Normal Organs Research Articles

Essentials of Theranostics: A Guide for Physicians and Medical Physicists.

Radiopharmaceutical therapies (RPTs) are gaining increased interest with the recent emergence of novel safe and effective theranostic agents, improving outcomes for thousands of patients. The term theranostics refers to the use of diagnostic and therapeutic agents that share the same molecular target; a major step toward precision medicine, especially for oncologic applications. The authors dissect the fundamentals of theranostics in nuclear medicine. First, they explain the radioactive decay schemes and the characteristics of emitted electromagnetic radiation used for imaging, as well as particles used for therapeutic purposes, followed by the interaction of the different types of radiation with tissue. These concepts directly apply to clinical RPTs and play a major role in the efficacy and toxicity profile of different radiopharmaceutical agents. Personalized dosimetry is a powerful tool that can help estimate patient-specific absorbed doses, in tumors as well as normal organs. Dosimetry in RPT is an area of active investigation, as most of what we know about the relationship between delivered dose and tissue damage is extrapolated from external-beam radiation therapy; more research is needed to understand this relationship as it pertains to RPTs. Tumor heterogeneity is increasingly recognized as an important prognostic factor. Novel molecular imaging agents, often in combination with fluorine 18-fluorodeoxyglucose, are crucial for assessment of target expression in the tumor and potential hypermetabolic disease that may lack the molecular target expression. ©RSNA, 2023 Test Your Knowledge questions are available in the supplemental material.

Motion Management: The Road Map to Accurate Radiation Treatment Delivery

Radiation therapy is a key contributor to positive outcomes in hematological malignancies. However, this is contingent on minimizing the exposure of critical normal organs. The introduction of computed tomography (CT) for radiation treatment planning and the development of sophisticated dose calculation algorithms has transformed the radiation therapy field and made it possible to transition from conventional involved-field radiation to modern involved-site radiation therapy. Thanks to rapid advances in drug discovery, treatment strategies for many hematological malignancies have evolved to incorporate targeted and cellular therapies, in some cases even allowing the replacement of chemotherapy. As a result, new opportunities have been created for radiation to address relapses after more lines of therapy, identify disease-involving sanctuary sites, and bridge to the subsequent therapy. When considering radiation in patients receiving novel therapies, who may also be more heavily pretreated, respecting the critical and normal structures at all costs is imperative. In this document, we will describe modern techniques used to deliver state-of-the-art radiation therapy and practical considerations to ensure the accurate treatment of the target while avoiding normal organs at risk.

ATP-responsive copper(II)-doped ZIF-nanoparticles for synergistic cancer therapy: combining cuproptosis and chemo/chemodynamic therapy.

Cancer, a pressing global health challenge, is characterized by its rapid onset and high mortality rates. Conventional treatment methods prove insufficient in achieving the desired therapeutic outcomes, underscoring the critical need to identify an effective and safe approach for cancer treatment. In this study, a copper-doped nanoparticle known as Cu2+-DOX@ZIF-90 is designed by incorporating copper(II) (Cu(II)) and encapsulating doxorubicin (DOX) within ZIF-90. Leveraging the elevated ATP levels in cancer cells relative to normal cells, Cu2+-DOX@ZIF-90 undergoes intracellular degradation, leading to the release of DOX and Cu(II). DOX, a traditional chemotherapy drug for clinical use, induces apoptosis in cancer cells. Cu(II) interacts with glutathione (GSH) to generate Cu(I), catalyzing H2O2 to produce ˙OH, thereby prompting apoptosis in cancer cells. Concurrently, the reduction of GSH enhances the therapeutic effect of chemodynamic therapy (CDT). Furthermore, Cu(II) triggers the aggregation of lipoylated mitochondrial proteins, leading to the formation of DLAT oligomers and ultimately promoting cuproptosis in cancer cells. In vivo experimental findings demonstrate that Cu2+-DOX@ZIF-90 does not cause damage to normal tissues and organs in tumor-bearing mice, with a notable tumor inhibition rate of 86.18%. This synergistic approach, combining chemotherapy, CDT, and cuproptosis, holds significant promise for the effective and safe treatment of cancer.

