Treatment Of Deep-seated Tumors Research Articles

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.

Nanoplatforms with synergistic redox cycles and rich defects for activatable image-guided tumor-specific therapy

<h2>Summary</h2> Multifunctional nanoplatforms for the early diagnosis and treatment of deep-seated tumors with high specificity are particularly desirable but face many challenges. Herein, nanoplatforms containing copper/manganese chalcogenide nanoflowers (CMC NFs) and ¹⁹F probes have been developed, which exhibit enhanced therapeutic efficiency and activatable ¹⁹F magnetic resonance imaging (MRI) capability within a tumor microenvironment (TME). CMC NFs containing synergistic redox pairs (Cu^ox/Cu^red, Mn^ox/Mn^red) and rich defects acted as integrated cascade enzyme mimics to effectively destroy the redox homeostasis of tumors via generation of reactive oxygen species (ROS) and GSH depletion. In addition, the ¹⁹F MRI signal could be switched on by attenuation of the paramagnetic relaxation enhancement (PRE) effect under TME conditions, affording a TME-activatable ¹⁹F MRI-guided tumor-specific chemodynamic therapeutic. These nanoplatforms could simultaneously boost therapeutic efficacy and regulate signal output, exhibiting significant potential for <i>in vivo</i> drug tracking and deep-seated tumor diagnosis and treatment.

Genetically encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors

Photodynamic therapy (PDT) is one of the most appealing photonic modalities for cancer treatment based on anticancer activity of light-induced photosensitizer-mediated reactive oxygen species (ROS), but a limited depth of light penetration into tissues does not make possible the treatment of deep-seated neoplasms and thus complicates its widespread clinical adoption. Here, we introduce the concept of genetically encoded bioluminescence resonance energy transfer (BRET)-activated PDT, which combines an internal light source and a photosensitizer (PS) in a single-genetic construct, which can be delivered to tumors seated at virtually unlimited depth and then triggered by the injection of a substrate to initiate their treatment. To illustrate the concept, we engineered genetic NanoLuc-miniSOG BRET pair, combining NanoLuc luciferase flashlight and phototoxic flavoprotein miniSOG, which generates ROS under luciferase-substrate injection. We prove the concept feasibility in mice bearing NanoLuc-miniSOG expressing tumor, followed by its elimination under the luciferase-substrate administration. Then, we demonstrate a targeted delivery of NanoLuc-miniSOG gene, via tumor-specific lentiviral particles, into a tumor, followed by its successful elimination, with tumor-growth inhibition (TGI) coefficient exceeding 67%, which confirms a great therapeutic potential of the proposed concept. In conclusion, this study provides proof-of-concept for deep-tissue “photodynamic” therapy without external light source that can be considered as an alternative for traditional PDT.

Flourish of Proton and Carbon Ion Radiotherapy in China.

Proton and heavy ion therapy offer superior relative biological effectiveness (RBE) in the treatment of deep-seated tumors compared with conventional photon radiotherapy due to its Bragg-peak feature of energy deposition in organs. Many proton and carbon ion therapy centers are active all over the world. At present, five particle radiotherapy institutes have been built and are receiving patient in China, mainly including Wanjie Proton Therapy Center (WPTC), Shanghai Proton Heavy Ion Center (SPHIC), Heavy Ion Cancer Treatment Center (HIMM), Chang Gung Memorial Hospital (CGMH), and Ruijin Hospital affiliated with Jiao Tong University. Many cancer patients have benefited from ion therapy, showing unique advantages over surgery and chemotherapy. By the end of 2020, nearly 8,000 patients had been treated with proton, carbon ion or carbon ion combined with proton therapy. So far, there is no systemic review for proton and carbon ion therapy facility and clinical outcome in China. We reviewed the development of proton and heavy ion therapy, as well as providing the representative clinical data and future directions for particle therapy in China. It has important guiding significance for the design and construction of new particle therapy center and patients’ choice of treatment equipment.

