Phase‐shifted pentafluorobutane nanoparticles for ultrasound imaging and ultrasound‐mediated hypoxia modulation

Abstract

The integration of ultrasound (US) contrast enhancement with oxygen‐loading nanoagents provide the synergistic strategy for simultaneously US imaging and hypoxic microenvironment modulation. Herein, we synthesize pentafluorobutane (PFB)‐loading methoxy poly(ethylene glycol)‐b‐poly(l‐lactide) (PLLA) nanoparticle as the novel US‐contrast‐enhanced agent and demonstrate that PFB@PLLA effectively loads oxygen. We characterize the nanosize, phase‐transformation property and oxygen‐loading amount of PFB@PLLA and investigate the effectiveness of these nanoagents in US‐contrast‐enhanced imaging. The PFB@PLLA displays a perfect temperature‐responsive phase‐transition property and its liquid‐to‐gas phase transition temperature is 45°C, which produces microbubbles in the targeted regions. Moreover, PFB@PLLA loads high amount of oxygen and US‐triggering PFB@PLLA reoxygenation effectively inhibits the expression of hypoxia‐related proteins (HIF‐1α and CAIX), reduces lactate secretion and glycolysis, which modulates hypoxic microenvironment and inhibits cancer cell migration and invasion in vitro. This study demonstrates that the US contrast‐enhanced activity of PFB@PLLAs and the promising utility of oxygen‐loading nanoagents to improve hypoxic microenvironment.

Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

“…[41] For example, Chen et al successfully constructed an "oxygen-carrying" nanoplatform (PFB@PLLA) capable of releasing O 2 in response to ultrasound stimulus by encapsulating methoxy poly(ethylene glycol)-b-poly(l-lactide) (mPEG-PLLA) shell onto liquid pentafluorobutane (PFB) core (Figure 4A). [42] Experiments demonstrated that PFB@PLLA released a large amount of oxygen at the tumor site with ultrasound stimulus, effectively downregulating hypoxia-related proteins (HIF-1 and carbonic anhydrase IX (CAIX)) and glycolysis-related proteins (HK2 and GLUT1), and thereby reducing lactate production (Figure 4B,C). "Oxygen-generating" nanomaterials are a class of materials that can induce oxygen-production reactions in the TME (with overexpressed H + and H 2 O 2 ), mainly including selfdecomposition oxygen-production (CaO 2 , [43] Au 2 O 3 , [44] etc.)…”

“…Reproduced with permission. [42] Copyright 2019, Wiley-VCH. D) Schematic design of the PLANT nanosystem fabricated by vegetable thylakoid and various nanoparticles.…”

“…C) Lactate production of HepG2, MDA-MB-231 after different treatments. Reproduced with permission [42]. Copyright 2019, Wiley-VCH.…”

Modulating hypoxia inducible factor‐1 by nanomaterials for effective cancer therapy

“…The synthesis of perfluorocarbon (PFC) NPs and ultrasonic stimulation of oxygen transport provide a new strategy to solve these problems. Based on this, Chen et al (2019) designed PFC‐loaded NPs as ultrasound contrast agents for oxygen‐carrying regulation of anoxic tumors. The synthesized phase‐deformable nano‐agent (PFC@PLLA) was composed of liquid PFC core and methoxy poly(ethylene glycol)‐b‐poly( l ‐lactide) shell, which effectively released oxygen under the stimulation of ultrasound, thus inhibiting the accumulation of HIF‐1 along with its downstream cytokines including VEGF and glucose metabolic factors (HK2 and GLUT1), indicating an effective approach to alleviate the anoxic microenvironment of cancer cells and affect glycolysis as well.…”

“…The synthesized phase‐deformable nano‐agent (PFC@PLLA) was composed of liquid PFC core and methoxy poly(ethylene glycol)‐b‐poly( l ‐lactide) shell, which effectively released oxygen under the stimulation of ultrasound, thus inhibiting the accumulation of HIF‐1 along with its downstream cytokines including VEGF and glucose metabolic factors (HK2 and GLUT1), indicating an effective approach to alleviate the anoxic microenvironment of cancer cells and affect glycolysis as well. Therefore, the combination of bifunctional PFC@PLLA nano‐agents with ultrasonic imaging has a synergistic effect in improving ultrasonic efficiency and oxygen‐carrying capacity (Chen et al, 2019).…”