Lymphatic and Blood Vessels in Normal Rhesus Monkey Organs by Immunohistochemical Staining with Frozen Sections: Structure and Function Relationship

Lymphatic and Blood Vessels in Normal Rhesus Monkey Organs by Immunohistochemical Staining with Frozen Sections: Structure and Function Relationship

Peptide L13S Derived from the BRN2 POU Domain Reduces Metastasis In Vivo and Inhibits Cell Migration and Invasion In Vitro.

The Brain-Specific Homeobox/POU Domain Protein 2 (BRN2) transcription factor supports melanoma progression by regulating the expression of several genes involved in cell migration and invasion. We hypothesized that a peptide designed based on the POU domain of BRN2 could block the BRN2 transcription activity and, consequently, reduce metastasis. Cell viability was accessed by Trypan Blue exclusion dye assay and xCelligence platform. Wound-healing scratch assay and transwell invasion with matrigel membrane assay were performed to analyze cell migration and invasion. The internalization mechanism of the L13S peptide was investigated using confocal microscopy and wound-healing scratch assay. The impact of L13S on cell protein expression was analyzed through western blotting. In vivo assays were conducted to evaluate the protective effect and toxicity of L13S in a metastatic model using murine melanoma cells. Here, we show that the peptide named L13S can inhibit the migration and invasion of murine melanoma cells (B16F10-Nex2) as well as the migration of human melanoma cells (SK-MEL-25 and A375) by regulating the expression of proteins involved in motility. Mechanistically, we found that L13S is internalized by murine melanoma cells via macropinocytosis and binds actin filaments and nuclei. More importantly, in vivo studies indicated that the peptide was able to significantly inhibit lung metastasis in syngeneic models without off-target effects and with virtually no cytotoxicity toward normal organs. L13S peptide is a strong candidate for further development as an anticancer agent for the treatment of melanoma metastasis.

Application of High Molecular Hydrogel in The Treatment of Myocardial Infarction

Myocardial infarction (MI) is the world's leading disabling and fatal disease. Currently, clinical treatment methods mainly include drug therapy, angioplasty, and coronary artery bypass grafting. These traditional treatment methods are difficult to repair damaged myocardial tissue and cannot restore normal necrotic and fibrotic myocardium. Therefore, it is imperative to improve the efficacy of traditional treatment methods and find new treatment strategies. More and more studies have found that stem cell transplantation can repair damaged myocardium, but stem cells transplanted to the affected site undergo oxidative damage, compression loss, and low cell survival and retention rates. At present, there is an urgent need to seek new methods that can effectively repair damaged myocardium and restore cardiac function. In recent years, with the development of regenerative medicine engineering and the continuous optimization of polymer technology and the development of new biomaterials, it has become a reality to create lost or functionally damaged tissues and organs through theoretical methods of biology and engineering, enabling them to have the structure and function of normal tissues and organs. This article will focus on the latest progress in methods for repairing damaged myocardium in myocardial infarction through polymer hydrogel materials.

Glutathione-Responsive Organosilica Hybrid Nanosystems for Targeted Dual-Starvation Therapy in Luminal Breast Cancer.

