Neutrophil-mediated clinical nanodrug for treatment of residual tumor after focused ultrasound ablation

Jian Shen,Hairong Liu,Yuanyi Zheng,Jianrong Wu,Yan Wang,Bing Hu,Xiaojun Cai,Yini Chen,Junnian Hao

doi:10.1186/s12951-021-01087-w

Abstract

BackgroundThe risk of local recurrence after high-intensity focused ultrasound (HIFU) is relatively high, resulting in poor prognosis of malignant tumors. The combination of HIFU with traditional chemotherapy continues to have an unsatisfactory outcome because of off-site drug uptake.ResultsHerein, we propose a strategy of inflammation-tendency neutrophil-mediated clinical nanodrug targeted therapy for residual tumors after HIFU ablation. We selected neutrophils as carriers and PEGylated liposome doxorubicin (PLD) as a model chemotherapeutic nanodrug to form an innovative cell therapy drug (PLD@NEs). The produced PLD@NEs had a loading capacity of approximately 5 µg of PLD per 106 cells and maintained the natural characteristics of neutrophils. The targeting performance and therapeutic potential of PLD@NEs were evaluated using Hepa1-6 cells and a corresponding tumor-bearing mouse model. After HIFU ablation, PLD@NEs were recruited to the tumor site by inflammation (most in 4 h) and released PLD with inflammatory stimuli, leading to targeted and localized postoperative chemotherapy.ConclusionsThis effective integrated method fully leverages the advantages of HIFU, chemotherapy and neutrophils to attract more focus on the practice of improving existing clinical therapies.Graphical

Highlights

The risk of local recurrence after high-intensity focused ultrasound (HIFU) is relatively high, resulting in poor prognosis of malignant tumors
This effective integrated method fully leverages the advantages of HIFU, chemotherapy and neutrophils to attract more focus on the practice of improving existing clinical therapies
HIFU-induced cell death creates an inflammatory environment in the residual tumor (1a and b), and the released chemokines induce neutrophils to migrate to the tumor site (2)

Summary

Introduction

The risk of local recurrence after high-intensity focused ultrasound (HIFU) is relatively high, resulting in poor prognosis of malignant tumors. Radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation are the most commonly used ablation techniques for the clinical treatment of solid tumors. High-intensity focused ultrasound (HIFU) is the only noninvasive hyperthermic ablation modality [1]. HIFU has been routinely used in the clinical treatment of prostate disease and gynecological tumors [2,3,4]. HIFU is being explored as a promising hyperthermic technology for potential application in the clinical treatment of solid tumors such as thyroid tumors, liver cancer, and kidney cancer [5,6,7,8]. As for other ablation techniques, incomplete ablation is still the main limitation and challenge of HIFU. Incomplete ablation can be caused by several factors: (a) poor detection of the tumor borders using current imaging techniques, especially for small tumors; (b) loss of accurate detection caused by the respiratory motion of patients; (c) scattering or absorption of acoustic waves at the gas or bone interface in the sound field; and (d) a “heat-sink” effect, known as the “cool-down”

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Conclusion