Tumor Therapy Research Articles

Two-dimensional MXene-based nano-prodrug for synergistic chemo-photothermal therapy on cancer treatment

In cancer treatment, although prodrugs have been developed to overcome obstacles such as undesirable pharmacokinetic performance and serious off-target toxicity of most chemotherapeutics, the combination of prodrugs with nanotechnology could be used to overcome the shortcomings of conventional prodrug strategies and facilitate more efficient drug delivery and accumulation of anticancer prodrugs at specific sites/tissues. Phototherapy is a method that uses near-infrared (NIR) light to achieve local and non-invasive tumor therapy. The combination of chemotherapy and phototherapy has shown many therapeutic advantages, including synergistic therapeutic effects and the reduction of toxic and side effects of drugs through dose reduction. In this work, a hydrazone linkage was reported to conjugate Ti3C2Tx MXene nanosheets with doxorubicin hydrochloride (DOX) and methoxy poly(ethylene glycol) benzaldehyde (mPEG-CHO) through a chemical surface modification to form a two-dimensional (2D) nano-prodrug Ti3C2Tx-DOX/PEG (TDP) for synergistic chemo-photothermal therapy. First, hydrazide functionalized Ti3C2Tx was obtained. Then, the carbonyl group of DOX and the aldehyde group of mPEG-CHO can form a pH-responsive hydrazone bond with hydrazide-functionalized Ti3C2Tx. The high surface area of Ti3C2Tx could overcome the reduced drug loading caused by conjugation. Aqueous stability and biocompatibility were enhanced by the introduction of PEG, making the material capable of prolonged circulation in the body’s bloodstream. By achieving excellent antitumor results with this nano-prodrug, we have added another brick to the edifice of Ti3C2Tx MXene as an anticancer drug carrier, and given new vitality to the study of anticancer prodrugs combined with nanotechnology.

Research Progress of Chitosan-based Multifunctional Nanoparticles in Cancer Targeted Therapy.

Conventional tumor therapeutic modalities, such as radiotherapy, chemotherapy, and surgery, involve low tumor inhibition efficiency, non-targeted drug delivery, and side effects. The development of novel and practical nano-drug delivery systems (DDSs) for targeted tumor therapy has become particularly important. Among various bioactive nanoparticles, chitosan is considered a suitable candidate for drug delivery due to its non-toxicity, good biocompatibility, and biodegradability. The amino and hydroxyl groups of chitosan endow it with the diverse function of chemical modification, thereby improving its physical and biological properties to meet the requirements of advanced biomedical applications. Therefore, it is necessary to review the property and applications of chitosan-based materials in biomedicine. In this review, the characteristics of chitosan related to its applications are first introduced, and then the preparation and modification of chitosan-based nanoparticles, including the function tailoring of chitosan-modified nanoparticles, are demonstrated and discussed. Finally, the opportunities and challenges of chitosan-based nanomaterials in this emerging field are proposed from the perspective of the rational and systematic design for the biomedicine field.

Tailored Covalent Organic Framework Platform: From Multistimuli, Targeted Dual Drug Delivery by Architecturally Engineering to Enhance Photothermal Tumor Therapy.

Engineering bulk covalent organic frameworks (COFs) to access specific morphological structures holds paramount significance in boosting their functions in cancer treatment; nevertheless, scant effort has been dedicated to exploring this realm. Herein, silica core-shell templates and multifunctional COF-based reticulated hollow nanospheres (HCOFs) are novelly designed as a versatile nanoplatform to investigate the simultaneous effect of dual-drug chemotherapy and photothermal ablation. Taking advantage of the distinct structural properties of the template, the resulting two-dimensional (2D) HCOF, featuring large internal voids and a peripheral interconnected mesoporous shell, presents intriguing benefits over its bulk counterparts for cancer treatment, including a well-defined morphology, an outstanding drug loading capability (99.6%) attributed to its ultrahigh surface area (2087 m2/g), great crystallinity, improved tumor accumulation, and an adjustable drug release profile. After being loaded with hydrophilic doxorubicin with a remarkable loading capacity, the obtained drug-loaded HCOFs were coated with gold nanoparticles (Au NPs) to confer them with three properties, including pore entrance blockage, active-targeting capability, and improved biocompatibility via secondary modification, besides high near infrared (NIR) absorption for efficient photothermal hyperthermia cancer suppression. The resultant structure was functionalized with mono-6-thio-β-cyclodextrin (β-CD) as a second pocket to load docetaxel as the hydrophobic anticancer agent (combination index = 0.33). The dual-drug-loaded HCOF displayed both pH- and near-infrared-responsive on-demand drug release. In vitro and in vivo evaluations unveiled the prominent synergistic performance of coloaded HCOF in cancer elimination upon NIR light irradiation. This work opens up a new avenue for exciting applications of structurally engineered HCOFs as hydrophobic/hydrophilic drug carriers as well as multimodal treatment agents.