Starvation therapy is an innovative approach in cancer treatment aimed at depriving cancer cells of necessary resources by impeding tumor angiogenesis or blocking the energy supply. In addition to the commonly observed anaerobic glycolysis energy supply mode, adipocyte-rich tumor tissue triggers the fatty acid energy supply pathway, which fuels the proliferation and metastasis of cancer cells. To completely disrupt these dual-energy-supply pathways, we developed an exceptional nanoreactor. This nanoreactor consisted of yolk-shell mesoporous organosilica nanoparticles (YSMONs) loaded with a fatty acid transport inhibitor (Dox), conjugated with a luminal breast-cancer-specific targeting aptamer, and integrated with a glucose oxidation catalyst (GOx). Upon reaching cancer cells with the assistance of the aptamer, the nanoreactor underwent a structural collapse of the shell triggered by the high concentration of glutathione within cancer cells. This collapse led to the release of GOx and Dox, achieving targeted delivery and exhibiting significant efficacy in starving therapy. Additionally, the byproducts of glucose metabolism, gluconic acid and H2O2, enhanced the acidity and reactive oxygen species levels of the intracellular microenvironment, inducing oxidative damage to cancer cells. Simultaneously, released Dox acted as a potent broad-spectrum anticancer drug, inhibiting the activity of carnitine palmitoyltransferase 1A and exerting marked effects. Combining these effects ensures high anticancer efficiency, and the "dual-starvation" nanoreactor has the potential to establish a novel synergistic therapy paradigm with considerable clinical significance. Furthermore, this approach minimizes damage to normal organs, making it highly valuable in the field of cancer treatment.

Dosimetry Impact of Bladder Volume Changes and Rectum Filling/Emptying at Proton Therapy of Prostate Cancer; A Simulation Study

Purpose: In the recent decade, proton therapy facilities are increasing worldwide. This study aimed to analyze the influence of volumetric changes in bladder and rectum filling on the dose received by normal surrounding tissues at prostate cancer proton therapy. In this work, an anthropomorphic phantom dedicated to the prostate organs and nearby tissues has been developed using the FLUKA simulation code.
 Materials and Methods: The geometry of the prostate and normal nearby tissues, bladder volumetric changes, and rectum filling/emptying status were simulated according to a database of real patients to mimic actual treatment, assuming the prostate as the target receives the prescribed dose uniformly with no over- and under dosage at each treatment session. Furthermore, the dosimetric effect of air- and water-filled balloons as prostate fixation tools was considered on the rectum, during our simulation process.
 Results: Final analyzed results showed that the overall dose received by normal nearby organs with be decreased at proton therapy of prostate cancer if the bladder is full, although this dose reduction is not remarkable. Moreover, rectum filling/emptying and also implementation of balloons with different matters have no significant effect on the amount of dose received by this organ.
 Conclusion: The dosimetric impact of bladder volumetric variations onto normal nearby organs will not be a crucial issue in proton therapy of prostate cancer if the prescribed high dose is delivered on the target with proper uniformity laterally and in-depth. Based on the obtained results, a full bladder is recommended while target bombarding by a proton beam.

The anticancer mechanisms of exopolysaccharide from Weissella cibaria D-2 on colorectal cancer via apoptosis induction

Exopolysaccharide (EPS) from Weissella cibaria has been devoted to the study of food industry. However, the anticancer activity of W. cibaria derived EPS has not yet been investigated. In this study, we obtained the EPS from W. cibaria D-2 isolated from the feces of healthy infants and found that D-2-EPS, a homopolysaccharide with porous web like structure, could effectively inhibit the proliferation, migration, invasion and induce cell cycle arrest in G0/G1 phase of colorectal cancer (CRC) cells. In HT-29 tumor xenografts, D-2-EPS significantly retarded tumor growth without obvious cytotoxicity to normal organs. Furthermore, we revealed that D-2-EPS promoted the apoptosis of CRC cells by increasing the levels of Fas, FasL and activating Caspase-8/Caspase-3, indicating that D-2-EPS might induce apoptosis through the extrinsic Fas/FasL pathway. Taken together, the D-2-EPS has the potential to be developed as a nutraceutical or drug to prevent and treat colorectal cancer.

