Treatment Of Deep-seated Tumors Research Articles

Tumor microenvironment-modulated nanoparticles with cascade energy transfer as internal light sources for photodynamic therapy of deep-seated tumors

Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.

In situ hydrogel based on Cu–Fe3O4 nanoclusters exploits oxidative stress and the ferroptosis/cuproptosis pathway for chemodynamic therapy

Chemodynamic therapy (CDT) involving the use of metal nanozymes presents new opportunities for the treatment of deep-seated tumors. However, the lower ROS catalytic rate and dependence on high H2O2 concentrations affect therapeutic efficacy. To address this issue, a hydrogel was constructed for the treatment of osteosarcoma by combining Cu–Fe3O4 nanozymes (NCs) and artemisinin (AS) coencapsulated in situ with sodium alginate (ALG) and calcium ions. This hydrogel can release nanoparticles and AS within tumor tissue for an extended period of time, utilizing the multienzyme activity of NCs to achieve ROS accumulation. The carbon radicals (•C) generated from the interaction of Fe2+/Cu2+ with AS amplify oxidative stress, leading to tumor cell damage. Simultaneously, the NCs activate ferroptosis via the GPX4 pathway by depleting GSH and activate cuproptosis via the DLAT pathway by causing intracellular copper overload, enhancing therapeutic efficacy. In vitro experiments confirmed that the NCs-AS-ALG hydrogel has an excellent tumor cell killing effect, while in vivo experimental results demonstrated that it can effectively eliminate tumors with excellent biocompatibility, providing a new approach for osteosarcoma treatment.

Cascade Nanoreactor Employs Mitochondrial-Directed Chemodynamic and δ-ALA-Mediated Photodynamic Synergy for Deep-Seated Oral Cancer Therapy.

The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggers δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT/CDT-induced apoptosis generates δ-ALA-containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment.

Enriched photosensitizer for deep-seated-tumor photodynamic therapy

Photodynamic therapy (PDT) is an innovative approach that utilizes photochemical reactions for non-invasive disease treatment. Conventional PDT is limited by the low penetration depth of visible light required for activation. Herein, we employed upconversion nanoparticles (UCNPs) to extend the activation wavelength of photosensitizers into the infrared range, enabling a treatment depth of over 10 mm. Furthermore, we also used the abundant amino groups of branched polyethyleneimine (PEI) with spatial structure to enhance the loading capacity of protoporphyrin (PPIX), and we ultimately improved skin tumor clearance rates. Moreover, we achieved tumor-specific treatment by utilizing folic acid (FA) targeting and active enrichment of PPIX. According to cellular experimental results, we demonstrated the remarkable reactive oxygen species generation capability of the material and ultra-low dark toxicity. Additionally, we investigated the apoptosis mechanism and demonstrated that the synthesized nanoparticle stimulates the up-regulation of apoptosis-associated proteins Bax/Bcl-2 and Cyto c. During in vivo experiments involving intravenous injection in mouse tails, we investigated the anticancer efficacy of the nanoparticle, confirming its excellent PDT effects. This research provides a promising avenue for future non-invasive treatment of deep-seated tumors, offering a method for the treatment and management of specific cancers.

Radiation protection aspects in the design of a Boron Neutron Capture Therapy irradiation room

Boron Neutron Capture Therapy (BNCT) is a radiotherapy whose effect is due to the combination of low-energy neutron irradiation prior chemical targeting of tumour tissues with boron-10. The context of this work is the design of a clinical BNCT facility based on a Radio-Frequency Quadrupole proton accelerator, manufactured by the Italian National Institute of Nuclear Physics (INFN). Such a machine can provide a neutron beam suitable for the treatment of deep-seated tumours when coupled to a beryllium target and a Beam Shaping Assembly whose main constituent is densified lithiated aluminium fluoride. This paper refines the design of the facility, already addressed in preliminary studies, from the point of view of dosimetric quantities in the room and in the patient. The presented calculations have been performed with different Monte Carlo codes, and assess the time evolution of the dose due to the neutron activation of the irradiated materials. A comprehensive evaluation of the dose absorbed in the healthy organs of the patient is provided, with focus on the residual radioactivity of the patient urine, for three different treatment positions. Borated concrete is confirmed to be the best material for constructing the walls of the treatment room. A lead shielding at the beam-port is proposed to reduce the gamma dose at the irradiation position due to the activation of the Beam Shaping Assembly.