Heating Power of Millimeter-Sized Implanted Coils for Tumor Ablation: Numerical-Analytic Analysis and Optimization

Minimally invasive thermal ablation procedures of tumors with implanted devices are very promising, especially for the repetitive treatment of deep-seated tumors. The implanted devices are heated without contact by an alternating magnetic field from outside the patient&#x2019;s body. In this paper, the heating power of millimeter-sized implanted coils is analyzed and optimized with a numerical-analytic analysis and the dependencies on spatial, electrical, and magnetic parameters are evaluated and presented for being able to choose the optimum implanted coil for a specific set of parameters. The analysis is done with focus on the implanted coils based on a homogeneous alternating magnetic field. A heating power of 1.5 W required for achieving an adequate rise of tissue temperature is determined in a thermal analysis and the corresponding specific absorption rate (SAR) is evaluated along with the power transfer efficiency (PTE) and the coupling coefficient for different types of implanted coils. For uncompensated implanted coils, a SAR of 306 mW/kg, a PTE of 4.62 &#x00B7; 10^-3 and a coupling coefficient of 2.49 &#x00B7; 10^-3 is achieved by a magnetic field strength of 1727 A/m, whereas a SAR of 1.84 mW/kg, a PTE of 436 &#x00B7; 10^-3 and a coupling coefficient of 2.3 &#x00B7; 10^-3 is achieved by a magnetic field strength of 134 A/m for serial compensated implanted coils. With this, the ratio of heating power to required magnetic field strength is maximized, which reduces the risk of unwanted heating of healthy tissue and other implanted devices and therefore enhances the safety as well as the well-being of the patients.

Deep Seated Tumour Treatments With Electrons of High Energy Delivered at FLASH Rates: The Example of Prostate Cancer.

Different therapies are adopted for the treatment of deep seated tumours in combination or as an alternative to surgical removal or chemotherapy: radiotherapy with photons (RT), particle therapy (PT) with protons or even heavier ions like 12C, are now available in clinical centres. In addition to these irradiation modalities, the use of Very High Energy Electron (VHEE) beams (100–200 MeV) has been suggested in the past, but the diffusion of that technique was delayed due to the needed space and budget, with respect to standard photon devices. These disadvantages were not paired by an increased therapeutic efficacy, at least when comparing to proton or carbon ion beams. In this contribution we investigate how recent developments in electron beam therapy could reshape the treatments of deep seated tumours. In this respect we carefully explored the application of VHEE beams to the prostate cancer, a well-known and studied example of deep seated tumour currently treated with high efficacy both using RT and PT. The VHEE Treatment Planning System was obtained by means of an accurate Monte Carlo (MC) simulation of the electrons interactions with the patient body. A simple model of the FLASH effect (healthy tissues sparing at ultra-high dose rates), has been introduced and the results have been compared with conventional RT. The study demonstrates that VHEE beams, even in absence of a significant FLASH effect and with a reduced energy range (70–130 MeV) with respect to implementations already explored in literature, could be a good alternative to standard RT, even in the framework of technological developments that are nowadays affordable.

Sonodynamic Therapy with Metal Complexes: A New Promise in Cancer Therapy.

In recent years, to overcome the problem of low tissue penetration power of light in photodynamic therapy (PDT), sonodynamic therapy (SDT) with ultrasound (US) as the drug stimulus has emerged as a potential alternative to PDT. The significantly higher tissue penetration capacity of US is reported to allow the treatment of deep-seated tumours. In general, organic molecules and nanomaterials dominate as the sonosensitizers in this area of research, and the potential of metal complexes in SDT is not yet well explored. In this highlight, we have summarized two recent literature reports in which researchers have explored the efficiency of metal complexes as sonosensitizers for the first time. These reports indicate the high potential of metal complexes in SDT.