Interim Phase I Safety Study of Anti-Transferrin Receptor Antibody(PPMX-T003) in Patients with Polycythemia Vera

Background: Transferrin Receptor (TfR) 1 is thought to be anti-cancer target by controlling ion supply for decades. Anti-TfR1 fully human monoclonal antibody (PPMX-T003) has an uniqe epitope on the ligand-binding domain of TfR1. This antibody can efficiently inhibit iron influx into cells rather than preceding reported similar antibodies (US20220332838). This antibody can inhibit growth of erythroblast as well as various cancer cell lines at subnanomolar level, both cells are highly expressed TfR. Antibody administrated on normal cell expressing TfR at low levels has little effect except for RBC formation. Prior to apply cancer therapy, the safety was evaluated at low dose in healty volunteers (Ogama et al., 2023). In this study, we aimed to determine safety profiles at higher dose in patients with polycythemia vera (PV) by inhibiting elevation of erythropoiesis, followed by P1a study. Except for an antibody drug conjugate (CX-2029), this is the first-in-class trial of an unmodified human antibody other than the murine P1a trial conducted in the 1990s. Methods: This is a multicenter, open-label intra-patient dose escalation study (NCT05074550). Adults patients are eligible who were diagnosed with PV and had periodical phlebotomy (PLB) between 4 to 9 weeks. Patients were excluded if they had cytoreductive therapy. The primary objective is to evaluate the safety and the pharmacokinetics after single dose of administration. The secondary objective is pharmacodynamics, such as RBC count, hemoglobin, hematocrit. Dose escalation is an intra-patient dose escalation design, due to disease progression being individually different in each patient. Starting dose (0.25mg/kg) was determined as previous P1a trial in healty volunteers (n=40) observed decreased hemoglobin level out of normal value. A single dose of PPMX-T003 is intravenously infused for 1 hour, one day after a scheduled PLB. Dose is increased (0.25, 0.4, 0.64, 1mg/kg) when the next PLB treatment scheduled within 4 to 9 weeks, depending on the participants' adverse event (AE) profiles. The primary endpoint is the incidence and severity of treatment-related AEs, Key secondary end point meets next PLB does not required for more than 12 weeks. Results: As the data cutoff at the end of June 2023, all three cases did not require PLB for more than 12 weeks as reached endpoint. Two cases did not require PLB immediately after the first single dose of 0.25mg/kg. Both cases were observed no AE. Another patient was required periodical PLB within 4 to 9 weeks interval at two consecutive doses of 0.25-0.4mg/kg, then escalated up to the third dose of 0.64mg/kg till reached end point with mild AE, which was significant fatigue and mild fever, up to 37.6℃ within 24 hours after the highest dose of infusion, approximately 6.5 mg/dL CRP elevation after 3days after infusion, lymphopenia 2days after infusion recovered after 7 days. Those AEs are considered to be standard Infusion Related Reactions observed in other antibody therapeutics. Hematocrit and hemoglobin were controlled below 50% and 15.5g/dL, respectively, while RBC count are rather elevated up to 7 million/mL and MCV was down to 73 fL. Pharmacokinetics revealed half-life of the antibody was up to 12hrs, which is shorter than other antibody therapeutics. Enrollment is on going. Conclusions: AEs are mild as observed within the level of previous healthy volunteer's trial. Efficacy observed in all erythroid parameters including hematocrit, hemoglobin and other parameter shown symptoms seen in iron deficiency anemia. This antibody can specifically suppress erythrocyte differentiation by inhibiting iron influx in the target erythroid lineage, which cells are highly expressed TfR1, without any significant AE on other normal organs with low expression level of TfR. PPMX-T003 affects on erythrocyte differentiation in bone marrow may expect to reduce PLB treatment clinically. This preliminary result could be given helpful safety prospect recently initiated P1/2 trial in patients with aggressive NK leukemia (NCT05863234), supported by a grant from the Japan Agency for Medical Research and Development (23nk0101231j0002).

Multi-planner validation of RapidPlan knowledge-based model for volumetric modulated arc therapy in prostate cancer.

