Non-invasive Cancer Treatment Research Articles

The abscopal effects of sonodynamic therapy in cancer

AbstractThe abscopal effect is a phenomenon wherein localised therapy on the primary tumour leads to regression of distal metastatic growths. Interestingly, various pre-clinical studies utilising sonodynamic therapy (SDT) have reported significant abscopal effects, however, the mechanism remains largely enigmatic. SDT is an emerging non-invasive cancer treatment that uses focussed ultrasound (FUS) and a sonosensitiser to induce tumour cell death. To expand our understanding of abscopal effects of SDT, we have summarised the preclinical studies that have found SDT-induced abscopal responses across various cancer models, using diverse combination strategies with nanomaterials, microbubbles, chemotherapy, and immune checkpoint inhibitors. Additionally, we shed light on the molecular and immunological mechanisms underpinning SDT-induced primary and metastatic tumour cell death, as well as the role and efficacy of different sonosensitisers. Notably, the observed abscopal effects underscore the need for continued investigation into the SDT-induced ‘vaccine-effect’ as a potential strategy for enhancing systemic anti-tumour immunity and combating metastatic disease. The results of the first SDT human clinical trials are much awaited and are hoped to enable the further evaluation of the safety and efficacy of SDT, paving the way for future studies specifically designed to explore the potential of translating SDT-induced abscopal effects into clinical reality.

Integrating All-rounder TiO2 Accelerated Electrochemiluminescence with Dual-Quenching PDA@COF Probes for Sensitive Quantification and Protein Profiling of Tumorous Exosomes.

Exosomes have been perceived as promising biomarkers for noninvasive cancer diagnosis and treatment monitoring. However, the sensitive and accurate quantification and phenotyping of exosomes remains challenging. Herein, a versatile electrochemiluminescence (ECL) aptasensor was proposed for the sensitive analysis of tumorous exosomes. Specifically, a ternary nanohybrid (Ru-HAuTiO2), by covalently linking ECL luminophore Ru(dcbpy)32+ with gold nanoparticles (AuNPs)-decorated hollow urchin-like TiO2 (HTiO2), was ingeniously designed as a highly luminescent and self-enhanced ECL nanoemitter. Notably, the porous HTiO2 played an "all-rounder" role, including the carrier for ECL luminophores and AuNPs, coreaction accelerator, and specific exosome capturing scaffold through Ti-phosphate coordination interaction. On the other hand, a polydopamine modified covalent organic framework (PDA@COF) was employed as a quencher to remarkably attenuate the ECL of Ru-HAuTiO2 through a dual-quenching mechanism, and further labeled with a specific aptamer (Apt) of exosomal surface protein. Based on forming a Ru-HAuTiO2/exosome/Apt-PDA@COF sandwich structure on the electrode, a "signal on-off" ECL platform for tumorous exosomes was constructed, realizing sensitive detection within the range of 3.1 × 103 particles/mL to 1 × 108 particles/mL and a low limit of detection of 1.41 × 103 particles/mL, achieving phenotypic profiling of surface proteins on different tumorous exosomes. This work provides a promising alternative method for the detection and analysis of exosomes.

Fluorocarbon-Functionalized Polymerization-Induced Self-Assembly Nanoparticles Alleviate Hypoxia to Enhance Sonodynamic Cancer Therapy.

Sonodynamic therapy (SDT) is an ultrasound-based, noninvasive cancer treatment that targets tumor cells by triggering reactive oxygen species production. However, the limited accumulation of sonosensitizers and the insufficient supply of O2 to the hypoxic environment at the tumor site greatly limit the effectiveness of SDT. To address these issues, positively charged porphyrin-containing nanoparticles (NPs) from self-assembling of fluorocarbon/polyethylene glycol amphiphilic block copolymer, which is synthesized through reversible addition-fragmentation chain transfer polymerization, are constructed. The NPs with fluorocarbon core and positively charged hydrophilic shells not only stabilize the sonosensitizer and improve its cellular uptake, but also act as an O2 carrier alleviating the hypoxic tumor environment. In vitro and in vivo experiments demonstrate that the NPs effectively deliver O2 to the tumor and supply sufficient O2 to Renca cells after ultrasound treatment. Consequently, the NPs inhibit hypoxia-induced resistance to SDT and significantly produce reactive oxygen species by activated porphyrin moieties, inducing apoptosis in cancer cells. These oxygen-enhanced sonosensitizer NPs hold promise for cancer therapies such as photodynamic therapy, radiotherapy, and chemotherapy by overcoming hypoxia-induced resistance.

