Microfluidics-Assisted Engineering of pH/Enzyme Dual-Activatable ZIF@Polymer Nanosystem for Co-Delivery of Proteins and Chemotherapeutics with Enhanced Deep-Tumor Penetration

Jie Shen; Ming Ma; Muhammad Shafiq; Huizhu Yu; Zhengyi Lan; Hangrong Chen

doi:10.1002/anie.202113703

Microfluidics-Assisted Engineering of pH/Enzyme Dual-Activatable ZIF@Polymer Nanosystem for Co-Delivery of Proteins and Chemotherapeutics with Enhanced Deep-Tumor Penetration

Angew Chem Int Ed Engl. 2022 Mar 28;61(14):e202113703. doi: 10.1002/anie.202113703. Epub 2022 Feb 10.

Authors

Jie Shen^{1

2}, Ming Ma^{1

2

3}, Muhammad Shafiq⁴, Huizhu Yu¹, Zhengyi Lan¹, Hangrong Chen^{1

2

3}

Affiliations

¹ State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China.
² Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
³ School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, P. R. China.
⁴ Department of Biotechnology, Faculty of Life Sciences, University of Central Punjab, Lahore, 54000, Pakistan.

PMID: 34989079
DOI: 10.1002/anie.202113703

Abstract

The impermeable barriers of solid tumors restrict the co-delivery of protein-based drugs and chemotherapeutics for cancer treatment. Therefore, we developed a ZIF-DOX/RA@DG nanosystem that encapsulates ribonuclease A (RA) and doxorubicin (DOX) in a zeolitic imidazolate framework (ZIF-8) core, with a dextran-based coating (DG). The nanosystem exhibits dual-responsiveness due to γ-glutamyl transpeptidase-activatable cationization and acidic microenvironment-triggered degradation. The DG-coating process was achieved using a microfluidic approach, which stabilized the polymer responsiveness, ZIF-8-based structure, and bioactivity of the encapsulated therapeutics. In vivo results confirmed that the nanosystem could co-deliver RA and DOX to deep impermeable lesions with a synergistic anticancer therapeutic effects. Such a multi-drug delivery system based on an intelligent-responsive design and a microfluidics-assisted synthesis strategy shows great clinical prospects.

Keywords: Cancer therapy; Co-delivery; Deep penetration; Dual-responsive systems; Microfluidics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Doxorubicin / chemistry
Drug Delivery Systems
Humans
Hydrogen-Ion Concentration
Microfluidics
Neoplasms* / drug therapy
Polymers / chemistry
Tumor Microenvironment
Zeolites*

Substances

Polymers
Zeolites
Doxorubicin