To investigate the performance of a model-based optimization process for volumetric modulated arc therapy (VMAT) applied to prostate cancer patients with the multi-planner. The 120 prostate plans for VMAT treatment were entered into the database system of the RapidPlan (RP) knowledge-based treatment planning. The treatment planning data for each plan was used to create and train the RP model. Twelve prostate cancer cases were selected and were used for planning by a manual of 12 planners based on the clinical protocol for dose constraints. Then, the treatment plans for each patient were compared with the RP model plans and analyzed with Wilcoxon tests. On average, the RP models can estimate comparable doses among all planner plans and clinical plans for the PTV, which Dmax , D95% , D98% , HI, and CI were used to evaluate. For the normal organ doses of the bladder, rectum, penile bulb, and femoral head, all RP model plans showed comparable or better dose sparing than all planner plans and clinical plans. Moreover, the average planning time of the RP model was faster than manual plans by about two times. The RP model can significantly reduce the variation dose of the normal organs compared with the manual plans among the planners. The automated plans of the RP model might benefit from further fine-tuning of the dose constraints of the normal organs, although both procedure plans are acceptable and fulfill the clinical protocol goals so that the RP model can enhance the efficacy and quality of plans.

Empowering Vision Transformer by Network Hyper-Parameter Selection for Whole Pelvis Prostate Planning Target Volume Auto-Segmentation

U-Net, based on a deep convolutional network (CNN), has been clinically used to auto-segment normal organs, while still being limited to the planning target volume (PTV) segmentation. This work aims to address the problems in two aspects: 1) apply one of the newest network architectures such as vision transformers other than the CNN-based networks, and 2) find an appropriate combination of network hyper-parameters with reference to recently proposed nnU-Net (“no-new-Net”). VT U-Net was adopted for auto-segmenting the whole pelvis prostate PTV as it consisted of fully transformer architecture. The upgraded version (v.2) applied the nnU-Net-like hyper-parameter optimizations, which did not fully cover the transformer-oriented hyper-parameters. Thus, we tried to find a suitable combination of two key hyper-parameters (patch size and embedded dimension) for 140 CT scans throughout 4-fold cross validation. The VT U-Net v.2 with hyper-parameter tuning yielded the highest dice similarity coefficient (DSC) of 82.5 and the lowest 95% Haussdorff distance (HD95) of 3.5 on average among the seven recently proposed deep learning networks. Importantly, the nnU-Net with hyper-parameter optimization achieved competitive performance, although this was based on the convolution layers. The network hyper-parameter tuning was demonstrated to be necessary even for the newly developed architecture of vision transformers.

Acid-triggered controlled release and fluorescence-switchable phthalocyanine nanoassemblies combined with O2-economizer for tumor imaging and collaborative photodynamic antitumor therapy

Photodynamic therapy (PDT) has emerged as a highly efficacious therapeutic modality for malignant tumors owing to its non-invasive property and minimal adverse effects. However, the pervasive hypoxic microenvironment within tumors significantly compromises the efficacy of oxygen-dependent PDT, posing a formidable challenge to the advancement of high-efficiency PDT. Here, we developed a nanostructured photosensitizer (PS) assembled by cationic and anionic zinc phthalocyanines to load oxygen-throttling drug atovaquone (ATO), which was subsequently coated with polydopamine to obtain the final product ATO/ZnPc-CA@DA. ATO/ZnPc-CA@DA exhibited excellent stability, particularly in the blood milieu. Interestingly, the acidic microenvironment can trigger drug release from ATO/ZnPc-CA@DA, leading to a significant enhancement in fluorescence and an augmented generation of reactive oxygen species (ROS). ATO/ZnPc-CA@DA can induce synergistic cytotoxicity of PS and ATO, and significantly enhance the killing ability against tumor cells under hypoxic conditions. The mechanism underlying cytotoxicity of ATO/ZnPc-CA@DA was demonstrated to be associated with augmented cell apoptosis, disruption of mitochondrial membrane potential, diminished ATP production, heightened intracellular ROS generation, and reduced intracellular oxygen consumption. The animal experiments indicated that ATO/ZnPc-CA@DA possessed enhanced tumor targeting capability, along with a reduction in PS distribution within normal organs. Furthermore, ATO/ZnPc-CA@DA exhibited enhanced inhibitory effect on tumor growth and caused aggravated damage to tumor tissue. The construction strategy of nanostructured PS and the synergistic antitumor principle of combined oxygen-throttling drugs can be applied to other PSs, thereby advancing the development of photodynamic antitumor therapy and promoting the clinical translation.

