 . DOI:10.1039/C6BM00878Jhttp://doi.org/10.1039/C6BM00878J .

Chen, M.; Wu, J.; Ning, P.; Wang, J.; Ma, Z.; Huang, L.; Plaza, G. R.; Shen, Y.; Xu, C.; Han, Y.; Lesniak, M . S.; Liu, Z.; Cheng, Y. Remote control of mechanical forces via mitochondrial-targeted magnetic nanospinners for efficient cancer treatment . Small , 2020 . 16 e1905424 DOI:10.1002/smll.201905424http://doi.org/10.1002/smll.201905424 .

Krainz, T.; Gaschler, M. M.; Lim, C.; Sacher, J. R.; Stockwell, B. R.; Wipf, P . A Mitochondrial-targeted nitroxide is a potent inhibitor of ferroptosis . ACS Cent. Sci. , 2016 . 2 653 -659 . DOI:10.1021/acscentsci.6b00199http://doi.org/10.1021/acscentsci.6b00199 .

Huang, Y.; Li, Y . Drug delivery and reversal of MDR . Mol. Pharmaceutics , 2014 . 11 2493 -2494 . DOI:10.1021/mp500438xhttp://doi.org/10.1021/mp500438x .

Cui, H.; Huan, M. L.; Ye, W. L.; Liu, D. Z.; Teng, Z. H.; Mei, Q. B.; Zhou, S. Y . Mitochondria and nucleus dual delivery system to overcome DOX resistance . Mol. Pharmaceutics , 2017 . 14 746 -756 . DOI:10.1021/acs.molpharmaceut.6b01016http://doi.org/10.1021/acs.molpharmaceut.6b01016 .

Bhatta, A.; Krishnamoorthy, G.; Marimuthu, N.; Dihingia, A.; Manna, P.; Biswal, H . T.; Das, M.; Krishnamoorthy, G. Chlorin e6 decorated doxorubicin encapsulated chitosan nanoparticles for photo-controlled cancer drug delivery . Int. J. Biol. Macromol. , 2019 . 136 951 -961 . DOI:10.1016/j.ijbiomac.2019.06.127http://doi.org/10.1016/j.ijbiomac.2019.06.127 .

Yang, R.; Wei, T.; Goldberg, H.; Wang, W.; Cullion, K.; Kohane, D. S . Getting drugs across biological barriers . Adv. Mater. , 2017 . 29 1606596 DOI:10.1002/adma.201606596http://doi.org/10.1002/adma.201606596 .

Gao, H.; Bi, Y.; Wang, X.; Wang, M.; Zhou, M.; Lu, H.; Gao, J.; Chen, J.; Hu, Y . Near-infrared guided thermal-responsive nanomedicine against orthotopic superficial bladder cancer . ACS Appl. Mater. Inter. , 2017 . 3 3628 -3634. .

Jin, Q.; Deng, Y.; Chen, X.; Ji, J . Rational design of cancer nanomedicine for simultaneous stealth surface and enhanced cellular uptake . ACS Nano , 2019 . 13 954 -977. .

Sun, Q.; Zhou, Z.; Qiu, N.; Shen, Y. Rational design of cancer nanomedicine: nanoproperty integration and synchronization. 2017, 29, 1606628.

Chen, B.; Dai, W.; He, B.; Zhang, H.; Wang, X.; Wang, Y.; Zhang, Q . Current multistage drug delivery systems based on the tumor microenvironment . Theranostics , 2017 . 7 538 -558 . DOI:10.7150/thno.16684http://doi.org/10.7150/thno.16684 .

Yang, Y.; Zhu, W.; Cheng, L.; Cai, R.; Yi, X.; He, J.; Pan, X.; Yang, L.; Yang, K.; Liu, Z.; Tan, W.; Chen, M . Tumor microenvironment (TME)-activatable circular aptamer-PEG as an effective hierarchical-targeting molecular medicine for photodynamic therapy . Biomaterials , 2020 . 246 119971 DOI:10.1016/j.biomaterials.2020.119971http://doi.org/10.1016/j.biomaterials.2020.119971 .

Zhou, M.; Huang, H.; Wang, D.; Lu, H.; Chen, J.; Chai, Z.; Yao, S. Q.; Hu, Y . Light-triggered PEGylation/dePEGylation of the nanocarriers for enhanced tumor penetration . Nano Lett. , 2019 . 19 3671 -3675 . DOI:10.1021/acs.nanolett.9b00737http://doi.org/10.1021/acs.nanolett.9b00737 .

Zhu, Y.; Chen, C.; Cao, Z.; Shen, S.; Li, L.; Li, D.; Wang, J.; Yang, X . On-demand PEGylation and dePEGylation of PLA-based nanocarriers via amphiphilic mPEG-TK-Ce6 for nanoenabled cancer chemotherapy . Theranostics , 2019 . 9 8312 -8320 . DOI:10.7150/thno.37128http://doi.org/10.7150/thno.37128 .