Magnetostrictive-piezocatalytic CoFe2O4@UiO-66 nanohybrid and its potential for deep-seated tumor treatment.

Magnetostrictive CoFe2O4 (CFO) nanoparticles were encapsulated within a UiO-66 metal-organic-framework layer to form a CFO@UiO-66 nanohybrid. The deforming of CFO, in response to a high-frequency AC magnetic field, initiates the piezocatalytic property of UiO-66 to generate ˙OH radicals, which can kill cancer cells buried in thick tissues, showcasing bright potential for deep-seated tumor treatment.

Enhancing Deep-Seated Melanoma Therapy through Wearable Self-Powered Microneedle Patch.

Effective treatment of deep-seated tumors relies on enhanced drug penetration in transdermal drug delivery systems. While microneedles (MNs) and iontophoresis techniques have shown improved transdermal drug delivery efficiency, challenges such as skin elasticity, high electrical resistance of the stratum corneum, and external power supply requirements hinder their efficacy in treating deep-seated tumors. In this study, a wearable, self-powered MN patch that integrates a flexible triboelectric nanogenerator (F-TENG) is presented, aimed at advancing deep-seated tumor therapy. MNs are composed of water-soluble materials mixed with negatively charged pH-responsive nanoparticles (NPs) loaded with therapeutic drugs. The F-TENG harnesses personal mechanical movements generate electrical energy. Leveraging the advantages of both MNs and F-TENG, therapeutic NPs can penetrate deep skin locations upon MN patch insertion, releasing drugs rapidly in acidic tumor tissues. Owing to these features, a single administration of the integrated MN-patch in a mouse model with deep-seated melanoma exhibits superior therapeutic efficacy in inhibiting deep-located tumor compared to using the MN-patch alone, indicating promising potential for treating tumors at deep sites.

New Advantage in Stereotactic Treatment of Lung and Pancreatic Cancer. Performance of Ultra-High Energy Electron (VHEE) Therapy Adjuvanted to the FLASH Effect: Clinical Implications and Treatment Plans Analysis

Very High-Energy Electron (VHEE) beams delivered at ultra-high dose rates and hence profiting from the FLASH effect, may be a viable alternative to conventional treatment plans for the treatment of deep-seated tumors. Experimental data support the evidence of a considerable normal tissue sparing effect when treatments are delivered with dose rates much larger (100 times or more) compared to the conventional ones. Lung cancer and pancreatic cancer are considered the two biggest cancer killers. We urgently need more research in these areas, more awareness that support improvement in treatment strategies. To evaluate the potential of FLASH VHEE irradiation in these two clinical situations, we investigated the achievable sparing of healthy tissues and critical dose-limiting structures, with the goal of performing a higher dose prescription. The study on the potential of VHEE for the stereotactic treatment of pancreatic and lung lesions was carried out on two clinical cases treated with Volumetric Modulated Arc Therapy (VMAT) techniques at University Hospital Campus Bio-Medico of Rome. The Planning Target Volume (PTV) was identified and the constraints on the Organs at Risk (OAR) and details on the irradiation approach were defined. The VHEE plan was designed to optimize the dose delivery to best activate the modelled FLASH effect based on the current experimental knowledge. In particular the impact on a dose threshold to activate the effect was studied. The VHEE treatment plan was based on an accurate Monte Carlo simulation of the electrons interactions and the results achievable with different FLASH effect models were studied. The simulation allowed the estimation of dose maps, which were used as input to an optimization algorithm that modified the fluence of each beam to meet treatment prescriptions in terms of dose to PTV. At the end the VHEE DVH plans were compared to VMAT plans. The results demonstrated that FLASH therapy with VHEE beams of 70-130 MeV, could represent a promising alternative to standard radiotherapy allowing a comparable sparing of the healthy tissues. In the case of pancreatic cancer, the Dose Volume Histograms (DVH) showed how such a technique can be effective in sparing the duodenum. In case of lung cancers, the result showed how pulmonary tissue sparing can lead to a substantial reduction of pulmonary toxicity in comparison with the VMAT technique. In the case of pancreatic cancer and assuming a non-negligible contribution from the FLASH effect, the DVH showed how the duodenum healthy tissue sparing could allow a higher dose to be prescribed at the target while keeping the constraints respected, improving the therapeutic ratio. In the case of lung cancer, the advantages of the technique are additionally increased by the significant benefit that could be related to the treatment delivery time reduction (<1s) and to the corresponding advantage coming from a reduced organ movement that translates in a lower risk of lung toxicity.

