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WIREs Nanomed Nanobiotechnol
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Enhancing cancer therapeutic efficacy through ultrasound‐mediated micro‐to‐nano conversion

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Abstract Over the last century, significant progress has been made towards the development of microbubbles (MBs) as a contrast agent for imaging and as a carrier for the delivery of therapeutic moieties. The unparalleled ability of MBs to respond to ultrasound (US) render them advantageous for molecular imaging, and US‐responsive targeted delivery. However, the use of MBs has broadened far beyond the imaging contrast agent or drug delivery system alone. Notably, there has been an enormous surge in the design and fabrication of multimodal MBs for cancer therapy. Furthermore, MBs in the presence of the US has unique ability to convert itself from the micro to nanoscale, which offers diagnostic and therapeutic ability in both dimensions. In this review, we summarize the design considerations of MBs, with particular emphasize on their size and composition. In addition, different MBs formulations are discussed in the context of their current progress as an imaging contrast agent and a vehicle for drug/gene delivery. We further highlight recent advancements in the micro‐to‐nano conversion of MBs and their potential application for cancer theranostics. This article is characterized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies
In vivo CEUS and fluorescence imaging in a subcutaneous PC‐3 tumor model. (a) In vivo CEUS in a subcutaneous PC‐3 tumor model. CEUS imaging of the tumorsite before (pre) and after i.v. of PGL‐MBs. (b) Fluorescence imaging in vivo at different time points after i.v. of PGL‐MBs, with or without LFUS (400 kPa, 3 min) exposure. Tumors are circled with yellow dashed lines. (c) Images of organs excised at 24 h after injection. Organs of tumor‐bearing mice without PGL‐MBs injection were excised as negative controls. (d) Quantitative analysis of fluorescence intensity for the excised organs (n =3). (Youet al., 2018)
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Plot of % cellular metabolic activity for (a) BxPC3 (b) T110299 (c) MIA PaCa‐2 and (d) Panc‐01 cells following treatment with (i) untreated, (ii) ultrasound only, (iii) O2MB‐RBonly, (iv) O2MB‐RB plus ultrasound, (v) O2MB‐Gem only, (vii) combined O2MB‐Gem andO2MB‐RB, (viii) combined O2MB‐RB and O2MB‐Gem plus ultrasound. *p  < 0.05,**p < 0.01, ***p < 0.001. Error bars represent ± the standard error, n = 6 (Nesbitt et al., 2018)
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TEM images of 50 wt % SiPCL microcapsules with (a) no treatment, (b) enzymatic degradation, and (c) hydrolytic (PBS) degradation (Tsao & Hall, 2016)
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In vivo ultrasound images of the mouse kidney after intravenous injection of PBS and SonoVue microbubble and PM solutions (frequency = 8 MHz, and MI = 0.2). Ultrasound images of the mouse kidney after intravenous injection of PBS (a);ultrasound images of the mouse kidney after intravenous injection of the SonoVue microbubbles at different time intervals of 10 s (b) and 2 min (c); and ultrasound images of the mouse kidney after intravenous injection of the PMs at different time intervals of 1 (d), 4 (e), and 8 min (f). The red circlesindicate the kidney regions of the mouse. (Song et al., 2018)
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Schematic of the lipid‐shelled microbubble used in this study. Three different lipid acyl chain lengths (C16, C18, C24) were used to generate microbubbles of different physicochemical properties, while the emulsifier (DSPE‐PEG2000), the molar ratio between the main lipid and the emulsifier (9:1), the gas core (PFB), and the size of the microbubbles (4–5 μm) were keptthe same in order to focus on the effects of lipid hydrophobic chain length. (Wu, Chen, Tung, Olumolade, & Konofagou, 2015)