Dosimetry and radioprotection evaluations of very high energy electron beams

Very high energy electrons (VHEEs) represent a promising alternative for the treatment of deep-seated tumors over conventional radiotherapy (RT), owing to their favourable dosimetric characteristics. Given the high energy of the electrons, one of the concerns has been the production of photoneutrons. In this article we explore the consequence, in terms of neutron yield in a water phantom, of using a typical electron applicator in conjunction with a 2 GeV and 200 MeV VHEE beam. Additionally, we evaluate the resulting ambient neutron dose equivalent at various locations between the phantom and a concrete wall. Through Monte Carlo (MC) simulations it was found that an applicator acts to reduce the depth of the dose build-up region, giving rise to lower exit doses but higher entrance doses. Furthermore, neutrons are injected into the entrance region of the phantom. The highest dose equivalent found was approximately 1.7 mSv/Gy in the vicinity of the concrete wall. Nevertheless, we concluded that configurations of VHEEs studied in this article are similar to conventional proton therapy treatments in terms of their neutron yield and ambient dose equivalent. Therefore, a clinical implementation of VHEEs would likely not warrant additional radioprotection safeguards compared to conventional RT treatments.

Degradable FeCuS-Lipid Nanoparticles Confer Ultrasound-Activated CO Release and O2-Independent Radical Production for Synergistic Therapy

Ultrasound (US)-activated nanoagents capable of producing cytotoxic species have been promising for the treatment of deep-seated tumors; however, poor tumor uptake and insufficient generation of cytotoxic agents have largely limited their therapeutic efficacy in vivo. Herein, we report a hybrid FeCuS-lipid nanoparticle (AIBA@FeCuS-FeCO) by amphiphilic lipids-assisted emulsion of a free radical initiator (AIBA), a radical-sensitive CO donor (Fe3(CO)12), and radical-degradable FeCuS nanodisks for US-activated synergistic therapy of deep-located orthotopic gastric tumors in living mice. Upon US irradiation, AIBA@FeCuS-FeCO could be degraded and release cytotoxic AIBA radicals, CO, Fe2+, and Cu2+, allowing us to (1) enhance tumor uptake of AIBA@FeCuS-FeCO through CO-mediated vasodilation, (2) promote hydroxyl radical production and induce tumor ferroptosis via intracellular accumulation of Fe2+/Cu2+, and (3) kill tumor cells. Moreover, the subsequent administration of disulfiram (DSF) could further chelate with the liberated Cu2+, yielding toxic bis(N,N-diethyl dithiocarbamato)copper(II) chelates to synergize the therapeutic effect to ablate deep-seated orthotopic gastric tumors.

Electrochemotherapy of Deep-Seated Tumors: State of Art and Perspectives as Possible "EPR Effect Enhancer" to Improve Cancer Nanomedicine Efficacy.

Simple SummaryElectroporation-based therapies (reversible electroporation, irreversible electroporation, electrochemotherapy) are used for the selective treatment of deep-seated tumors. The combination of the structural modifications of the lipid bilayer of cell membranes, due to the application of electrical pulses in the targeted tissue, with the concomitant systemic (intravenous) administration of drugs can be considered as a sort of bridge between local-regional and systemic treatments. A possible further application of these techniques can be envisaged in their use as enhancers of the so-called “enhanced permeability and retention” effect. The intratumoral uptake of drug-loaded nanocarriers concomitant with the application of electric pulses in the target tumor is a new scenario worthy of attention and can represent a potential new frontier for drug delivery in oncology.Surgical resection is the gold standard for the treatment of many kinds of tumor, but its success depends on the early diagnosis and the absence of metastases. However, many deep-seated tumors (liver, pancreas, for example) are often unresectable at the time of diagnosis. Chemotherapies and radiotherapies are a second line for cancer treatment. The “enhanced permeability and retention” (EPR) effect is believed to play a fundamental role in the passive uptake of drug-loaded nanocarriers, for example polymeric nanoparticles, in deep-seated tumors. However, criticisms of the EPR effect were recently raised, particularly in advanced human cancers: obstructed blood vessels and suppressed blood flow determine a heterogeneity of the EPR effect, with negative consequences on nanocarrier accumulation, retention, and intratumoral distribution. Therefore, to improve the nanomedicine uptake, there is a strong need for “EPR enhancers”. Electrochemotherapy represents an important tool for the treatment of deep-seated tumors, usually combined with the systemic (intravenous) administration of anticancer drugs, such as bleomycin or cisplatin. A possible new strategy, worthy of investigation, could be the use of this technique as an “EPR enhancer” of a target tumor, combined with the intratumoral administration of drug-loaded nanoparticles. This is a general overview of the rational basis for which EP could be envisaged as an “EPR enhancer” in nanomedicine.