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer.

Inhibitors of Apoptosis Proteins (IAP) are inhibitors that can block programmed cell death, are expressed at high levels in various cancers, and are recognized as a therapeutic target for cancer therapy. In the past few years, several small molecule IAP protein inhibitors have been designed to mimic the endogenous IAP antagonist, but no IAP inhibitors have been approved for marketing worldwide. Previously, xevinapant has been awarded a breakthrough therapy designation by the FDA. In addition, a combination of Smac-mimetics and chemotherapeutic compounds has been reported to improve anticancer efficacy. According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.

High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities. The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.

Pluronic-Based Nanoparticles for Delivery of Doxorubicin to the Tumor Microenvironment by Binding to Macrophages.

The active targeting drug delivery system based on special types of endogenous cells such as macrophages has emerged as a promising strategy for tumor therapy, owing to its tumor homing property and biocompatibility. In this work, the active tumor-targeting drug delivery system carrying doxorubicin-loaded nanoparticles (DOX@MPF127-MCP-1, DMPM) on macrophage (RAW264.7) surfaces via the mediation of interaction with the CCR2/MCP-1 axis was exploited. Initially, the amphiphilic block copolymer Pluronic F127 (PF127) was carboxylated to MPF127 at the hydroxyl terminus. Subsequently, MPF127 was modified with MCP-1 peptide to prepare MPF127-MCP-1 (MPM). The DOX was wrapped in MPM to form DMPM nanomicelles (approximately 100 nm) during the self-assembly process of MPM. The DMPM spontaneously bound to macrophages (RAW264.7), which resulted in the construction of an actively targeting delivery system (macrophage-DMPM, MA-DMPM) in vitro and in vivo. The DOX in MA-DMPM was released in the acidic tumor microenvironment (TME) in a pH-responsive manner to increase DOX accumulation and enhance the tumor treatment effect. The ratio of MA-DMPM homing reached 220% in vitro compared with the control group, indicating that the MA-DMPM was excellently capable of tumor-targeting delivery. In in vivo experiments, nonsmall cell lung cancer cell (NCI-H1299) tumor models were established. The results of the fluorescence imaging system (IVIS) showed that MA-DMPM demonstrated tremendous tumor-targeting ability in vivo. The antitumor effects of MA-DMPM in vivo indicated that the proportion of tumor cell apoptosis in the DMPM-treated group was 63.33%. The findings of the tumor-bearing mouse experiment proved that MA-DMPM significantly suppressed tumor cell growth, which confirmed its immense potential and promising applications in tumor therapy.

Sorafenib sensitization in tumor therapy by iron overload and AMPK activation

Sorafenib sensitization in tumor therapy by iron overload and AMPK activation

Liquid exfoliation of molybdenum metallenes for non-inflammatory photothermal therapy of tumors.

Tissue damage and cell death occurring during photothermal therapy (PTT) for tumors can induce an inflammatory response that is detrimental to tumor therapy. Herein, ultrathin Mo metallene nanosheets with a thickness of <5 nm prepared by liquid phase exfoliation were explored as functional hyperthermia agents for non-inflammatory ablation of tumors. The obtained Mo metallene nanosheets exhibited good photothermal conversion properties and significant reactive oxygen species (ROS) scavenging ability, thus achieving superior cancer cell ablation and anti-inflammatory effects in vitro. For in vivo experiments, 4T1 tumors were ablated while the inflammation-related cytokine levels did not obviously increase, demonstrating that the inflammatory response induced by PTT was inhibited by the anti-inflammatory properties of Mo metallene nanosheets. Moreover, Mo metallene nanosheets depicted good dispersibility and biocompatibility, beneficial for biomedical applications. This work introduces Mo metallenes as promising hyperthermia agents for non-inflammatory PTT of tumors.