Zinc phthalocyanine-bridged periodic mesoporous organosilica nanoparticle as biodegradable photosensitizer for photodynamic therapy

The development of efficient photosensitizers is vital for advancing photodynamic therapy (PDT), a non-invasive cancer treatment. Although zinc phthalocyanine (ZnPc) has garnered significant attention as a photosensitizer in preclinical studies, its clinical application is hindered by poor solubility and a tendency to aggregate, despite its high absorption coefficient and low dark toxicity. To address these challenges, we developed a novel ZnPc-conjugated periodic mesoporous organosilica (PMO) nanoparticle, which enhances the photosensitizer's solubility, photostability, and biodegradability. The PMO nanoparticles retained the characteristic mesoporous structure, exhibited strong fluorescence emission, and effectively generated singlet oxygen. In vitro studies using 4T1 cells, along with in vivo experiments on a tumor-bearing mouse model, demonstrated that under 675nm laser irradiation, the ZnPc-PMO nanophotosensitizer induced reactive oxygen species, leading to significant inhibition of tumor growth. This ZnPc-bridged PMO nanophotosensitizer holds great promise for enhancing PDT efficacy and biocompatibility, offering a potential platform for multimodal phototherapeutic strategies.

Au-H2Ti3O7 nanotubes for non-invasive anticancer treatment by simultaneous photothermal and photodynamic therapy

Treating lung and prostate cancer cells is a major health problem that may be solved through the interactions of laser beams with nanoparticles. In the paper, Au-H2Ti3O7 nanotubes (NTs) are proposed as a treatment agent and the interactions of different laser beams with the nanostructure are considered to solve the mentioned health problem. Also, the NTs are employed to treat the cancers in dark conditions. The results are motivating because Au-H2Ti3O7 NPs do not affect healthy cells, while they strongly affect cancer cells, and the viability percentage of LNCap cells reaches 16% for incubation times of 48 h. Furthermore, treating LNCap cells using the irradiated Au-H2Ti3O7 NTs by NIR beam at 808 nm has no cytotoxicity, while cytotoxicity of 92% is obtained using an irradiation laser beam at 532 nm. Also, applying the laser beam at 635 nm to the NTs leads to a cytotoxicity of ∼53% in lung cancer (A549 cells). In total, the Au-H2Ti3O7 NTs have a selective effect on cancer cells and greatly reduce the viability in the given dark and irradiation conditions, leading to the introduction of them as a promising agent for the non-invasive treatment of prostate cancer and a moderate candidate for lung cancer therapy.

DNA logic gate for cancer cells identification, detection, and modulation of cell–cell interactions

The precise detection of cancer cells and modulation of cell–cell interactions would be highly desired for noninvasive and nontoxic cancer treatments but it remains challenging due to the existence of biomarkers on both normal and tumor cells. In this work, we engineered a logic-gated DNA molecular machine incorporating a membrane protein aptamer and an extracellular acid responsive split i-motif for the precise identification and detection of cancer cells, as well as the mediation of cell–cell interactions. In this system, only in the presence of both the membrane protein and protons, the logic-gated DNA molecular machine is activated to perform the “AND” logic operation to induce catalytic hairpin assembly (CHA) on the electrode, leading to the formation of G-quadruplex/hemin and the generation of an amplified electrochemical signal. On the other hand, the formed “AND” logic could hybridize with the DNA fragment on T-cell, effectively shorting the distance between T-cell and cancer cells. Benefiting from the DNA logic gate and CHA, this strategy could not only precisely identify cancer cells, but also show a sensitive analysis of cancer cells with a detection limit of 15 cells/mL. The logic-gated DNA molecular machine achieved the identification of cancer cells and modulation of intercellular interactions, providing a new idea for precise disease diagnosis and therapy.