Charge identification of fragments with the emulsion spectrometer of the FOOT experiment

Abstract The FOOT (FragmentatiOn Of Target) experiment is an international project designed to carry out the fragmentation cross-sectional measurements relevant for charged particle therapy (CPT), a technique based on the use of charged particle beams for the treatment of deep-seated tumors. The FOOT detector consists of an electronic setup for the identification of Z ≥ 3 Z\ge 3 fragments and an emulsion spectrometer for Z ≤ 3 Z\le 3 fragments. The first data taking was performed in 2019 at the GSI facility (Darmstadt, Germany). In this study, the charge identification of fragments induced by exposing an emulsion detector, embedding a C 2 H 4 {{\rm{C}}}_{2}{{\rm{H}}}_{4} target, to an oxygen ion beam of 200 MeV/n is discussed. The charge identification is based on the controlled fading of nuclear emulsions in order to extend their dynamic range in the ionization response.

Abstract 3057: Development of radiation-triggered phosphor platform for localized activation in combinatory cancer treatment

Abstract A defined spatial and temporal control of induction of toxicity in response to external ionizing radiation such as X-rays has unique clinical benefits over conventional systems such as passive drug delivery or its activation. Here, we have combined X-rays with well characterized nanoscintilators emitting light that activates paired photosensitizers in photodynamic therapy (PDT) that improves the prowess of PDT to deep seated tumor treatment. Yttrium oxide nanoparticle construct doped with Europium (YOE) and coated with a silica layer entrapping methylene blue (MB) as the photosensitizer was fabricated. The nanoconstruct (YSM, for YOE, silica, MB) was decorated with polyethylene glycol (PEG) to make it biocompatible and characterized extensively for physicochemically parameters. Transmission electron microscopy (TEM) revealed a resultant average nanoparticle diameter of 24.1 ± 5.7 nm, and dynamic light scattering (DLS) a hydrodynamic diameter of 135.3 ± 17.9 nm. This nanoconstruct was evaluated for its ability to generate singlet oxygen reactive oxygen species upon irradiation using singlet oxygen sensor green (SOSG) fluorescence assay. Further, demonstrated that this nanoconstruct was taken up by cancer cells in vitro and by tumors in vivo. The uptake of YSM particles by Panc02 murine pancreatic cancer cells was tested by inductively coupled plasma – mass spectrometry. This demonstrated robust uptake in cells after 24hr incubation. No noticeable cell death occurred with doses of 0 Gy and 4 Gy, cell viability decreased significantly after a dose of 8 Gy irradiation in cells cultured with YSM when compared to controls. Since 8 Gy is within the range of a clinically applicable dose used routinely in stereotactic radiotherapy regimens, these results verified the potential of YSM to be used as scintillator-photosensitizer complexes for x-ray activated photodynamic therapy. Finally the biodistribution of YSM nanoconstructs in vivo in C57BL6 mice harboring subcutaneous Panc02 tumors show YSM accumulation in tumors. A versatile, biocompatible Yttrium oxide scintillator-photosensitizer complex (YSM) that can generate x-ray induced cytotoxic reactive oxygen species is fabricated. This is capable of facilitating x-ray activated photodynamic therapy (XPDT (external beam) and/or iXPDT (internal x-ray source)). It shows promise in maximizing the efficacy of the combinatory treatment and enhanced improvement of the quality of life and overall survival of cancer patients. Citation Format: Rao V. Papineni, Sunil Krishnan, Ajayan Pulickel, Onur Sahin. Development of radiation-triggered phosphor platform for localized activation in combinatory cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3057.

Electroporation-based treatments in minimally invasive percutaneous, laparoscopy and endoscopy procedures for treatment of deep-seated tumors.