ATP Inhibition for Starvation/Mild Photothermal/Photodynamic Synergy Therapy Using Polypeptide Nanoparticles Conjugating 2-Deoxy-D-Glucose and Dye under NIR Phototheranostic Strategy.

Rapid propagation of tumor cells requires plenty of energy, which is adenosine triphosphate (ATP) dependent. ATP inhibition in tumors not only results in the starvation of tumor cells but also down-regulation of the level of heat shock proteins (HSPs), which usually increase during traditional photothermal therapy (PTT), especially when the temperature is up 50°C. 2-deoxy-D-glucose (2DG) is an anti-glycolytic reagent and can be used as an efficient agent for ATP inhibition in tumors. Compared with typical PTT, low-temperature mild photothermal therapy (MPTT) is receiving more and more attention due to it avoiding the high temperatures causing damage to the normal tissue, and the increase of HSPs which decrease PTT. Here, we have prepared multifunctional polypeptide nanoparticles pDG@Ahx conjugating both a NIR probe Ahx-BDP and 2DG into the side chain of the amphiphilic polypeptide. In vitro and in vivo studies reveal that the as-prepared nanoparticles achieve a synergistic effect of starvation/MPTT/PDT (photodynamic therapy), and it provides a new strategy to NIR-I/II fluorescence imaging-guided starvation/MPTT/PDT synergy therapy for tumors. This article is protected by copyright. All rights reserved.

Nanomedical Sonocatalyst Tailored for Enhanced Hypoxic Tumor Therapy Based on Crystal Facet Engineering Strategy

Nanomedical Sonocatalyst Tailored for Enhanced Hypoxic Tumor Therapy Based on Crystal Facet Engineering Strategy

Steering Piezocatalytic Therapy for Optimized Tumoricidal Effect

AbstractPiezocatalysts, because of their mechano‐electrical conversion properties, are exploited for various medical applications, such as sterilization, tissue engineering, biosensing, and disease theranostics. In particular, based on the unique advantage of the piezoelectric effect, piezocatalytic therapy (PCT) has been developed as a novel and promising candidate for tumor therapy. To optimize the utilization of piezocatalysts in tumor therapy, a comprehensive understanding of the antitumor mechanism associated with these materials is imperative. Here, the piezocatalytic action principle is elucidated by investigating piezocatalysts, reactants, energy inputs, and products. Subsequently, the antitumor mechanisms of PCT have been extensively discussed and are recapitulative as follows: restraining cell proliferation, inducing cell programmed death, hindering tumor metastasis, inhibiting tumor angiogenesis, and enhancing antitumor immunity. Additionally, the optimized therapeutic outcomes of PCT‐centric synergistic cancer therapy are systematically described. Finally, the main challenges and future research directions of piezocatalysis applied in cancer therapy are envisioned. It is believed that PCT will serve as a new‐generation ingenious tool for cancer treatment.

Assessment of thermal damage for plasmonic photothermal therapy of subsurface tumors.

Plasmonic photothermal therapy (PPTT) involves the use of nanoparticles and near-infrared radiation to attain a temperature above 50°C within the tumor for its thermal damage. PPTT is largely explored for superficial tumors, and its potential to treat deeper subsurface tumors is dealt feebly, requiring the assessment of thermal damage for such tumors. In this paper, the extent of thermal damage is numerically analyzed for PPTT of invasive ductal carcinoma (IDC) situated at 3-9mm depths. The developed numerical model is validated with suitable tissue-tumor mimicking phantoms. Tumor (IDC) embedded with gold nanorods (GNRs) is subjected to broadband near-infrared radiation. The effect of various GNRs concentrations and their spatial distributions [viz. uniform distribution, intravenous delivery (peripheral distribution) and intratumoral delivery (localized distribution)] are investigated for thermal damage for subsurface tumors situated at various depths. Results show that lower GNRs concentrations lead to more uniform internal heat generation, eventually resulting in uniform temperature rise. Also, the peripheral distribution of nanoparticles provides a more uniform spatial temperature rise within the tumor. Overall, it is concluded that PPTT has potential to induce thermal damage for subsurface tumors, at depths of upto 9mm, by proper choice of nanoparticle distribution, dose/concentration and irradiation parameters based on the tumor location. Moreover, intravenous administration of nanoparticles seems a good choice for shallower tumors, while for deeper tumors, uniform distribution is required to attain the necessary thermal damage. In the future, the algorithm may be extended further, involving 3D patient-specific tumors and through mice model-based experiments.