Deng, H.; Yang, W.; Zhou, Z.; Tian, R.; Lin, L.; Ma, Y.; Song, J.; Chen, X . Targeted scavenging of extracellular ROS relieves suppressive immunogenic cell death . Nat. Commun. , 2020 . 11 4951 DOI:10.1038/s41467-020-18745-6http://doi.org/10.1038/s41467-020-18745-6 .

Ingle, N. P.; Malone, B.; Reineke, T. M . Poly(glycoamidoamine)s: a broad class of carbohydrate-containing polycations for nucleic acid delivery . Trends Biotechnol. , 2011 . 29 443 -453 . DOI:10.1016/j.tibtech.2011.04.012http://doi.org/10.1016/j.tibtech.2011.04.012 .

Wang, J. L.; Tang, G. P.; Shen, J.; Hu, Q. L.; Xu, F. J.; Wang, Q. Q.; Li, Z. H.; Yang, W. T . A gene nanocomplex conjugated with monoclonal antibodies for targeted therapy of hepatocellular carcinoma . Biomaterials , 2012 . 33 4597 -4607 . DOI:10.1016/j.biomaterials.2012.02.045http://doi.org/10.1016/j.biomaterials.2012.02.045 .

Ren, J.; Sun, M.; Zhou, H.; Ajoolabady, A.; Zhou, Y.; Tao, J.; Sowers, J. R.; Zhang, Y . FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity . Sci. Adv. , 2020 . 6 eabc8561 DOI:10.1126/sciadv.abc8561http://doi.org/10.1126/sciadv.abc8561 .

Pai, J.; Hyun, S.; Hyun, J. Y.; Park, S. H.; Kim, W. J.; Bae, S. H.; Kim, N . K.; Yu, J.; Shin, I. Screening of pre-miRNA-155 binding peptides for apoptosis inducing activity using peptide microarrays . J. Am. Chem. Soc. , 2016 . 138 857 -867 . DOI:10.1021/jacs.5b09216http://doi.org/10.1021/jacs.5b09216 .

Zhou, M.; Zhang, X.; Xie, J.; Qi, R.; Lu, H.; Leporatti, S.; Chen, J.; Hu, Y . pH-sensitive poly(β-amino ester)s nanocarriers facilitate the inhibition of drug resistance in breast cancer cells . Nanomaterials , 2018 . 8 952 DOI:10.3390/nano8110952http://doi.org/10.3390/nano8110952 .

Zhen, W.; An, S.; Wang, S.; Hu, W.; Li, Y.; Jiang, X.; Li, J . Precise subcellular organelle targeting for boosting endogenous-stimuli-mediated tumor therapy . Adv. Mater. , 2021 . 33 e2101572 DOI:10.1002/adma.202101572http://doi.org/10.1002/adma.202101572 .

Wang, H.; Shi, W.; Zeng, D.; Huang, Q.; Xie, J.; Wen, H.; Li, J.; Yu, X.; Qin, L.; Zhou, Y . pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer . J. Nanobiotechnol. , 2021 . 19 152 DOI:10.1186/s12951-021-00895-4http://doi.org/10.1186/s12951-021-00895-4 .

Wu, M.; Zhang, H.; Tie, C.; Yan, C.; Deng, Z.; Wan, Q.; Liu, X.; Yan, F.; Zheng, H . MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma . Nat. Commun. , 2018 . 9 4777 -4777 . DOI:10.1038/s41467-018-07250-6http://doi.org/10.1038/s41467-018-07250-6 .

Lamb, R.; Harrison, H.; Hulit, J.; Smith, D. L.; Lisanti, M. P.; Sotgia, F . Mitochondria as new therapeutic targets for eradicating cancer stem cells: quantitative proteomics and functional validation via MCT1/2 inhibition . Oncotarget , 2014 . 5 11029 -11037 . DOI:10.18632/oncotarget.2789http://doi.org/10.18632/oncotarget.2789 .

Liu, J. P.; Wang, T. T.; Wang, D. G.; Dong, A. J.; Li, Y. P.; Yu, H. J . Smart nanoparticles improve therapy for drug-resistant tumors by overcoming pathophysiological barriers . Acta Pharmacol. Sin. , 2017 . 38 1 -8 . DOI:10.1038/aps.2016.84http://doi.org/10.1038/aps.2016.84 .

Wang, J.; Zhou, M.; Chen, F.; Liu, X.; Gao, J.; Wang, W.; Wang, H.; Yu, H . Stimuli-sheddable nanomedicine overcoming pathophysiological barriers for potentiating immunotherapy of cancer . J. Biomed. Nanotechnol. , 2021 . 17 1486 -1509 . DOI:10.1166/jbn.2021.3134http://doi.org/10.1166/jbn.2021.3134 .

Huang, L.; Chen, F.; Lai, Y.; Xu, Z.; Yu, H . Engineering nanorobots for tumor-targeting drug delivery: from dynamic control to stimuli-responsive strategy . ChemBioChem , 2021 . 22 3369 -3380 . DOI:10.1002/cbic.202100347http://doi.org/10.1002/cbic.202100347 .

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