Electroporation (EP) techniques, used alone (Irreversible Electroporation, IRE) or in combination with anti-cancer drugs (Electrochemotherapy, ECT), have been shown to be effective in the treatment of several types of cancers. The efficacy of ECT and IRE is well demonstrated for the treatment of non-superficial tumor metastases, and it depends on the applied electrical parameters. Particularly, ECT is an effective local therapy that uses electroporation to enhance the cytotoxic effect of bleomycin or cisplatin injected intravenously or intratumorally. Pre-clinical investigations to test alternative anti-cancer drugs, explore new combinations of treatment modalities, and evaluate different sets of pulse protocols for effective tissue electroporation, are ongoing. Further ECT developments include the treatment of deep-seated tumors with percutaneous, laparoscopy, and endoscopy approaches, with the aim of establishing a less invasive approach. ECT is highly effective in the treatment of tumors of any histology, in minimizing the damage of critical normal tissue or organs, and in reducing pain and muscular contractions. This work describes the new technological advances in the field of ECT treatment for deep-seated tumors.

Upregulating Aggregation-Induced-Emission Nanoparticles with Blood-Tumor-Barrier Permeability for Precise Photothermal Eradication of Brain Tumors and Induction of Local Immune Responses.

Compared to other tumors, glioblastoma (GBM) is extremely difficult to treat. Recently, photothermal therapy (PTT) has demonstrated advanced therapeutic efficacy; however, because of the relatively low tissue-penetration efficiency of laser light, its application in deep-seated tumors remains challenging. Herein, bradykinin (BK) aggregation-induced-emission nanoparticles (BK@AIE NPs) are synthesized; these offer selective penetration through the blood-tumor barrier (BTB) and strong absorbance in the near-infrared region (NIR). The BK ligand can prompt BTB adenosine receptor activation, which enhances transportation and accumulation inside tumors, as confirmed by T1 -weighted magnetic resonance and fluorescence imaging. The BK@AIE NPs exhibit high photothermal conversion efficiency under 980nm NIR laser irradiation, facilitating the treatment of deep-seated tumors. Tumor progression can be effectively inhibited to extend the survival span of mice after spatiotemporal PTT. NIR irradiation can eradicate tumor tissues and release tumor-associated antigens. It is observed that the PTT treatment of GBM-bearing mice activates natural killer cells, CD3+ T cells, CD8+ T cells, and M1 macrophages in the GBM area, increasing the therapeutic efficacy. This study demonstrates that NIR-assisted BK@AIE NPs represent a promising strategy for the improved systematic elimination of GBMs and the activation of local brain immune privilege.

Magnetothermally Triggered Free-Radical Generation for Deep-Seated Tumor Treatment

Tumor hypoxia and the tissue penetration limitation of excitation light hamper the widespread clinical use of photodynamic therapy. The development of new therapeutic strategies that can generate oxygen-independent free radicals without penetration depth limitation is of great demand. Herein, a novel magnetothermodynamic strategy for deep-seated tumor therapy is reported. In this system, a radical initiator (AIPH) was loaded into porous hollow iron oxide nanoparticles (PHIONs). Under the induction of an alternating magnetic field (AMF), PHIONs can generate heat to trigger the release and decomposition of AIPH, resulting in the generation of oxygen-independent alkyl radicals. The resulting alkyl radicals can effectively kill cancer cells under hypoxic conditions. More importantly, this magnetothermally triggered free-radical generator exhibits significant therapeutic efficacy for orthotopic liver tumors in a rat model. This magnetothermodynamic therapy strategy with the advantages of oxygen independence and no limitation of penetration depth holds great promise in deep-seated solid tumor treatment.

ROS-based dynamic therapy synergy with modulating tumor cell-microenvironment mediated by inorganic nanomedicine