A Review on Recent Trends in Photo-Drug Efficiency of Advanced Biomaterials in Photodynamic Therapy of Cancer.

Photodynamic Therapy (PDT) has emerged as a highly efficient and non-invasive cancer treatment, which is crucial considering the significant global mortality rates associated with cancer. The effectiveness of PDT primarily relies on the quality of the photosensitizers employed. When exposed to appropriate light irradiation, these photosensitizers absorb energy and transition to an excited state, eventually transferring energy to nearby molecules and generating Reactive Oxygen Species (ROS), including singlet oxygen [1O2]. The ability to absorb light in visible and nearinfrared wavelengths makes porphyrins and derivatives useful photosensitizers for PDT. Chemically, Porphyrins, composed of tetra-pyrrole structures connected by four methylene groups, represent the typical photosensitizers. The limited water solubility and bio-stability of porphyrin photosensitizers and their non-specific tumor-targeting properties hinder PDT effectiveness and clinical applications. Therefore, a wide range of modification and functionalization techniques have been used to maximize PDT efficiency and develop multidimensional porphyrin-based functional materials. Recent progress in porphyrin-based functional materials has been investigated in this review paper, focusing on two main aspects including the development of porphyrinic amphiphiles that improve water solubility and biocompatibility, and the design of porphyrin-based polymers, including block copolymers with covalent bonds and supramolecular polymers with noncovalent bonds, which provide versatile platforms for PDT applications. The development of porphyrin-based functional materials will allow researchers to significantly expand PDT applications for cancer therapy by opening up new opportunities. With these innovations, porphyrins will overcome their limitations and push PDT to the forefront of cancer treatment options.

Wireless Light‐Emitting Diode‐Driven Functional Microneedle Devices for Skin Cancer Therapy

AbstractPhotodynamic therapy, a noninvasive cancer treatment strategy, is a promising remedy for malignant skin cancers. However, treatment of skin cancer with this method requires sufficient photosensitizer molecules to permeate into cancer cells before illumination for effective activation to induce potent reactive oxygen species for eliminating cancer cells. However, transdermal drug delivery using conventional photosensitizers faces major challenges due to skin barriers, diminishing the effectiveness of drug penetration and therapeutic efficacies. To overcome these limitations, biocompatible, physiologically dissolvable, and optically activatable functional microneedle devices are applied for effective percutaneous penetration of drug molecules into solid tumors in a murine model. The proposed wireless light‐emitting diode light‐driven functional microneedle device that effectively induces apoptosis of cancer cells and disruption of the tumor area and can enhance in vitro, ex vivo, and in vivo drug‐delivery effectiveness for treating skin cancer. The design and strategy of the present functional microneedle devices can help shed light on future advanced cancer therapy.

Experimental and clinical combined photodynamic therapy for malignant and premalignant lesions using various types of radiation

The aim of the study was to present various types of radiation that can increase the effectiveness of combined photodynamic therapy (PDT) for malignant and premalignant lesions. Material and Methods. The Web of Science, Scopus, MedLine, Library, and RSCI databases were used for finding publications on this topic, mainly over the last 10 years. Of 230 sources, 64 were included in the review. Results. Photodynamic therapy is a new cancer treatment technology that has become increasingly popular in recent years. It is often an alternative method of treating cancer when there is a high risk of side effects and complications during traditional treatments such as surgery, radiation therapy and chemotherapy. PDT requires a photosensitizer, light energy, and oxygen to create reactive oxygen species that destroy cancer cells. This review examines the basic principles and mechanisms of PDT used alone and in combination with other traditional therapies. Despite the fact that PDT is an effective and non-invasive cancer treatment, it has some limitations, such as low light penetration depth, ineffective photosensitizers and tumor hypoxia. Our study examines new strategies that use other energy sources, such as infrared- and x-rays, ultrasound, as well as electric and magnetic fields, to enhance the PDT effect and overcome its limitations. Great hopes are also associated with the use of a combination of PDT and neutron capture therapy (NСT). Currently, chlorin derivatives associated with boron carriers have been developed. They can be used for both fluorescence diagnostics and PDT, as well as for NСT. The synthesized compounds have a high selectivity of accumulation in the tumor. To date, encouraging preclinical results of high efficiency of combined use of NСT and PDT have already been obtained. Conclusion. Combination with various energy sources is a key factor for further development of PDT. Future research aimed at overcoming the limitations of PDT will contribute to unlocking the full potential of this technology in clinical practice.

