Tumor microenvironment triple-responsive nanoparticles enable enhanced tumor penetration and synergetic chemo-photodynamic therapy

Man Shu; Junjie Tang; Lili Chen; Qiang Zeng; Chao Li; Shuting Xiao; Zhaozhong Jiang; Jie Liu

doi:10.1016/j.biomaterials.2020.120574

Tumor microenvironment triple-responsive nanoparticles enable enhanced tumor penetration and synergetic chemo-photodynamic therapy

Biomaterials. 2021 Jan:268:120574. doi: 10.1016/j.biomaterials.2020.120574. Epub 2020 Nov 25.

Authors

Man Shu¹, Junjie Tang¹, Lili Chen², Qiang Zeng¹, Chao Li¹, Shuting Xiao¹, Zhaozhong Jiang³, Jie Liu⁴

Affiliations

¹ School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
² Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
³ Department of Biomedical Engineering, Integrated Science and Technology Center, Yale University, 600 West Campus Drive, West Haven, CT, 06516, United States. Electronic address: zhaozhong.jiang@yale.edu.
⁴ School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China. Electronic address: liujie56@mail.sysu.edu.cn.

PMID: 33271451
DOI: 10.1016/j.biomaterials.2020.120574

Abstract

A novel combined chemo/photodynamic therapy has been developed to use pH/ROS/MMP-2 triple-responsive drug nanocarriers for treating solid tumor with an extraordinarily high efficiency. The designed poly(ethylene glycol)-peptide-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-thiodipropionate) (PEG-M-PPMT) nanoparticles (NPs) encapsulating anticancer drug sorafenib (SRF) and photosensitizer chlorin e6 (Ce6) are stable in serum-containing aqueous media and can effectively accumulate in tumor as a result of the EPR effect after intravenous administration in vivo. In the presence of MMP-2 overexpressed in extracellular tumor matrix, the PEG-M-PPMT NPs can partially shed PEG corona to form smaller particles and penetrate deep into tumor tissue. After uptake by tumor cells, the acidic endosomal pH and high intracellular ROS level would trigger substantial swelling of the NPs to accelerate the drug release for rapid killing of the cancer cells. In the current combined chemo/photodynamic therapy, the intracellular ROS generation in tumor is amplified by photosensitizer Ce6 activated with external laser irradiation. As the result, the highly elevated intracellular ROS concentration can both directly induce apoptosis of ROS-stressed tumor cells and magnify acceleration of the drug release from the ROS-responsive PEG-M-PPMT NPs to gain extraordinary therapeutic efficacy. In particular, after the chemo-photodynamic therapeutic treatment with SRF/Ce6-loaded PEG-M-PPMT nanoparticles, all human lung tumors (A549) xenografted in nude mice shrank substantially with approximately 29% of the tumors being completely eradicated. Additionally, SRF/Ce6-loaded PEG-M-PPMT NPs show negligible in vivo toxicity toward major organs such as heart, liver, spleen, lung and kidney. These results demonstrate great potential of the combined chemo/photodynamic therapy based on the stimuli-responsive PEG-M-PPMT nanoparticles for efficient tumor treatment.

Keywords: Drug delivery; MMP-2; Nanoparticles; Photodynamic therapy; ROS amplification; pH and ROS-Responsive.

Publication types

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

MeSH terms

Animals
Cell Line, Tumor
Humans
Mice
Mice, Nude
Nanoparticles*
Photochemotherapy*
Photosensitizing Agents
Porphyrins*
Tumor Microenvironment

Substances

Photosensitizing Agents
Porphyrins