Bioreducible exosomes encapsulating glycolysis inhibitors potentiate mitochondria-targeted sonodynamic cancer therapy via cancer-targeted drug release and cellular energy depletion

Nanocarrier-assisted sonodynamic therapy (SDT) has shown great potential for the effective and targeted treatment of deep-seated tumors by overcoming the critical limitations of sonosensitizers. However, in vivo SDT using nanocarriers is still constrained by their intrinsic toxicity and nonspecific cargo release. In this study, we developed bioreducible exosomes for the safe and tumor-specific delivery of mitochondria-targeting sonosensitizers [triphenylphosphonium-conjugated chlorin e6 (T-Ce6)] and glycolysis inhibitors (FX11). Redox-cleavable diselenide linker-bearing lipids were embedded into exosomes to trigger drug release in response to overexpressed glutathione in the tumor microenvironment. Bioreducible exosomes facilitate the cytoplasmic release of their payload in the reducing environment of tumor cells. They significantly enhance drug release and sonodynamic effects when irradiated with ultrasound (US). The mitochondria-targeted accumulation of T-Ce6 efficiently damaged the mitochondria of the cells under US irradiation, accelerating apoptotic cell death. FX11 substantially inhibited cellular energy metabolism, potentiating the antitumor efficacy of mitochondria-targeted SDT. Bioreducible exosomes effectively suppressed tumor growth in mice without significant systemic toxicity, via a combination of mitochondria-targeted SDT and energy metabolism-targeted therapy. This study offers new insights into the use of dual stimuli-responsive exosomes encapsulating sonosensitizers for safe and targeted sonodynamic cancer therapy.

Treatment planning of intracranial lesions with VHEE: comparing conventional and FLASH irradiation potential with state-of-the-art photon and proton radiotherapy

The treatment of deep-seated tumours with electrons of very high energies (VHEE, 70–150 MeV) has already been explored in the past, suggesting that a dosimetric coverage comparable with state-of-the-art proton (PT) or photon radiotherapy (RT) could be achieved with a large (&gt; 10) number of fields and high electron energy. The technical and economical challenges posed by the deployment of such beams in treatment centres, together with the expected small therapeutic gain, prevented the development of such technique. This scenario could radically change in the light of recent developments that occurred in the compact, high-gradient, electron acceleration technology and, additionally, of the experimental evidence of the sparing of organs at risk achieved in ultra-high dose rate irradiation, also referred to as FLASH. Electrons with the energy required to treat intracranial lesions could be provided, at dose rates compatible with what is needed to trigger the FLASH effect, by accelerators that are a few metres long, and the organ sparing could be exploited to significantly simplify the irradiation geometry, decreasing the number of fields needed to treat a patient. In this paper, the case of two patients affected by a chordoma and a meningioma, respectively, treated with protons in Trento (IT) is presented. The proton plans have been compared with VHEE plans and X-ray intensity-modulated radiotherapy (IMRT) plans. The VHEE plans were first evaluated in terms of physical dose distribution and then assuming that the FLASH regimen can be achieved. VHEE beams demonstrated their potential in obtaining plans that have comparable tumour coverage and organs at risk sparing when benchmarked against current state-of-the-art IMRT and PT. These results were obtained with a number of explored fields that was in the range between 3 and 7, consistent with what is routinely performed in IMRT and PT conventional irradiations. The FLASH regimen, in all cases, showed its potential in reducing damage to the organs placed nearby the target volume, allowing, particularly in the chordoma case where the irradiation geometry is more challenging, a better tumour coverage with respect to the conventional treatments.