A review of sonodynamic therapy for brain tumors.

Sonodynamic therapy (SDT) is gaining attention as a promising new noninvasive brain tumor treatment that targets and selectively kills tumor cells, with limited side effects. This review examines the mechanisms of SDT and ongoing clinical trials looking at optimization of sonication parameters for potential treatment of glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). The results in the first patient with recurrent GBM treated at the Mayo Clinic are briefly discussed. The authors of this literature review used electronic databases including PubMed, EMBASE, and OVID. Articles reporting relevant preclinical and clinical trials were identified by searching for text words/phrases and MeSH terms, including the following: "sonodynamic therapy," "SDT," "focused ultrasound," "5-ALA," "ALA," "brain tumors," "diffuse pontine glioma," "glioblastoma," and "high grade glioma." Preclinical and clinical trials investigating the specific use of SDT in brain tumors were reviewed. In preclinical models of high-grade glioma and GBM, SDT has shown evidence of targeted tumor cell death via the production of reactive oxygen species. Emerging clinical trial results within recurrent GBM and DIPG show evidence of successful treatment response, with minimal side effects experienced by recruited patients. So far, SDT has been shown to be a promising noninvasive cancer treatment that is well tolerated by patients. The authors present pilot data suggesting good radiological response of GBM to a single SDT treatment, with unpublished observation of a lack of off-target effects even after multiple (monthly) sonication outpatient treatments. The scope of the clinical trials of SDT is to investigate whether it can be the means by which the fatal diagnosis of GBM or DIPG is converted into that of a chronic, treatable disease. SDT is safe, repeatable, and better tolerated than both chemotherapy and radiotherapy. It has been shown to have an effect in human cancer therapy, but more clinical trials are needed to establish standardized protocols for sonosensitizer delivery, treatment parameters, and combination therapies. The most appropriate timing of treatment also remains to be determined-whether to prevent recurrence in the postoperative period, or as a salvage option in patients with recurrent GBM for which redo surgery is inappropriate. It is hoped that SDT will also be developed for a wider spectrum of clinical indications, such as metastases, meningioma, and low-grade glioma. Further clinical trials are in preparation.

Donor-Acceptor-Donor Strategy Rouses the Photodynamic Therapy Anticancer Activity of a Bis-terpyridyl Ru(II) Complex.

Photodynamic therapy has been regarded as a noninvasive treatment for cancer with spatiotemporal control over drug activation. Bis-terpyridyl Ru(II) complexes exhibit a promising achiral structure but suffer from low photoreactivity due to deviation from the ideal octahedral geometry. Herein, we introduce the donor-acceptor-donor motif to construct a dinuclear bis-terpyridyl Ru(II) complex (Ru2). Ru2 exhibits superior light absorption properties compared with mononuclear complex Ru1. Importantly, upon 595 nm light excitation, Ru2 shows promising synergetic type I/II photosensitization and photocatalytic activity, while Ru1 is inactive. Anticancer mechanistic studies reflect that Ru2 induces intracellular redox imbalance and affects the biosynthetic and metabolic processes, leading to cell apoptosis. Overall, this work provides a simple strategy to rouse the PDT efficiency of bis-terpyridyl Ru(II) complexes.

Peptide-IR820 Conjugate: A Promising Strategy for Efficient Vascular Disruption and Hypoxia Induction in Melanoma.