Abstract Dynamic therapy (DT) by in situ ROS generation is emerging as an attractive therapeutic modality with potential to treat deep-seated tumors, avoiding side effects to healthy tissues. As one kind of DT, photodynamic therapy (PDT) has been clinically approved for cancer treatment, but restricted to superficial lesions due to the poor tissue penetration depth of excitation lights. Therefore, there is an urgent need to find out some new strategies to produce ROS under external stimulation with high penetrability or even independent of external excitation. Inorganic nanomaterials-based nanomedicine, or inorganic nanomedicine which can be designed with unique physicochemical properties, can respond to external excitations such as near-infrared (NIR) light, ultrasound (US), X-ray, and microwave (MW), or trigger internal chemical/biological reaction in tumor region to produce ROS for DT, showing great advantages for deep-seated tumor treatment with high specificity, safety, and non-invasiveness. However, most of the DT strategies are highly relied on oxygen, while the tumor microenvironment (TME), especially tumor cell-microenvironment is characterized with hypoxia and high concentration of reductive glutathione (GSH), which will impede the generation and accumulation of ROS, thus severely restricting ROS induced oxidative injury. Therefore, it is crucial to improve the efficacy of DT to enhance the anti-tumor effect. In this review, we briefly summarize the latest advances in developing types of DT related to ROS generation, including NIR-induced photo-/pyroelectric dynamic therapy, US-triggered sono-/piezo-dynamic therapy, X-ray-stimulated radio-/radiodynamic therapy, MW-triggered microdynamic therapy, alternating current-triggered electrodynamic therapy, as well as some others manners independent of external excitation such as chemodynamic therapy and self-lightened PDT. More importantly, we summarize various strategies to modulate tumor cell-microenvironment to enhance the efficacy of DT, by reliving hypoxia, augmenting hydrogen peroxide (H2O2), adjusting the pH, and depleting GSH. In addition, we also discuss the significance of nanotoxicity assessments in safely designing inorganic nanomaterials-based nanomdicine, address the challenges and limitations of DT, and further put forward the development direction of DT for future clinical translation. We hope that this timely and comprehensive review would make the value and future prospects of inorganic nanomedicine to be seen, and more in-depth studies are needed to realize the conversion of inorganic nanomedicine mediated DT strategies in clinics.

Recent Advances in Photodynamic Therapy for Deep-Seated Tumors with the Aid of Nanomedicine.

Photodynamic therapy (PDT) works through photoactivation of a specific photosensitizer (PS) in a tumor in the presence of oxygen. PDT is widely applied in oncology to treat various cancers as it has a minimally invasive procedure and high selectivity, does not interfere with other treatments, and can be repeated as needed. A large amount of reactive oxygen species (ROS) and singlet oxygen is generated in a cancer cell during PDT, which destroys the tumor effectively. However, the efficacy of PDT in treating a deep-seated tumor is limited due to three main reasons: Limited light penetration depth, low oxygen concentration in the hypoxic core, and poor PS accumulation inside a tumor. Thus, PDT treatments are only approved for superficial and thin tumors. With the advancement of nanotechnology, PDT to treat deep-seated or thick tumors is becoming a reachable goal. In this review, we provide an update on the strategies for improving PDT with nanomedicine using different sophisticated-design nanoparticles, including two-photon excitation, X-ray activation, targeting tumor cells with surface modification, alteration of tumor cell metabolism pathways, release of therapeutic gases, improvement of tumor hypoxia, and stimulation of host immunity. We focus on the difficult-to-treat pancreatic cancer as a model to demonstrate the influence of advanced nanomedicine in PDT. A bright future of PDT application in the treatment of deep-seated tumors is expected.

PEG-PLGA nanospheres loaded with nanoscintillators and photosensitizers for radiation-activated photodynamic therapy