Harnessing Nanomaterials for Cancer Sonodynamic Immunotherapy.

Immunotherapy has made remarkable strides in cancer therapy over the past decade. However, such emerging therapy still suffers from the low response rates and immune-related adverse events. Various strategies have been developed to overcome these serious challenges. Therein, sonodynamic therapy (SDT), as a non-invasive treatment, has received ever-increasing attention especially in the treatment of deep-seated tumors. Significantly, SDT can effectively induce immunogenic cell death to trigger systemic anti-tumor immune response, termed sonodynamic immunotherapy. The rapid development of nanotechnology has revolutionized SDT effects with robust immune response induction. As a result, more and more innovative nanosonosensitizers and synergistic treatment modalities are established with superior efficacy and safe profile. In this review, the recent advances in cancer sonodynamic immunotherapy are summarized with a particular emphasis on how nanotechnology can be explored to harness SDT for amplifying anti-tumor immune response. Moreover, the current challenges in this field and the prospects for its clinical translation are also presented. It is anticipated that this review can provide rational guidance and facilitate the development of nanomaterials-assisted sonodynamic immunotherapy, helping to pave the way for next-generation cancer therapy and eventually achieve a durable response in patients.

Aggregation-induced emission photosensitizer/bacteria biohybrids enhance Cerenkov radiation-induced photodynamic therapy by activating anti-tumor immunity for synergistic tumor treatment

Cerenkov radiation-induced photodynamic therapy (CR-PDT) gets rid of the limited tissue penetration depth of the external light source and provides a feasible scheme for the PDT excited by the internal light. However, due to the low luminescence intensity of Cerenkov radiation, CR-PDT alone cannot effectively inhibit tumor growth, curbing the potential clinical translation of CR-PDT. Herein, we reported an AIE-PS/bacteria biohybrid (EcN@TTVP) composed of Escherichia coli Nissle 1917 (EcN) loaded with aggregation-induced emission photosensitizer (AIE-PS) termed TTVP, which enhanced CR-PDT by activating anti-tumor immunity for synergistic tumor treatment. The preferential tumor-colonized EcN@TTVP and radiopharmaceutical 18F-fluorodeoxyglucose (18F-FDG) were administered sequentially to enable them to co-enrich in the tumor site, thereby triggering CR-PDT and promoting immunogenic tumor cell death. Most importantly, EcN acting as immunoadjuvants enhanced the maturation of dendritic cells (DCs) and priming of cytotoxic T cells (CTLs). Therefore, under the synergistic treatment of CR-PDT and immunotherapy, AIE-PS/bacteria biohybrids resulted in either efficient tumor remission or a survival prolongation in tumor-bearing mice, which presented significant advantages over single CR-PDT. Remarkably, no obvious toxic effects were observed during the treatment. In this study, we proposed a synergistic therapeutic strategy based on EcN@TTVP for combined CR-PDT and immunotherapy against tumors. Moreover, this strategy may have great potential in clinical translation and provide references for deep-seated tumor treatment. Statement of significancePDT is restricted due to the shallow penetration depth of light into tumor tissues. Using CR as the excitation light source for PDT can overcome the aforementioned issue and greatly expand the application of PDT. However, the low efficacy of single CR-PDT limits further its applications. Therefore, the design and development of feasible strategies to improve the efficacy of CR-PDT are of immediate importance. Introducing probiotics to our study can be used not only as tumor-targeting carriers of photosensitizers but also as immunoadjuvants. Under co-stimulation by immunogenic tumor cell death triggered by CR-PDT and probiotics acting as immunoadjuvants, anti-tumor immune responses were effectively activated, thus remarkably enhancing the efficacy of CR-PDT.

