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
- Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer
- 高分子科学（英文版） 2023年41卷第4期页码：525-537
- 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：
  
  This work was financially supported by the National Natural Science Foundation of China (Nos. 11875269 and 21574136), and the Beijing Natural Science Foundation (No. 7212212).;Electronic supplementary information (ESI) is available free of charge in the online version of this article at http://doi.org/10.1007/s10118-022-2775-4.
- DOI：10.1007/s10118-022-2775-4
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Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer[J]. 高分子科学（英文版）, 2023,41(4):525-537.

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, 2023,41(4):525-537.
Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer[J]. 高分子科学（英文版）, 2023,41(4):525-537. DOI： 10.1007/s10118-022-2775-4.

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, 2023,41(4):525-537. 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

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