Photothermal therapy (PTT) has emerged as a noninvasive and precise cancer treatment modality known for its high selectivity and lack of drug resistance. However, the clinical translation of many PTT agents is hindered by the limited biodegradability of inorganic nanoparticles and the instability of organic dyes. In this study, a peptide conjugate, IR820-Cys-Trp-Glu-Trp-Thr-Trp-Tyr (IR820-C), was designed to self-assemble into nanoparticles for both potent PTT and vascular disruption in melanoma treatment. When co-assembled with the poorly soluble vascular disrupting agent (VDA) combretastatin A4 (CA4), the resulting nanoparticles (IR820-C@CA4 NPs) accumulate efficiently in tumors, activate systemic antitumor immune responses, and effectively ablate melanoma with a single treatment and near-infrared irradiation, as confirmed by our in vivo experiments. Furthermore, by exploiting the resulting tumor hypoxia, we subsequently administered the hypoxia-activated prodrug tirapazamine (TPZ) to capitalize on the created microenvironment, thereby boosting therapeutic efficacy and antimetastatic potential. This study showcases the potential of short-peptide-based nanocarriers for the design and development of stable and efficient photothermal platforms. The multifaceted therapeutic strategy, which merges photothermal ablation with vascular disruption and hypoxia-activated chemotherapy, holds great promise for advancing the efficacy and scope of cancer treatment modalities.

Effectiveness and Patient Experiences of Rhenium Skin Cancer Therapy for Nonmelanoma Skin Cancer: Interim Results from the EPIC-Skin Study.

Nonmelanoma skin cancer and its treatment represent a significant global cancer burden for health care systems and patients. Rhenium skin cancer therapy (Rhenium SCT) is a novel noninvasive radionuclide nonmelanoma skin cancer treatment, which can be provided in a single outpatient session. The aim of this prospective, multicenter, single-arm, international, phase IV study (EPIC-Skin) is to assess clinic- and patient-reported outcomes of Rhenium SCT as a treatment for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Methods: Eligible patients had biopsy-proven stage I or stage II BCC or SCC lesions no more than 3 mm deep and no larger than 8 cm2 in area. Rhenium SCT resin was applied to an adhesive foil affixed to the target lesion in a single session. Interim efficacy and safety analysis were planned once 50% of target patients had recorded a 6-mo follow-up visit. Primary outcome is the proportion of lesions achieving complete response using modified RECIST. Secondary and other outcome measures include patient-reported quality of life (QoL), treatment comfort, and cosmesis. Results: A total of 182 patients was enrolled and administered Rhenium SCT (50 Gy dose to deepest point of target) to at least 1 BCC or SCC. Of 81 patients who reached the 6-mo posttreatment follow-up, it was found that 97.2% (103/106) of lesions showed complete responses and 2.8% (3/106) had partial responses. Improvements in QoL were also reported, whereas no patients reported any pain or discomfort during treatment. Adverse events were reported in 15.9% (29/182) of patients and were rated grade 1 (n = 19), grade 2 (n = 9), or grade 3 (n = 1). Conclusion: This preliminary analysis of the EPIC-Skin study indicates that Rhenium SCT is safe and effective for the treatment of BCC and SCC and is associated with significant QoL improvements. It will be particularly beneficial for lesions that are difficult to treat surgically because of size and location. It is also beneficial for patients with comorbidities or those unable to receive conventional fractionated radiotherapy.

Cimicifugoside H-2 as an Inhibitor of IKK1/Alpha: A Molecular Docking and Dynamic Simulation Study.