Current Updates in Bleomycin-Based Electrochemotherapy for Deep-Seated Soft-Tissue Tumors

Electrochemotherapy (ECT) has evolved significantly during the last decade, expanding treatment indications from superficial skin lesions to advanced-stage, deep-seated tumors in hard-to-reach areas. Electrodes have also shown steady technological improvement throughout the years. Besides standard and VEG (variable geometry electrode) electrodes, the introduction of laparoscopic electrodes has brought on a new era in ECT treatment, making the minimally invasive approach a reality. The exact role of ECT in the oncological dashboard is yet to be determined; however, increased tumor response, pain relief, and a low number of adverse events may yield the way for more widespread application of the technique with possible further inclusion of ECT in international oncological guidelines. The aim of this review is to give an overview on the current status of ECT in deep-seated tumor treatment and shed light on its emerging role in local anticancer therapy.

Design of Sonosensitizers Integrated with Resveratrol Motif for Synergetic Sonodynamic Therapy and Nuclear Factor Kappa B Transcription Suppression of Breast Cancer.

Sonodynamic therapy (SDT) has been recognized as a spatial-temporal and noninvasive modality for the treatment of deep-seated tumors. However, current sonosensitizers suffer from low sonodynamic efficacy. Herein, we reported the design of nuclear factor kappa B (NF-κB) targeting sonosensitizers (TR1, TR2, and TR3) by integrating a resveratrol motif into a conjugated electron donor-acceptor (triphenylamine benzothiazole) skeleton. Among these sonosensitizers, TR2 with two resveratrol units in one molecule was the most potent for inhibiting NF-κB signaling. Owing to the synergy of high sonodynamic efficacy and NF-κB activation inhibition, TR2 displayed a remarkable sonocytotoxicity to MCF-7 breast cancer cells. Xenograft mice studies demonstrated that TR2 had excellent anticancer potency and biosafety. This study thus opens up a new avenue for the development of efficient organic sonosensitizers for cancer ablation.

Design and Assessment of a Novel Biconical Human-Sized Alternating Magnetic Field Coil for MNP Hyperthermia Treatment of Deep-Seated Cancer.

Magnetic nanoparticle (MNP) hyperthermia therapy is a treatment technique that can be used alone or as an adjunct to radiation and/or chemotherapies for killing cancer cells. During treatment, MNPs absorb a part of electromagnetic field (EMF) energy and generate localized heat when subjected to an alternating magnetic field (AMF). The MNP-absorbed EMF energy, which is characterized by a specific absorption rate (SAR), is directly proportional to AMF frequency and the magnitude of transmitting currents in the coil. Furthermore, the AMF penetrates inside tissue and induces eddy currents in electrically conducting tissues, which are proportional to the electric field (J = σE). The eddy currents produce Joule heating (<J·E> = 0.5·σ·E2) in the normal tissue, the rate of energy transfer to the charge carriers from the applied electric fields. This Joule heating contains only the electric field because the magnetic field is always perpendicular to the velocity of the conduction charges, i.e., it does not produce work on moving charge. Like the SAR due to MNP, the electric field produced by the AMF coil is directly proportional to AMF frequency and the magnitude of transmitting currents in the coil. As a result, the Joule heating is directly proportional to the square of the frequency and transmitter current magnitude. Due to the fast decay of magnetic fields from an AMF coil over distance, MNP hyperthermia treatment of deep-seated tumors requires high-magnitude transmitting currents in the coil for clinically achievable MNP distributions in the tumor. This inevitably produces significant Joule heating in the normal tissue and becomes more complicated for a standard MNP hyperthermia approach for deep-seated tumors, such as pancreatic, prostate, liver, lung, ovarian, kidney, and colorectal cancers. This paper presents a novel human-sized AMF coil and MNP hyperthermia system design for safely and effectively treating deep-seated cancers. The proposed design utilizes the spatial distribution of electric and magnetic fields of circular coils. Namely, it first minimizes the SAR due to eddy currents in the normal tissue by moving the conductors away from the tissue (i.e., increasing coils' radii), and second, it increases the magnetic field at the targeted area (z = 0) due to elevated coils (|z| > 0) by increasing the radius of the elevated coils (|z| > 0). This approach is a promising alternative aimed at overcoming the limitation of standard MNP hyperthermia for deep-seated cancers by taking advantage of the transmitter coil's electric and magnetic field distributions in the human body for maximizing AMF in tumor regions and avoiding damage to normal tissue. The human-sized coil's AMF, MNP activation, and eddy current distribution characteristics are investigated for safe and effective treatment of deep-seated tumors using numerical models. Namely, computational results such as AMF, Joule heating SAR, and temperature distributions are presented for a full-body, 3D human model. The SAR and temperature distributions clearly show that the proposed human-sized AMF coil can provide clinically relevant AMF to the region occupied by deep-seated cancers for the application of MNP hyperthermia therapy while causing less Joule heating in the normal tissues than commonly used AMF techniques.

