Design and Challenges of Sonodynamic Therapy System for Cancer Theranostics: From Equipment to Sensitizers

Abstract

As a novel noninvasive therapeutic modality combining low-intensity ultrasound and sonosensitizers, sonodynamic therapy (SDT) is promising for clinical translation due to its high tissue-penetrating capability to treat deeper lesions intractable by photodynamic therapy (PDT), which suffers from the major limitation of low tissue penetration depth of light. The effectiveness and feasibility of SDT are regarded to rely on not only the development of stable and flexible SDT apparatus, but also the screening of sonosensitizers with good specificity and safety. To give an outlook of the development of SDT equipment, the key technologies are discussed according to five aspects including ultrasonic dose settings, sonosensitizer screening, tumor positioning, temperature monitoring, and reactive oxygen species (ROS) detection. In addition, some state-of-the-art SDT multifunctional equipment integrating diagnosis and treatment for accurate SDT are introduced. Further, an overview of the development of sonosensitizers is provided from small molecular sensitizers to nano/microenhanced sensitizers. Several types of nanomaterial-augmented SDT are in discussion, including porphyrin-based nanomaterials, porphyrin-like nanomaterials, inorganic nanomaterials, and organic-inorganic hybrid nanomaterials with different strategies to improve SDT therapeutic efficacy. There is no doubt that the rapid development and clinical translation of sonodynamic therapy will be promoted by advanced equipment, smart nanomaterial-based sonosensitizer, and multidisciplinary collaboration.

Keywords: cancer theranostics; sonodynamic therapy; sonosensitizer.

Figure 1

A) The schematic illustration of PET–CT–UUI trimodal imaging modality. B) Comparison of PET‐CT mode and UUI mode at the tumor site. C) Representative images of PET–CT–UUI imaging. D) Fused images of FDG uptake and perfused vessels in tumor growth. E) Representative images of metabolic activity in different timepoints. Reproduced with permission.^{[ 171 ]} Copyright 2018, Springer Nature.

Figure 2

A) Chemical structure of DVDMS. B) Cellular uptake of DVDMS and other traditional sensitizers in S180 and NIH3T3 cells. C) Tumor gross morphology after 15 days of treatment. D) The VEGF expression level in tumor cells after 15 days of treatment. Reproduced with permission.^{[ 203 ]} Copyright 2015, Springer.

Figure 3

A) Schematic diagram of multifunctional sonotheranostics based on R‐S‐NTP. B) Transmission electron microscope (TEM) image of R‐S‐NTP. C) The SDT protocol in HeLa tumor‐bearing mice. D,E) Antitumor effects of SDT in several groups. Reproduced with permission.^{[ 231 ]} Copyright 2019, Wiley‐VCH. F) Schematic diagram of the synthesis of Tf‐P NPs. G) Schematic diagram of ROS‐mediate SDT therapeutics. H) Fluorescence images of Tf‐P NPs biodistribution in vivo (left) and major organs/ tumor ex vivo. I) Fluorescence images of tumor slice. Reproduced with permission.^{[ 232 ]} Copyright 2019, Wiley‐VCH.

Figure 4

A) Schematic diagram of synthesis and enhanced SDT principle of IR780@O₂‐FHMONs. B) Time‐sweep O₂ concentration curves of IR780@O₂‐FHMONs and other treatment groups in hypoxic PANC‐1 cells. C) LCSM images show the in vivo evaluation of IR780@O₂‐FHMONs on hypoxia reversion. Reproduced with permission.^{[ 233 ]} Copyright 2017, American Chemical Society. D) Schematic diagram of Au@BP nanohybrids preparation and SDT treatment. E) Left: Tumor growth curve of Au@BP nanohybrids and other groups during 15 days treatment. Right: the antitumor effects of Au@BP. Reproduced with permission.^{[ 234 ]} Copyright 2018, The Royal Society of Chemistry.

Figure 5

A) Schematic diagram of synthesizing PMCS. B) Representative TEM images of PMCS. Scale bar = 200 nm. C) Schematic illustration of PMCS synthesis process. D) Schematic illustration of SDT protocol in vivo. E) Treatment efficacy of PMCS. F) Biosafety evaluation of PMCS‐based SDT. Reproduced with permission.^{[ 238 ]} Copyright 2019, Wiley‐VCH.