One of the most challenging issues scientists face is finding a suitable non-invasive treatment for cancer, as it is widespread around the world. The efficacy of phytochemicals that target oncogenic pathways appears to be quite promising and has gained attention over the past few years. We investigated the effect of docking phytochemicals isolated from the rhizomes of the Cimicifuga foetida plant on different domains of the IκB kinase alpha (IKK1/alpha) protein. The Cimicifugoside H-2 phytochemical registered a high docking score on the activation loop of IKK1/alpha amongst the other phytochemicals compared to the positive control. The interaction of the protein with Cimicifugoside H-2 was mostly stabilized by hydrogen bonds and hydrophobic interactions. A dynamic simulation was then performed with the Cimicifugoside H-2 phytochemical on the activation loop of IKK1/alpha, revealing that Cimicifugoside H-2 is a possible inhibitor of this protein. The pharmacokinetic properties of the drug were also examined to assess the safety of administering the drug. Therefore, in this in silico study, we discovered that the Cimicifugoside H-2 phytochemical inhibits the actively mutated conformation of IKK1/alpha, potentially suppressing the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway.

Reactive oxygen species responsive chitooligosaccharides based nanoplatform for sonodynamic therapy in mammary cancer

Sonodynamic therapy (SDT) has been extensively studied as a new type of non-invasive treatment for mammary cancer. However, the poor water solubility and defective biocompatibility of sonosensitizers during SDT hinder the sonodynamic efficacy. Herein, a nanoplatform has been developed to achieve high efficient SDT against mammary cancer through the host-guest interaction of β-cyclodextrin/5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (β-CD-TPP) and ferrocenecarboxylic acid/chitooligosaccharides (FC-COS). Moreover, the glucose oxidase (GOx) was loaded through electrostatic adsorption, which efficiently restricts the energy supply in tumor tissues, thus enhancing the therapeutic efficacy of SDT for tumors. Under optimal conditions, the entire system exhibited favorable water solubility, suitable particle size and viable biocompatibility. This facilitated the integration of the characteristics of starvation therapy and sonodynamic therapy, resulting in efficient inhibition of tumor growth with minimal side effects in vivo. This work may provide new insights into the application of natural oligosaccharides for construct multifunctional nanocarrier systems, which could optimize the design and development of sonodynamic therapy strategies and even combination therapy strategies.

Self-assembled IR dye/mitoxantrone loaded Porphysomes nanosystem for enhanced combinatorial chemo-photothermal cancer therapy

Chemo-photothermal therapy (PTT) is an emerging non-invasive cancer treatment modality. Light-responsive porphysomes (DPP IR Mtx @Lipo NPs) nanosystems ablate breast cancer cells upon oxidative stress and hyperthermia. The unique self-assembled porphysomes were formed spherical shape in the size range of 150 ± 30 nm formed by the co-assembly of porphyrins along with IR 775 and chemotherapeutic drug, Mitoxantrone (Mtx), forming a camouflaged nanosystem (DPP IR Mtx @Lipo NPs, porphysomes). The advent of the prepared porphysomes aids in proper tuning of NIR absorbance improving singlet oxygen species generation among other anticancer drugs. The eminent release of DPP and adjuvant chemo-drug, Mitoxantrone from the self-assembled porphysomes is triggered by IR 775, a NIR photosensitizer upon laser irradiation. These multifunctional DPP IR Mtx @Lipo NPs have an efficient photothermal conversion efficiency of 65.8% as well as bioimaging properties. In-vitro studies in 2D and 3D models showed a significant cell death of 4T1 cells via the apoptotic pathway when irradiated with NIR laser, causing minimal damage to nearby healthy cells. DPP IR Mtx @Lipo NPs exhibited commingled PDT/PTT interdependent via NIR laser exposure, leading to mitochondrial disruption. Interestingly, the transient transfection using p53-GFP in cancer cells followed by DPP IR Mtx @Lipo NPs treatment causes rapid cell death. The activation of p53-dependent apoptosis pathways was vividly expressed, evidenced by the upregulation of Bax and increased pattern of Caspase-3 cleavage. This effect was pronounced upon transfection and induction with DPP IR Mtx @Lipo NPs, particularly in comparison to non-transfected malignant breast cancer 4T1 cells.