Validation and optimization of the epithermal neutron flux detector using the 71Ga(n,γ)72Ga reaction

An intense epithermal neutron flux is necessary for boron neutron capture therapy (BNCT), a promising technique for the treatment of malignant tumors. The epithermal neutron flux is an essential characteristic of the BNCT neutron beam and its measurement is directly related to the reliability of the treatment planning system. Such a tool could be a cylindrical activation detector using 71Ga(n,γ)72Ga reaction. This paper describes a detector made in the likeness of the previously proposed one and presents the results of numerical simulation of the detector sensitivity and its experimental use. The paper notes the difference between the simulated sensitivity of the detector and the sensitivity of the previously proposed one and makes assumptions about the reason for this difference. The work also proposes an improvement of the detector, which allows not only to reduce the contribution of fast neutrons to the detector sensitivity, but also to provide a new opportunity to refine the spectrum of neutrons that are most effective for the treatment of deep-seated tumors.

Beam optics study for a potential VHEE beam delivery system

VHEE (Very High Energy Electron) therapy can be superior to conventional radiotherapy for the treatment of deep seated tumours, whilst not necessarily requiring the space and cost of proton or heavy ion facilities. Developments in high gradient RF technology have allowed electrons to be accelerated to VHEE energies in a compact space, meaning that treatment could be possible with a shorter linac. A crucial component of VHEE treatment is the transfer of the beam from accelerator to patient. This is required to magnify the beam to cover the transverse extent of the tumour, whilst ensuring a uniform beam distribution. Two principle methodologies for the design of a compact transfer line are presented. The first of these is based upon a quadrupole lattice and optical magnification of beam size. A minimisation algorithm is used to enforce certain criteria on the beam distribution at the patient, defining the lattice through an automated routine. Separately, a dual scattering-foil based system is also presented, which uses similar algorithms for the optimisation of the foil geometry in order to achieve the desired beam shape at the patient location.

Lysosome- and plasma membrane-accumulative and tumor-targetable polythiophene nanoparticles for enhanced sonodynamic therapy.

Sonodynamic therapy (SDT) has emerged as a promising treatment approach of solid tumors given its deep tissue penetration, non-invasiveness, few side effects, and negligible drug resistance. Herein, we report the first polythiophene derivative-based sonosensitizer (PT2) containing a quaternary ammonium salt and dodecyl chains with better ultrasound stability than that of traditional sonosensitizers, such as Rose Bengal and chlorin e6. PT2 was encapsulated by folic acid-containing polyethylene glycol. The obtained nanoparticles (PDPF NPs) exhibited excellent biocompatibility, cancer cell-targeting capacity, and accumulated mainly in the lysosomes and plasma membranes of cells. These NPs could generate singlet oxygen and superoxide anions simultaneously under ultrasound irradiation. In vitro and in vivo experimental results demonstrated that PDPF NPs could induce cancer-cell death through apoptosis and necrosis, inhibit DNA replication, and ultimately achieve tumor depletion upon US irradiation. These findings revealed that polythiophene could serve as an efficacious sonosensitizer for enhanced US treatment of deep-seated tumors.