Photodynamic Therapy (PDT) is an effective treatment modality for cancers, with Protoporphyrin IX (PPIX)-based PDT being the most widely used to treat cancers in patients. However, PDT is limited to superficial, thin (few mm in depth) lesions that can be accessed by visible wavelength light. Interstitial light-delivery strategies have been developed to treat deep-seated lesions (i.e. prostate cancer). The most promising of these are X-ray-induced scintillation nanoparticles, which have shown potential benefits for PDT of deep-seated tumors. Herein, the design and use of a new nanoscintillator-based radiation-activated PDT (radioPDT) system is investigated in the treatment of deep-seated tumors. Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG-PLGA) nanospheres were loaded with a scintillator (LaF3:Ce3+) and photosensitizer (PPIX) to effect radioPDT. UV–Vis spectroscopy and electron microscopy studies demonstrated efficient encapsulation of nanoscintillators and PPIX (>90% efficiency) into the PEG-PLGA nanospheres. The nanoparticles were uniform in size and approximately 100 nm in diameter. They were highly stable and functional for up to 24 h under physiological conditions and demonstrated slow release kinetics. In vitro and in vivo toxicity studies showed no appreciable drug toxicity to human skin fibroblast (GM38), prostate cancer cells (PC3), and to C57/BL mice. Cell uptake studies demonstrated accumulation of the nanoparticles in the cytoplasm of PC3 cells. When activated, fluorescent resonant energy transfer (FRET) was evident via fluorescent spectroscopy and singlet oxygen yield. Determination of stability revealed that the nanoparticles were stable for up to 4 weeks. The nanoparticle production was scaled-up with no change in properties. This nanoparticle represents a unique, optimally designed therapeutic and diagnostic agent (theranostic) agent for radioPDT with characteristics capable of potentially augmenting radiotherapy for deep-seated tumors and integrating into current cancer radiotherapy.

Accompanying photocytotoxic activity of gold nanoechinus and zinc phthalocyanine on cancerous cell lines.

Near-infrared triggered photodynamic therapy (NIR-PDT) has been introduced as a relatively deep tumor treatment modality. The gold Nanoechinus (Au NE) is a rare type of nanostructures that act as a transducer to change NIR wavelength to ultraviolet (UV) and visible lights. During the photodynamic process, Au nanoechinus (Au NE) converts the irradiation of 980 nm to 674 nm which is absorbed by Zn(II) Phthalocyanine tetrasulfonic acid (ZnPcS). In this study the cooperation effect of Au NE and ZnPcS in PDT on MCF7 and Hela cells was investigated. Cytotoxicity and phototoxicity of the composition having different concentrations of Au NE and ZnPcS upon irradiation of 980 nm NIR light were evaluated against MCF7 and Hela cells after two different incubation times and irradiating with two different power densities of laser. Among different experimental groups, in MCF7 cells, which were incubated for 48 h with 50 μg/mL Au NE+2μM ZnPcS and were treated by 980 nm laser with a power density of 200 mW cm-2 for 15 and 30 min, 48 and 38% cell viability were recorded. No appreciable result was observed due to PDT of Hela cells. Comparing to other PDT modalities against MCF7 cells, NIR-PDT procedure suggested in this study with the synergistic effect of Au NE and ZnPcS could be a secure promising modality in the treatment of deep-seated tumors. Carefully increasing the power density and ambient temperature, to the extent of skin tolerance threshold value, seems to be efficient in the treatment of Hela cells.

Photothermal Fenton Nanocatalysts for Synergetic Cancer Therapy in the Second Near-Infrared Window.

Chemodynamic therapy (CDT) that utilizes endogenous hydrogen peroxide (H2O2) to produce reactive oxygen species (ROS) to kill cancer cells has shown a promising strategy for malignant tumor treatment. Nevertheless, limited H2O2 levels in the tumor microenvironment often compromise the therapeutic benefits of CDT, leading to cancer recurrence and metastasis. Herein, a second near-infrared (NIR-II) photothermal Fenton nanocatalyst (PFN) was developed for activatable magnetic resonance imaging (MRI)-guided synergetic photothermal therapy (PTT) and CDT of pancreatic carcinoma. Such a PFN consists of manganese dioxide (MnO2), copper sulfide (CuS), and human serum albumin (HSA), which serve as the activatable imaging contrast agent, the NIR-II photothermal agent and Fenton catalyst, and the stabilizer, respectively. The acidic tumor microenvironment increased the relaxivity of PFN by 2.1-fold, allowing for improved imaging performance and monitoring of nanoparticle accumulation in tumors. Under NIR-II laser irradiation at 1064 nm, PFN generates local heat, which not only permits PTT but also enhances the nanocatalyst-mediated Fenton-like reaction. As such, PFN exerts a synergetic action to completely ablate xenografted tumor models in living animals, while the sole CDT fails to do so. This study thus provides an NIR-II photothermal nanocatalyst for potential treatment of deep-seated tumors.