A “Transformers”‐like nanochain for precise navigation and efficient cancer treatment

AbstractIntegrated multimodal imaging in theranostics nanomaterials offers extensive prospects for precise and noninvasive cancer treatment. Precisely controlling the structural evolution of plasmonic nanoparticles is crucial in the development of photothermal agents. However, previous successes have been limited to static assemblies and single‐component structures. Here, an activatable plasmonic theranostics system utilizing self‐assembled 1D silver‐coated gold nanochains (1D nanochains) is presented for precise tumor diagnosis and effective treatment. The absorbance of the adaptable core–shell chain structure can shift from visible to near‐infrared (NIR) regions due to the fusion between nearby Au@Ag nanoparticles induced by elevated H2O2 levels in the tumor microenvironment (TME), resulting in the creation of a novel 3D aggregates with strong NIR absorption. With a high photothermal conversion efficiency of 60.2% at 808 nm, nanochains utilizing the TME‐activated characteristics show remarkable qualities for photoacoustic imaging and significantly limit tumor growth in vivo. This study may pave the way for precise tumor diagnosis and treatment through customizable, optically tunable adaptive plasmonic nanostructures.

Bacteria-driven nanosonosensitizer delivery system for enhanced breast cancer treatment through sonodynamic therapy-induced immunogenic cell death

BackgroundSonodynamic therapy (SDT) has shown promise as a non-invasive cancer treatment due to its local effects and excellent tissue penetration. However, the limited accumulation of sonosensitizers at the tumor site hinders its therapeutic efficacy. Although nanosonosensitizers have improved local tumor accumulation through passive targeting via the enhanced permeability and retention effect (EPR), achieving sufficient accumulation and penetration into tumors remains challenging due to tumor heterogeneity and inaccurate targeting. Bacteria have become a promising biological carrier due to their unique characteristic of active targeting and deeper penetration into the tumor.MethodsIn this study, we developed nanosonosensitizers consisting of sonosensitizer, hematoporphyrin monomethyl ether (HMME), and perfluoro-n-pentane (PFP) loaded poly (lactic-co-glycolic) acid (PLGA) nanodroplets (HPNDs). These HPNDs were covalently conjugated onto the surface of Escherichia coli Nissle 1917 (EcN) using carbodiimine chemistry. EcN acted as an active targeting micromotor for efficient transportation of the nanosonosensitizers to the tumor site in triple-negative breast cancer (TNBC) treatment. Under ultrasound cavitation, the HPNDs were disrupted, releasing HMME and facilitating its uptakes by cancer cells. This process induced reactive oxygen species (ROS)-mediated cell apoptosis and immunogenic cell death (ICD) in vitro and in vivo.ResultsOur bacteria-driven nanosonosensitizer delivery system (HPNDs@EcN) achieved superior tumor localization of HMME in vivo compared to the group treated with only nanosonosensitizers. This enhanced local accumulation further improved the therapeutic effect of SDT induced-ICD therapeutic effect and inhibited tumor metastasis under ultrasound stimulation.ConclusionsOur research demonstrates the potential of this ultrasound-responsive bacteria-driven nanosonosensitizer delivery system for SDT in TNBC. The combination of targeted delivery using bacteria and nanosonosensitizer-based therapy holds promise for achieving improved treatment outcomes by enhancing local tumor accumulation and stimulating ICD.Graphical

Abstract 490: Significant anti-proliferative effects of targeted magnetoelectric nanoparticles as potential theragnostic tools