Can magnetic nanoparticles enhance adoptive cell therapy via driving migration of lymphocytes into tumors?

Therapy of malignant tumors still represents a huge problem for healthcare, since these diseases lead to a high rate of disability and premature death of the population. The main problems of adoptive cell therapy for malignant tumors are a low rate of migration of effector lymphocytes into tumors, as well as their low activity in tumors due to suppressive tumor microenvironment. In addition, it should be noted that systemic intravenous administration of a large number of activated lymphocytes may be accompanied by a pronounced cytokine release syndrome, which leads to significant negative side effects, including high temperature, blood clotting disorders, aggression of immune cells against their own tissues, even neurotoxicity. Functional nanomaterials, such as magnetic nanoparticles with various surface modifications (PEG, PEI, DMSA, citrate, etc.) are highly promising agents for targeted delivery of different anti-tumor substances. Magnet-driven enrichment of effector anti-tumor lymphocytes in tumors would highly increase the effectiveness and enhance safety of adoptive lymphocyte therapy. However, different research groups obtained opposing data about the feasibility and efficiency of such approach. Thus, this review is focused on experimental details of the contradicting studies and aims to elucidate the possible reasons of these controversies and the best practices to efficiently target lymphocytes into tumors.

Black Titania Janus Mesoporous Nanomotor for Enhanced Tumor Penetration and Near-Infrared Light-Triggered Photodynamic Therapy.

Thanks to their excellent photoelectric characteristics to generate cytotoxic reactive oxygen species (ROS) under the light-activation process, TiO2 nanomaterials have shown significant potential in photodynamic therapy (PDT) for solid tumors. Nevertheless, the limited penetration depth of TiO2-based photosensitizers and excitation sources (UV/visible light) for PDT remains a formidable challenge when confronted with complex tumor microenvironments (TMEs). Here, we present a H2O2-driven black TiO2 mesoporous nanomotor with near-infrared (NIR) light absorption capability and autonomous navigation ability, which effectively enhances solid tumor penetration in NIR light-triggered PDT. The nanomotor was rationally designed and fabricated based on the Janus mesoporous nanostructure, which consists of a NIR light-responsive black TiO2 nanosphere and an enzyme-modified periodic mesoporous organosilica (PMO) nanorod that wraps around the TiO2 nanosphere. The overexpressed H2O2 can drive the nanomotor in the TME under catalysis of catalase in the PMO domain. By precisely controlling the ratio of TiO2 and PMO compartments in the Janus nanostructure, TiO2&PMO nanomotors can achieve optimal self-propulsive directionality and velocity, enhancing cellular uptake and facilitating deep tumor penetration. Additionally, by the decomposition of endogenous H2O2 within solid tumors, these nanomotors can continuously supply oxygen to enable highly efficient ROS production under the NIR photocatalysis of black TiO2, leading to intensified PDT effects and effective tumor inhibition.

Interleukin-12 in multimodal tumor therapies for induction of anti-tumor immunity.

Interleukin-12 (IL-12) can be used as an immunomodulator in cancer immunotherapy. And it has demonstrated enormous potential in inhibiting tumor growth and improving the tumor microenvironment (TME) by several preclinical models. However, some disappointing results have showed in the early clinical trials when IL-12 used as a single agent for systemic cancer therapy. Combination therapy is an effective way to significantly fulfill the great potential of IL-12 as an immunomodulator. Here, we discuss the effects of IL-12 combined with traditional methods (chemotherapy, radiotherapy and surgery), targeted therapy or immunotherapy in the preclinical and clinical studies. Moreover, we summarized the potential mechanism underlying the anti-tumor effect of IL-12 in the combination strategies. And we also discussed the delivery methods and tumor-targeted modification of IL-12 and outlines future prospects for IL-12 as an immunomodulator.

Research progress of ZIC5 for tumor metastasis.

The zinc finger protein of the cerebellum (ZIC) family comprises five members (ZIC1-5), homologous with the odd-paired (OPA) gene in Drosophila melanogila. These transcription factors contain five Cys2His zinc finger domains, constituting one of the most abundant transcription factor families in human cells. ZIC proteins significantly contribute to transcriptional regulation and chromatin remodeling. As a member of the ZIC family, ZIC5 is essential for animal growth and development. Numerous studies have investigated the connection between ZIC proteins and cancer as well as tumor metastases in recent years. Many studies have found that within tumor tissues, the transcription and translation processes increase the expression of ZIC5 which is linked to tumor aggressiveness. This review aims to provide an objective summary of the impact of ZIC5 on tumor metastasis and consider the potential application of ZIC5 targets in both tumor therapy and the early detection of cancer.