Arvanil induces ferroptosis of hepatocellular carcinoma by binding to MICU1.

Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate that requires research and improved treatment strategies. Chemotherapy is still one of the main methods of HCC treatment, but it may lead to drug resistance and damage to normal organs. Capsaicin, a naturally occurring active ingredient in chili peppers, has demonstrated anticancer properties in a variety of malignant tumor cell lines. However, the anti-cancer mechanism of capsaicin needs to be further explored in HCC. In this study, we utilized Arvanil, a non-stimulating synthetic capsaicin analog, in place of capsaicin. We found that Arvanil induced high mitochondrial calcium flow, which contributed to a decrease in mitochondrial membrane permeability transition pore (mPTP) opening and oxidative phosphorylation levels, ultimately triggering cellular ferroptosis by live cells in real time with a high content screening (HCS) platform and confocal microscopy. It was further confirmed by vina molecular docking and point mutation experiments that Arvanil directly binds to two amino acid sites of mitochondrial calcium uptake protein 1 (MICU1), namely Ser47 and Phe128, to trigger this process, which in turn inhibits the growth of HCC cells. In addition, it was confirmed that Arvanil enhances cisplatin chemosensitivity by inducing HCC cellular ferroptosis in vivo. In conclusion, our study suggests that Arvanil induces ferroptosis in HCC cells and is a candidate drug for the treatment of HCC.

Genetic advancement in the detection of Systemic Lupus Erythematosus (SLE)

The disease lupus, also known as systemic lupus erythematosus (SLE), is an autoimmune condition, chronic in nature, that can affect any organ in the body. The immune system of the body becomes hyperactive in lupus, attacking normal tissues and organs such as the skin, skeletal, renal, brain, heart, lungs, and blood. Normally, the immunologic response protects the body against outside susceptibilities. Periods of illness, known as flares, and times of wellness, known as remissions, are characteristics of lupus. Lupus is challenging to diagnose since its symptoms are vastly adherent and often mistaken for those of other illnesses. The presence of complexities in this illness cannot be proven with a single laboratory test. Lupus has no recognised cause or treatment as of yet. However, research is going on to achieve improved health outcomes, and early identification and treatment are essential. Lupus has no recognised cause or treatment as of yet. Early detection and treatment, which can typically reduce a disease’s severity and course, are essential to enhancing health outcomes. NSAIDs, antimalarials, and steroids (including cortisone and others) are widely used to treat lupus. Patients with lupus may also receive cytotoxic chemotherapy comparable to chemotherapy used to treat cancer. Patients with lupus may also receive cytotoxic chemotherapy comparable to chemotherapy used to treat cancer. This well-known and respected resource has a new edition that blends basic and clinical science to present a translational medicine concept. A helpful resource for professionals in the diagnosis and treatment of Systemic Lupus Erythematous patients, SLE serves as a reference for hospital libraries and as a tool for measuring clinical activity for drug development and fundamental research. Beautifully depicted and in full colour throughout Basic science part has been enhanced to let readers concentrate on the most recent molecular medicine techniques and how they affect the expression and treatment of diseases.