Abstract Although current electroporation therapies have been demonstrated to be effective not only in ablating tumor tissue, but also in eliciting an anti-tumor immune response, they are limited in their application due to the strong risk factors associated with the high voltages required. Current methods of interacting with the body’s electrical currents are limited to traditional electrodes, which cause damage to surrounding tissue upon insertion, and require high voltages to create responses at the cellular level. Recent efforts at non-invasive interaction with the body’s electric fields have led to the fabrication of magnetoelectric nanoparticles (MENPs), a novel technology which has the ability to convert harmless magnetic fields into strong local electric fields, all while maintaining a diameter of ~70nm. These particles have been demonstrated to trigger neuronal firing under magnetic stimulation both in vitro and in vivo, and have been able to release chemotherapeutic agents on command in vitro and in vivo. This demonstrates the ability for MENPs to wirelessly generate electric fields within the body on demand with high temporal and spatial resolution. This suggests the potential for non-invasive electroporation therapy which could be triggered by external magnetic fields. Given the particles are themselves magnetic, this could show potential as a theragnostic tool as their magnetic properties suggest they may act simultaneously as an MRI contrast and an ablative therapy. To explore this possibility, we fabricated MENPs consisting of a magnetostrictive CoFe2O4 spinel core coupled with a piezoelectric BaTiO3 perovskite shell. These particles were then PEGylated to reduce agglomeration which is typical of magnetic nanoparticles. 50ul of a 1mg/ml PEG-MENP dispersion was deposited into a cell culture of SKOV-3 ovarian cancer cells. These cells were then stimulated by 120 10ms pulses of a 2kOe magnetic field over the course of 30 minutes. An cell-titre glo ATP assay was performed to indicate viability 24 hours after treatment. Treatment wells were compared to controls of no intervention, magnetic stimulation with no particles, and particles with no stimulation. The combination of particles and magnetic stimulation was the only group which showed significant decreases in viability, with a 32% reduction in viability. Particles on their own showed no effect on cell viability, neither did magnetic-only stimulation. This preliminary investigation into the use of MENPs as a non-invasive cancer treatment has shown some potential. The ability to wirelessly activate the particles provides an inherent targeting mechanism not found in traditional chemotherapeutics, while the nanometer diameter provides a non-invasive method to generate strong electric fields within the body. Citation Format: Max Shotbolt, Elric Zhang, Emily Zhu, Wael El-Rifai, John Bryant, Ping Liang, Sakhrat Khizroev. Significant anti-proliferative effects of targeted magnetoelectric nanoparticles as potential theragnostic tools [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 490.

Abstract 2334: Computational methods for optimizing marker selection, clonal lineage reconstruction, and longitudinal tracking of clonal dynamics via circulating tumor DNA (ctDNA)

Abstract Background: Technologies for blood-based profiling of tumor DNA (“liquid biopsy”) have offered great prospects for non-invasive early cancer diagnosis, treatment monitoring, and clinical guidance, but further advances in computational models and data analysis to optimize monitoring protocols and develop liquid biopsy as a robust quantitative assay of tumor clonal evolution. Methods: We propose new computational methods to improve our ability to characterize tumor clonal dynamics from circulating tumor DNA (ctDNA). Our methods address how to apply ctDNA assays most effectively to two distinct questions in profiling tumor clonal dynamics: 1) How to apply longitudinal ctDNA data to refine phylogenetic tree models of clonal evolution, and 2) how to most effectively characterize changes in clonal frequencies that may be indicative of treatment response or tumor progression. We pose these questions computationally in terms of a probabilistic framework for optimally identifying maximum likelihood markers for the preceding tasks and applying measured marker concentrations to their solution. We apply this framework by first evaluating the distribution of plausible clonal lineage models using bootstrap samples over pre-treatment tissue-based genetic variation data, then refining these lineage models and the clonal frequencies we can infer from them over successive longitudinal samples of selected markers. Results: We tested our method on synthetic data under various model assumptions and showed the method to be effective at refining distribution tree models and clonal frequencies over longitudinal samples so as to minimize measures of tree distance relative to the ground truth. We further apply the methods to a real ovarian cancer case and show their ability to develop and refine a clonal lineage model and assess clonal frequencies. Conclusion: Our methods show the power of ctDNA assays in conjunction with computational optimization to lead to improved marker selection, clonal lineage reconstruction, and tracking of clonal dynamics, with potential for more precise and quantitative profiling of tumor progression enabling improved clinical decision-making. Citation Format: Xuecong Fu, Yueqian Deng, Zhicheng Luo, William Laframboise, David Bartlett, Russell Schwartz. Computational methods for optimizing marker selection, clonal lineage reconstruction, and longitudinal tracking of clonal dynamics via circulating tumor DNA (ctDNA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2334.