Theranostic Nanoplatform with Sequential SDT and ADV Effects in Response to Well-Programmed LIFU Irradiation for Cervical Cancer

Abstract

Background: Some patients with cervical cancer have the need to preserve fertility; therefore, a minimally invasive treatment option that can effectively inactivate tumors in these patients is necessary. Methods: In this paper, we designed and prepared nanoparticles (NPs) carrying IR780 and perfluorohexane (PFH) and characterized their properties. We focused on the promotion of programmed low-intensity focused ultrasound (LIFU) irradiation on the penetration and treatment of cervical cancer. First we used penetration-enhancing LIFU irradiation to promote the penetration of the NPs into 3D multicellular tumor spheroids (MCTSs) and tumors in tumor-bearing nude mice. Then we used re-therapeutic LIFU irradiation to achieve antitumor effects in vitro and in vivo. Photoacoustic (PA) and magnetic resonance (MR) imaging were used to monitor and evaluate the targeting and therapeutic effects of these NPs on tumor tissues. Results:The NPs prepared in this paper exhibited high affinity for HeLa cells, and can selectively achieve mitochondrial localization in the cell due to IR780 assistance. The penetration-enhancing LIFU irradiation have the ability to promote the penetration of the NPs into cervical cancer models in vivo and in vitro. Under LIFU irradiation, the cytotoxic reactive oxygen species (ROS) produced by IR780 during the first half of the re-therapeutic LIFU irradiation and the physical acoustic droplet vaporization (ADV) effect after PFH phase transition during the second half of the re-therapeutic LIFU irradiation can achieve synergistic minimally invasive treatment of tumors, which can be visualized and evaluated by PA and MR imaging in vivo. Conclusion:Well-programmed LIFU irradiation can promote NP penetration into deep tumor tissue and achieve antitumor effects simultaneously. Linking ROS + ADV effects can induce cell coagulation necrosis and lead to a comprehensive, long-term impact on tumor tissue, providing a conceptual theranostic nanoplatform for cervical cancer.

Tumor Spheroids as Model to Design Acoustically Mediated Drug Therapies: A Review

“…In addition, the efficacy of SDT is often evaluated in association with chemotherapy, PDT, or targeted therapies [ 32 , 80 , 81 , 82 , 83 ]. As previously described for acoustically mediated drug delivery, the efficacy and safety of SDT strongly depend on (i) the pharmacological properties of sensitizers [ 83 , 84 , 85 ], (ii) the physiology of tumor tissue [ 83 ], (iii) US devices and parameters [ 80 ], and (iv) SDT treatment schemes on their own or combined with other anticancer therapies, including chemotherapy, radiotherapy, PDT, and therapeutic ultrasound [ 80 , 81 , 86 , 87 , 88 , 89 ]. In the next section, we will present and discuss the studies that exploited spheroids and MCTSs for the design of SDT protocols ( Table 3 ).…”

“…As previously reported, the in-homogeneous tumor vasculature and the increased interstitial pressure restricted the penetration and accumulation of NPs inside the tumor core [ 4 , 90 , 91 ]. Zhou et al [ 86 ] investigated the efficacy of low-intensity focused ultrasound (LIFU) to enhance the intratumoral diffusion of NPs inside cervical cancer (HeLa) spheroids after one week of culture in spheroid microplates. In this study, the authors developed theranostic nanoparticles (NPs) loaded with a sonosensitizer, IR780, a magnetic resonance imaging contrast agent, gadolinium diethylenetriaminepentacetate, and a phase transition material, perfluorohexane, for the treatment of cervical cancer using SDT and acoustic droplet vaporization.…”

“…In addition, some examples, where the authors confirmed their data obtained on spheroids or MCTSs, in subcutaneous or orthotopic tumor xenograft models, revealed that the lack of vessels in spheroids and MCTSs is still a major drawback for the full design and validation of acoustically mediated drug therapies [ 31 , 71 , 81 , 85 , 86 ]. Indeed, the spheroids were incubated directly with the free drugs or drug-loaded sonosensitive particles (e.g., MBs and liposomes), whereas these latter were administered intravenously in vivo.…”

ROS-Triggered Self-Assembled Nanoparticles Based on a Chemo-Sonodynamic Combinational Therapy Strategy for the Noninvasive Elimination of Hypoxic Tumors

“…Ultrasound (US) irradiation activates the sonosensitizer accumulated at the tumor site and excites large amounts of reactive oxygen species (ROS) to kill tumor cells . SDT mainly produces high-energy singlet oxygen ( 1 O 2 ) and hydroxyl radicals ( • OH), which cause apoptosis of tumor cells. , Additionally, US radiation rapidly raises the mechanical pressure of the tissue fluid, and the development of numerous cavitated microbubble triggers mechanical dynamic processes that lead to ROS generation, cell membrane rupture, and increased permeability. , SDT has been successively incorporated into clinical treatment protocols for a variety of tumors, including pancreatic, hepatocellular, and urologic cancers. − And nanoparticles containing IR780 and perfluoro-hexane have been used in SDT for CCa based on the idea of pretreatment penetration . SDT generates ROS that break the intracellular redox balance and is a reliable option for effective noninvasive treatment of hypoxic cervical tumors …”

Intensity-adjustable pain management with prolonged duration based on phase-transitional nanoparticles-assisted ultrasound imaging-guided nerve blockade

“…Ultrasound irradiation may trigger the phase-transition process and transform liquid-phase perfluoropentane (PFP) into a gas phase for ultrasound imaging [33,34]. More importantly, the phase-transitional ultrasonic contrast agent could change the acoustic environment and facilitate drug delivery based on the inert cavitation effect [34,35]. Even so, pain management is still limited by the insufficient retention time of the nanoparticles in vivo.…”