Page 2 - An ultrasound-driven immune-boosting molecular machine for systemic tumor suppression

SCIENCE ADVANCES | RESEARCH ARTICLE

HEALTH AND MEDICINE Copyright © 2021
The Authors, some
An ultrasound-driven immune-boosting molecular rights reserved;
exclusive licensee
machine for systemic tumor suppression American Association
for the Advancement
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Liu Wang , Guangzhe Li *, Lei Cao , Yi Dong , Yang Wang , Shisheng Wang , Yueqing Li , of Science. No claim to
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Xiuhan Guo , Yi Zhang , Fangfang Sun , Xuemei Du , Jiangan Su , Qing Li , Xiaojun Peng , original U.S. Government
Works. Distributed
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Kun Shao *, Weijie Zhao * under a Creative
Commons Attribution
Exploring facile and effective therapeutic modalities for synergistically controlling primary tumor and metastasis License 4.0 (CC BY).
remains a pressing clinical need. Sonodynamic therapy (SDT) offers the possibility of noninvasively eradicating
local solid tumors, but lacks antimetastatic activity because of its limited ability in generating systemic antitumor
effect. Here, we exploited a previously unidentified ultrasound-driven “molecular machine,” DYSP-C34 (C34 for short),
with multiple attractive features, emerging from preferential tumor accumulation, potent ultrasound-triggered
cytotoxicity, and intrinsic immune-boosting capacity. Driven by the ultrasound, C34 functioned not only as a
tumor cell killing reagent but also as an immune booster that could potentiate robust adaptive antitumor immunity
by directly stimulating dendritic cells, resulting in the eradication of the primary solid tumor along with the inhibition
of metastasis. This molecular machine, C34, rendered great promise to achieve systemic treatment against cancer
via unimolecule-mediated SDT.
INTRODUCTION Notably, accumulating evidence has suggested that the SDT pro-
Cancer therapy has evolved slowly with very rare successes (1). cess could initiate, but in a very limited way, host antitumor immunity
Although conventional therapies, such as radiation therapy, surgery, (10) by inducing immunogenic cell death (ICD) of dying cancer cells,
and chemotherapy, have improved treatment effects against well- which is characterized by the release of “danger” signals (11–13),
defined primary solid tumors, curative outcomes still remain unsat- thus enabling antigen-presenting cells (APCs) to trigger “vaccine-like”
isfactory especially in patients with the occurrence of metastatic immune responses. Unfortunately, the extent of immune responses
tumor, which actually contributes to more than 90% of mortality in arising from SDT is not yet robust enough to efficiently control tumor
cancer patients (2). The reason could be a result of less accessibility growth and metastasis (14, 15). To harness the potency of the sys-
of most therapeutics to microscopic tumor lesions, which occurred temic antitumor immunity, the development of sono/immuno-
in secondary organs. For this case, by mounting a dynamic antitu- combinational therapy has been exploited as an attractive strategy
mor immune response, immunotherapy has been shown to be most to amplify the overall therapeutic effect (16), mostly through the Downloaded from https://www.science.org at Dalian University of Technology on October 20, 2021
beneficial in tackling the tumor cells, particularly the ones hiding in nanocarriers to co-deliver the sonosensitizers and the adjuvants or
the “corner” of the body (3, 4). However, the immunotherapeutic checkpoint inhibitors, of which the effectiveness in mouse models
effect against solid tumors was hindered by the unamiable tumor has been validated in many studies (10, 12, 17). While the importance
microenvironment (5). Therefore, the development of a novel can- of nanomedicine continues to be highlighted, the biodegradability
cer therapeutic modality, which is able to destroy the primary solid and biosafety of these complicated nanosystems are always brought
tumor together with recognizing, suppressing, and even eliminat- as the major concerns for their further clinical translation. Driven
ing the residual cancer cells at the site of metastasis, has been widely by practical clinical benefits, the motivation for exploring a “small
considered as the ultimate goal in the battle against cancer. molecular machine,” which is equipped with synchronized functions
Being a representative noninvasive cancer treatment, sonodynamic of tumor targetability, acoustic responsive activity, and immune-
therapy (SDT), which was adapted from photodynamic therapy boosting capacity to achieve profound antitumor outcomes, has become
(PDT), has recently garnered substantial interests in cancer therapy, more realistic.
mainly because of its great advantage of deep tissue penetration Natural products are a constant source of leads for many bioactive
(6, 7). SDT uses synergetic interaction between the low-intensity molecules, which hold promise for being developed as new medi-
ultrasound (US) and a sonosensitizer to elicit cytotoxic effects. Cur- cines (18). Chlorin e6 (Ce6), isolated from green plants or silkworm
rently, the most accepted mechanism suggests that the US-activated excrement, is a second-generation sensitizer with potent sonosensi-
sonosensitizers lead to conversion of molecular oxygen to various tivity (19). A number of studies have shown that Ce6-mediated SDT
highly reactive oxygen species (ROS), which induces apoptosis and was capable of suppressing the proliferation of hepatoma cells (20),
necrosis of tumor cells (8, 9). breast cancer cells (21), human lung adenocarcinoma cells (22), etc.
However, low bioavailability, poor solubility, and tendency to ag-
gregate in the biologic medium hinder in vivo applications of Ce6
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State Key Laboratory of Fine Chemicals, Department of Pharmacy, School of (23). Many new types of chlorin-based sensitizers have been exten-
Chemical Engineering, Dalian University of Technology, Dalian 116024, China.
2 sively exploited because of their structural flexibility for straight-
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian
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University of Technology, Dalian 116024, China. Nuclear Medicine, First Affiliated forward chemical modification. For example, talaporfin sodium
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Hospital of Dalian Medical University, Dalian 116021, China. EEC Biotech Co. Ltd, [mono-l-aspartyl Ce6 (NPe6)] has been approved in Japan in 2003
Guangzhou 510070, China. as a commercial photosensitizer for the treatment of early-stage lung
*Corresponding author. Email: [email protected] (G.L.); [email protected]
(K.S.); [email protected] (W.Z.) cancers (24). Previously, in our laboratory, a chlorophyll derivative
Wang et al., Sci. Adv. 2021; 7 : eabj4796 20 October 2021 1 of 15