Bridging OER Electrocatalysis and Tumor Therapy: Utilizing Piezoelectric‐Hole‐Induced OER Electrocatalysis for Direct Oxygen Generation to Address Hypoxia

AbstractIn addressing the challenge of hypoxia within the tumor microenvironment (TME), a significant obstacle to effective cancer therapy, this research introduces a pioneering nanozyme engineered to utilize water and oxygen as reactants. Utilizing ultrasonic piezoelectricity, this nanozyme converts these substrates into oxygen (O2) and reactive oxygen species, thereby amplifying oxidative stress without relying on endogenous H2O2. This approach involves the strategic engineering of porous ZnSnOv:Mn nanosheets (named MZSO NSs), which are distinguished by oxygen‐rich vacancies and enhanced piezoelectric properties. This breakthrough represents the initial attempt to merge catalytic activities akin to catalase (CAT) with the electrocatalytic oxygen evolution reaction (OER), confirmed through both enzymatic reactions and electrochemical voltammetric analysis. The predominant mechanism of ultrasound‐augmented oxygen generation in MZSO is identified as piezoelectric hole‐induced OER. Supporting theoretical analyses clarify the synergistic impact of oxygen vacancies and Mn doping on the dynamics of carriers and the OER process, leading to a notable increase in catalytic efficiency. These findings highlight the potential of piezoelectric‐enhanced OER electrocatalysts to alleviate hypoxia in the TME, providing novel insights into the development of piezoelectric acoustic sensitizers for the treatment of cancer.

CAR T Cell Membrane Camouflaged Nanocatalyst Augments CAR T Cell Therapy Efficacy Against Solid Tumor.

The immunosuppressive tumor microenvironment (TME) reduces the chimeric antigen receptor (CAR) T-cell therapy against solid tumors. Here, a CAR T cell membrane-camouflaged nanocatalyst (ACSP@TCM) is prepared to augment CAR T cell therapy efficacy against solid tumors. ACSP@TCM is prepared by encapsulating core/shell Au/Cu2- xSe and 3-bromopyruvate with a CAR T cell membrane. It is demonstrated that the CAR T cell membrane camouflaging has much better-targeting effect than the homologous tumors cell membrane camouflaging. ACSP@TCM has an appealing synergistic chemodynamic/photothermal therapy (CDT/PTT) effect that can induce the immunogenic cell death (ICD) of NALM 6 cells. Moreover, 3-bromopyruvate can inhibit the efflux of lactic acid by inhibiting the glycolysis process, regulating the acidity of TME, and providing a more favorable environment for the survival of CAR T cells. In addition, the photoacoustic (PA) imaging and computed tomography (CT) imaging performance can guide the ACSP@TCM-mediated tumor therapy. The results demonstrated that the ACSP@TCM significantly enhanced the CAR T cell therapy efficacy against NALM 6 solid tumor mass, and completely eliminated tumors. This work provides an effective tumor strategy for CAR T cell therapy in solid tumors.

Tumor Microenvironment-Activatable Phototheranostic: Leveraging Nitric Oxide and Weak Acidity as Dual Biomarkers for Ratiometric Fluorescence, Photoacoustic Imaging, and Photothermal Therapy.

Tumor microenvironment-responsive phototheranostic agents are highly sought after for their ability to improve diagnostic accuracy and treatment specificity. Here, we introduce a novel single-molecule probe, POZ-NO, which is activated by nitric oxide (NO) and weak acidity, enabling dual-mode imaging and photothermal therapy (PTT) of tumors. In acidic environments with elevated NO levels, POZ-NO exhibits a distinctive ratiometric fluorescence signal shift from the red to near-infrared, accompanied by a 700 nm photoacoustic signal. Additionally, POZ-NO demonstrated potent photothermal effects upon NO and acidity activation, achieving an impressive conversion efficiency of 74.3% under 735 nm laser irradiation. In vivo studies confirm POZ-NO's ability to accurately image tumors through ratiometric fluorescence and photoacoustic modes while selectively treating tumors with PTT.

Safety and efficacy of peptide receptor radionuclide therapy in neuroendocrine tumors: A single center experience.

Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3-20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.