An engineered cascade-sensitized red-emitting upconversion nanoplatform with a tandem hydrophobic hydration-shell and metal-phenolic network decoration for single 808 nm triggered simultaneous tumor PDT and PTT enhanced CDT.

Near-infrared light (NIR) driven lanthanide-doped upconversion nanoparticle (UCNP) based photo-dynamic therapy (PDT) holds a great promise for the non-invasive treatment of deep-seated tumors. However, it has also been highly hindered by the low upconversion luminescence (UCL) efficiency, hypoxia nature of solid tumors, and low therapeutic efficiency using single modality. Herein, we present a novel Nd3+ → Yb3+ → Tm3+ → Er3+ cascade-sensitized red-emitting UCNP with tandem hydrophobic hydration-shell (HHS) and metal-phenolic network (Fe-tannic acid, Fe-TA) decoration (UCNP@HHS@Fe-TA, denoted as UCFS@Fe-TA) for single 808 nm triggered simultaneous tumor PDT and photothermal therapy (PTT) enhanced chemo-dynamic therapy (CDT). The UCNP can supply intense red emission under high tissue penetrating/minimized tissue overheating 808 nm excitation, and their HHS coating with perfluorocarbon/photosensitizer Ce6 co-doping can not only realize UCL-based PDT, but also strengthen PDT of as-formed UCFS via O2-carrying/UCL protection capacity of the HHS. Fe-TA coating can supply 808 nm triggered PTT, and the rise in temperature during PTT leads to enhanced Fenton catalytic activity of Fe-TA and faster ˙OH production rate of CDT to match with the real-timely released 1O2 in PDT. The as-designed UCFS@Fe-TA thus can achieve a single 808 nm triggered simultaneous PDT and PTT enhanced CDT, leading to a PTT-assisted reactive oxygen species storm for efficient tumor suppression. Such a design also renders the nanoplatform lower cell dark toxicity. In addition, the single excitation-triggered multimodal therapy mode might address the excitation wavelength mismatch issue in dual laser-triggered PTT/PDT mode. This study has therefore presented an efficient nanotherapeutic platform enabling synergistic multimodal tumor therapies with high biocompatibility.

In vivo ultrasound imaging of macrophages using acoustic vaporization of internalized superheated nanodroplets

Ultrasound (US) not only detects but also interacts with its contrast agents, potentially allowing the use of perfluorocarbon-filled nanodroplets (NDs) or microbubbles (MBs) for both the detection and treatment of deep-seated tumors. Cells labeled using MBs to allow their detection in vivo with clinical ultrasound scanner presents several advantages over PET and MRI: Ultrasound is 2–3 orders of magnitude more sensitive and can detect a single acoustically labeled cell in vivo. Furthermore, with high ultrasound intensities, drugs or genes that are loaded on NDs or MBs can be delivered with spatiotemporal control. Although the acoustic labeling of stem cells for in vivo imaging using MBs has been reported, the ability to load and image internalized low boiling point NDs has not been explored yet. We used perfluorobutane NDs to acoustically label macrophages, which were viable following post internalization and ultrasound-mediated phase change. We documented that internalized NDs are stable for at least 8 h, which is needed for macrophages to accumulate to diseased sites. Labeled macrophage accumulated in the liver of healthy rats as stable intracellular NDs were vaporized into MBs using a clinical scanner (Siemens ACUSON Sequoia, 10L4 transducer at 4 MHz, 1.4 MI) and remained visible after vaporization.