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Contrast enhancement in the kidney following bolus injections of size‐selected microbubbles. Microbubble suspensions of 100 μL containing 5×107 MB of (A) polydisperse, (B) 1‐2 μm, (C) 4‐5 μm, or (D) 6‐8 μm diameter bubbles were injected intravenously into anesthetized mice while continuously imaging the kidney using a 40‐MHz ultrasound probe. Gray scale images are shown before the bolus is injected (A1‐D1) and at the peak signal intensity (A2‐D2),typically 30‐60 seconds after the bolus was delivered. Contrast detection software was used to highlight the presence of microbubbles in green (A3‐D3). Areas outlined in white are ROIs selected for TIC analysis. (Sirsi, Feshitan, Kwan, Homma, & Borden, 2010)
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(a) Baseline and CEUS of DiR MBs showing linear and nonlinear signals in vitro. (b) CEUS imaging of DiR MBs which was injected into MCF‐7 tumor‐bearing nude mice intravenously to observe the perfusion of the DiRMBs in the tumor. (c) Time−intensity curve (TIC) of CEUS imaging of DiR MBs demonstrating the dynamic perfusion in the MCF‐7 tumor and duration in circulation were more than 5 min. (d) At 18 s injection, the tumor tissue was exposed to the ultrasound with a transient higher acoustic pressure emission to disrupt the DiR MBs. (Lin et al., 2019)
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(a) Schematic illustration of self‐assembly of PCF‐MBs with porphyrin grafted lipid (PGL) and camptothecin‐floxuridine conjugate (CF), which can be converted into PCF‐NPs by ultrasound targeted mb destruction;(b) intracellular distribution of PCFNPs PGL (red for blue for CF, green for AO) (scale bar: 10 μm); (c) celluptake (CPT, blue; PGL, red) and singlet oxygen generation (green) afterdifferent treatments (① control, ② PCF‐MBs, ③ PCF‐MBs+light, ④ PCF‐MBs+US, ⑤ PCF‐MBs+US+light, ⑥ PGL‐MBs+US+light)(scale bar: 20 μm); (d) Tumor growth profiles in nude mice treated withPBS, PCF‐MBs, PCF‐MBs+Light, PGL‐MBs+US+Light, CF‐MBs+US, and PCF‐MBs+US+Lighton days 0 and 3 (see arrows). Each PCF‐MBs injection dose was 13.5 mg/kg and PGL‐MBs injection dose was 10 mg/kg; (e) Body weight change after different treatments. Results are presented as mean ± SD (n = 6; ***p <0.001; Chen et al., 2018)
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(a) Schematic illustration of the siRNA loaded Porphyrin microbubble, ultrasound‐assisted PDT and FOXA1 KD strategy; (b) CLSM images of CpMBs/siRNA‐FAM; (c) fluorescence examination of the intracellular distribution of CpMBs/siRNA‐FAM with or without ultrasound sonication; (d) Tumour volume change curves with time after different treatments (Groups: PBS; CpMBs/F; CpMBs/F.US; CpMBs/F.L; CpMBs/NC.US.L; CpMBs/F.US.L) (n.6) (*p < 0.05 versus CpMBs/F.US.L); (e) Representative photographs showing therapeutic effect of the mice after various treatments (Groups: PBS; CpMBs/NC.US.L; CpMBs/F.US.L); (f)H&E staining of tumour slices excised at 72 h after different treatments. (Zhao et al., 2018)
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Schematic illustration of PGL‐DiR MBs: (a) the structure and conversion of thePGL‐DiR MBs into nanoparticles when exposed to sufficient ultrasound; (b) Cell viabilities of 4T1 cells treated by PGL NPs+US, DiR NPs+US, PGL‐DiRNPs+US, PGLDiR MBs, and PGL‐DiR MBs+US. All of the above groups were irradiated by 760 nm laser (1 W cm−2, 10 min) and 650 nm laser (200 mW cm−2, 3 min). in vivo ultrasound imaging and fluorescence imaging of 4T1 tumor‐bearing mice. (c) PGL‐DiR MBs were intravenously administrated into the 4T1 tumor‐bearing mice and the tumor was imaged with a clinical ultrasound probe (3–12 MHz). At 38 s,the tumor site was irradiated by the low‐frequency ultrasound with a higher mechanical index to destroy the MBs. (d) Time‐lapse NIR fluorescence imaging of mice intravenously administrated with PGL‐DiR NPs, and PGL‐DiR MBs combined with ultrasound exposure. The dashed circles indicate subcutaneous tumorregions. (e,f) The fluorescence images and quantitation of the fluorescence intensity of tumors and main organs after 24 h injection. The data were presented as the mean Å} SD (n = 3), *p < 0.05, **p < 0.01. (Xuet al., 2017)
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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