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

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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-b-P(Asp-co-AspDA) and PAE-b-P(Asp-co-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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Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. The author’s contact information: shilinqi@nankai.edu.cn (LQ.S.), marujiang@nankaiiedu.cn (R.J.M.)

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Acknowledgments

This work was financially supported by the National Key R&D Program of China (Nos. 2022YFA1205703 and 2022YFA1205702), the National Natural Science Foundation of China (Nos. 51773099, 51933006 and 52103183) and Haihe Laboratory of Sustainable Chemical Transformations (No. YYJC202102).

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Authors and Affiliations

  1. 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

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

  2. Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, 300192, China

    Lin-Qi Shi

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  1. Sai-Nan Liu
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  2. Jia-Hui Meng
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Correspondence to Lin-Qi Shi or Ru-Jiang Ma.

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

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Liu, SN., Meng, JH., Cui, LY. et al. A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect. Chin J Polym Sci (2024). https://doi.org/10.1007/s10118-024-3090-z

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