Figure 6

A) Surface modification of TiO₂ NPs with carboxymethyl dextran (CMD). B) HTiO₂ NP‐based SDT. C) Left: Quantification of ¹O₂ generation under the HTiO₂ NP‐based SDT. Right: Representative ex vivo fluorescence images of ¹O₂ (green signal) observation induced by HTiO₂ NP (red signal) ‐based SDT in the tumor tissue. D) Representative 3D‐rendered images of tumor volume after SDT. E) Representative images of the treated liver (Scale bar, 1 cm). F) Left: tumor volume variation after treatment. Right: representative images of major organs after SDT. Reproduced with permission.^{[ 245 ]} Copyright 2016, Springer Nature.

Figure 7

A) Schematic diagram of PMR‐based SDT modality. Reproduced with permission.^{[ 256 ]} Copyright 2018, American Chemical Society. B,C) Schematic diagram of MnWO_x‐PEG‐based SDT. D) Representative image of ROS generation (left) and quantification (right) of MnWO_x‐PEG. E) Left: the mass variation of W in mice body during the treatment period. Right: schematic illustration of MnWO_x body clearance. Reproduced with permission.^{[ 257 ]} Copyright 2019, Wiley‐VCH.

Figure 8

A) Schematic diagram of gas‐enhanced SDT therapy based on TPZ/HMTNPs‐SNO. B) Representative US images of TPZ/HMTNPs‐SNO. Reproduced with permission.^{[ 258 ]} Copyright 2019, Elsevier. C) Schematic diagram of HMME/MCC–HA NPs. D) Representative US images of HMME/MCC–HA in vivo. Reproduced with permission.^{[ 259 ]} Copyright 2018, Wiley‐VCH. E) Schematic illustration of Lip–AIPH liposome. F) Representative US images of tumor sites obtained post‐injection with Lip–AIPH and other groups. Reproduced with permission.^{[ 260 ]} Copyright 2019, The Royal Society of Chemistry.

Figure 9

A) Schematic illustration of sonoactivatable Dox‐pp‐lipo for antitumor treatment. B) TEM image of two liposomes (Scale bar, 100 nm). C) Schematic illustration of enhanced intratumoral drug delivery and deep penetration with Dox‐pp‐Lipo under US irradiation. D) Representative image of the biodistribution of Dox‐pp‐lipo during the SDT treatment. E) Accumulation of Dox‐pp‐lipo in tumor site (left side) and radiant efficiency of Dox‐pp‐lipo (right side) under different US intensity irradiation. Reproduced with permission.^{[ 262 ]} Copyright 2018, Elsevier.

Figure 10

A) Schematic diagram of chemo‐sonodynamic therapy based on DTX/X NPs. B) Schematic diagram of the immune cycle induced by DTX/X NPs. Reproduced with permission.^{[ 263 ]} Copyright 2018, Elsevier. C) Schematic diagram of chemo‐sonodynamic therapy based on PEI‐FA‐DSTNs. Reproduced with permission.^{[ 264 ]} Copyright 2019, American Chemical Society.

Figure 11

A) Schematic diagram of CCM‐HMTNPs/HCQ formulation and synergist chemo‐SDT therapy on breast cancer. Reproduced with permission.^{[ 265 ]} Copyright 2019, American Chemical Society. B) Schematic diagram of Lipo‐Ce6/TPZ@M_H preparation and synergistic chemo‐SDT therapy of cancer. Reproduced with permission.^{[ 266 ]} Copyright 2019, Wiley‐VCH.

Figure 12

A) Schematic diagram of PCF‐MB synthesis. B) Schematic diagram of trimodal cancer therapeutics based on triad PCF‐MB. C) US images of PCF‐MB in vivo at pre‐ or post‐injection timepoint. D) Left: in vivo fluorescence images of PCF‐MB after injection at different timepoints. Right: representative images of major organs after PCF‐MB injection for 24 h. E) The trimodal treatment effects in vivo. Reproduced with permission.^{[ 95 ]} Copyright 2018, American Chemical Society.

Figure 13

A) Schematic illustration of CDT‐enhanced SDT based on PtCu₃‐PEG. B) Representative TEM images of PtCu₃‐PEG nanocages. C) The effects of PtCu₃‐PEG in vitro. D) Multimodal images of PtCu₃‐PEG nanocages accumulation in the tumor site. E) The effects of CDT‐SDT synergistic treatment in vivo. Reproduced with permission.^{[ 28 ]} Copyright 2019, Wiley‐VCH.