Biomimetic codelivery overcomes osimertinib-resistant NSCLC and brain metastasis via macrophage-mediated innate immunity

Pengfei Zhao; Jiaxin Zhang; Aihua Wu; Meng Zhang; Yuge Zhao; Yisi Tang; Bing Wang; Tianxiang Chen; Feng Li; Qiang Zhao; Yongzhuo Huang

doi:10.1016/j.jconrel.2020.10.052

Biomimetic codelivery overcomes osimertinib-resistant NSCLC and brain metastasis via macrophage-mediated innate immunity

J Control Release. 2021 Jan 10:329:1249-1261. doi: 10.1016/j.jconrel.2020.10.052. Epub 2020 Oct 29.

Authors

Pengfei Zhao¹, Jiaxin Zhang², Aihua Wu³, Meng Zhang², Yuge Zhao⁴, Yisi Tang², Bing Wang², Tianxiang Chen⁵, Feng Li⁶, Qiang Zhao⁷, Yongzhuo Huang⁸

Affiliations

¹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China.
³ Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai 201203, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; Nanchang University College of Pharmacy, 461 Bayi Rd, Nanchang 330006, China.
⁵ Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
⁶ Auburn University Harrison School of Pharmacy, Auburn, AL 36849, USA.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China. Electronic address: zhaoq@simm.ac.cn.
⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China; Zhongshan Branch, The Institute of Drug Research and Development, Chinese Academy of Sciences, Zhongshan 528437, China. Electronic address: yzhuang@simm.ac.cn.

PMID: 33129919
DOI: 10.1016/j.jconrel.2020.10.052

Abstract

The third-generation of EGFR-TKI osimertinib has been approved as a first-line therapy in NSCLC, representing the most successful advance in molecularly targeted therapy. However, the rapid development of osimertinib resistance renders the unsustainable treatment benefit. Plus, brain metastasis (BMs) is a major mortality cause for NSCLC; there is no drug specifically approved for the osimertinib-resistant BMs of NSCLC yet. To tackle these critical issues, a BBB-permeable biomimetic codelivery system was designed for specifically treating osimertinib-resistant BMs. The T12 peptide-modified albumin nanoparticles coloaded with regorafenib and disulfiram/copper ion chelate repolarized the tumor-promoting CD206^hi TGF-β1⁺ MΦ via inhibition of FROUNT and thus remodeled tumor immune microenvironment. The treatment efficacy in both the subcutaneous H1975/AZDR model and the brain metastasized model demonstrated the effectiveness of the BBB-penetrating combination therapy and the macrophage-mediated innate immunity. This nanotherapeutic combination strategy provides a translational solution to the formidable challenges of overcoming TKI resistance and treating the TKI-resistant BMs.

Keywords: Brain metastasis; Brain targeting delivery; Combination therapy; Innate immunity; Osimertinib resistance; Tumor-associated macrophage.

Publication types

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

MeSH terms

Acrylamides
Aniline Compounds
Biomimetics
Brain Neoplasms* / drug therapy
Cell Line, Tumor
Drug Resistance, Neoplasm
ErbB Receptors / genetics
Humans
Immunity, Innate
Lung Neoplasms* / drug therapy
Macrophages
Mutation
Protein Kinase Inhibitors / pharmacology
Tumor Microenvironment

Substances

Acrylamides
Aniline Compounds
Protein Kinase Inhibitors
osimertinib
ErbB Receptors