A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect

Sai-Nan Liu; Jia-Hui Meng; Li-Yun Cui; Hua Chen; Lin-Qi Shi; Ru-Jiang Ma

doi:10.1007/s10118-024-3090-z

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A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect

RESEARCH ARTICLE | Updated：2024-04-12

- A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect
- Chinese Journal of Polymer Science Vol. 42, Issue 5, Pages: 559-569(2024)
- Affiliations：
  
  a.Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
  b.Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, China
- Author bio：
  
  shilinqi@nankai.edu.cn (L.Q.S.)
  marujiang@nankai.edu.cn (R.J.M.)
- Funds：
- DOI：10.1007/s10118-024-3090-z
  CLC：
- Received：25 November 2023，
  
  Revised：2023-12-26，
  
  Accepted：27 December 2023，
  
  Online First：28 February 2024，
  
  Published：01 May 2024
- Accepted：
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Liu, S. N.; Meng, J. H.; Cui, L. Y.; Chen, H.; Shi, L. Q.; Ma, R. J. A dynamic covalent bonding-based nanoplatform for intracellular co-delivery of protein drugs and chemotherapeutics with enhanced anti-cancer effect. Chinese J. Polym. Sci. 2024, 42, 559–569

Sai-Nan Liu, Jia-Hui Meng, Li-Yun Cui, et al. A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect[J]. Chinese Journal of Polymer Science, 2024, 42(5): 559-569.
Liu, S. N.; Meng, J. H.; Cui, L. Y.; Chen, H.; Shi, L. Q.; Ma, R. J. A dynamic covalent bonding-based nanoplatform for intracellular co-delivery of protein drugs and chemotherapeutics with enhanced anti-cancer effect. Chinese J. Polym. Sci. 2024, 42, 559–569 DOI： 10.1007/s10118-024-3090-z.

Sai-Nan Liu, Jia-Hui Meng, Li-Yun Cui, et al. A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect[J]. Chinese Journal of Polymer Science, 2024, 42(5): 559-569. DOI： 10.1007/s10118-024-3090-z.

摘要

A well-designed intracellular RNase A and DOX co-delivery system based on dynamic covalent bond was prepared with good stability and satisfied LC/EE under physiological conditions. This nanoplatform showed a synergistic and enhanced antic-cancer effect and may promote the development of anticancer combination therapy.

Abstract

Efficient intracellular delivery of protein drugs is critical for protein therapy. The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect. However

co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties. Herein

we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A (RNase A) and doxorubicin (DOX). Two polymers

PEG-

-P(Asp-

-AspDA) and PAE-

-P(Asp-

-AspPBA)

and two 2-acetylphenylboronic acid (2-APBA)-functionalized drugs

2-APBA-RNase A and 2-APBA-DOX

self-assemble into mixed-shell nanoparticles (RNase A/DOX@MNPs)

via

dynamic phenylboronic acid (PBA)-catechol bond between PBA and dopamine (DA) moieties. The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior. Under the slight acidic environment at tumor tissue

RNase A/DOX@MNPs are positively charged

promoting their endocytosis. Upon cellular uptake into endosome

further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two drugs. In cytoplasm

the high level of GSH removed the modification of 2-APBA on drugs. The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect. This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.

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