Lymphatic and Blood Vessels in Normal Rhesus Monkey Organs by Frozen Section Immunohistochemistry: A Conclusive Report

Lymphatic and Blood Vessels in Normal Rhesus Monkey Organs by Frozen Section Immunohistochemistry: A Conclusive Report

Preclinical Efficacy and Mechanism for a Novel BTK-Protacs Against Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL) that exhibits diverse clinical courses and biological contexts. Given the significance of Bruton tyrosine kinase (BTK) as a therapeutic target in MCL, this study aimed to design a range of BTK-PROTACs. The objective was to develop efficient BTK-PROTACs capable of degrading BTK proteins, inhibiting the proliferation of MCL cells, and overcoming resistance to both covalent and non-covalent BTK inhibitors in both in vivo and in vitro settings. Methods:A series of BTK-PROTACs were gradually screened by Western blot and MTS assays, and the best active drug was finally determined. Cell function experiments in vitro were applied to verify the screening results and therapeutic efficacy was tested in vivo in NSG mice. RNA sequencing identified differentially expressed genes and important signaling pathways that influenced by BTK-PROTACs. BTKi-resistant cell lines were constructed to evaluate the ability of BTK-PROTACs to degrade BTK protein and suppress the proliferation of MCL cells. R esults: BTK-PROTACs C23 demonstrated effective degradation of BTK protein and inhibition of tumor cell growth across various MCL cell lines. Additionally, C23 exhibited the ability to induce cell apoptosis, activate the ubiquitin pathway, and inhibit the B-cell receptor (BCR), NF-κB, and PI3K-AKT-mTOR signaling pathways. Importantly, C23 effectively degraded BTK in both Z138-BTK C481S and Z138-BTK L528W cells, suggesting its potential to overcome resistance to both covalent and non-covalent BTK inhibitors. In our in vivo experiments using MCL xenograft NSG mouse models, BTK-PROTACs C23 significantly impeded tumor proliferation in Z138-BTK WT, Z138-BTK C481S, and Z138-BTK L528W MCL models. Additionally, C23 induced the degradation of BTK in tumor tissues. Notably, HE staining revealed no significant adverse effects of BTK-PROTACs C23 on normal organs and tissues. Moreover, routine blood tests and liver function tests showed no impairment of hematopoietic or hepatic function caused by BTK-PROTACs C23. C onclusion: In this study, we successfully designed and synthesized BTK-PROTACs C23, which demonstrated a remarkable ability to degrade BTK protein and effectively suppress the proliferation of MCL cells both in vitro and in vivo. Importantly, BTK-PROTACs C23 showed promising potential to overcome resistance to both covalent and non-covalent BTK inhibitors.

β-Cyclodextrin Nanophotosensitizers for Redox-Sensitive Delivery of Chlorin e6.

The aim of this study is to prepare redox-sensitive nanophotosensitizers for the targeted delivery of chlorin e6 (Ce6) against cervical cancer. For this purpose, Ce6 was conjugated with β-cyclodextrin (bCD) via a disulfide bond, creating nanophotosensitizers that were fabricated for the redox-sensitive delivery of Ce6 against cancer cells. bCD was treated with succinic anhydride to synthesize succinylated bCD (bCDsu). After that, cystamine was attached to the carboxylic end of bCDsu (bCDsu-ss), and the amine end group of bCDsu-ss was conjugated with Ce6 (bCDsu-ss-Ce6). The chemical composition of bCDsu-ss-Ce6 was confirmed with 1H and 13C NMR spectra. bCDsu-ss-Ce6 nanophotosensitizers were fabricated by a dialysis procedure. They formed small particles with an average particle size of 152.0 ± 23.2 nm. The Ce6 release rate from the bCDsu-ss-Ce6 nanophotosensitizers was accelerated by the addition of glutathione (GSH), indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive photosensitizer delivery capacity. The bCDsu-ss-Ce6 nanophotosensitizers have a low intrinsic cytotoxicity against CCD986Sk human skin fibroblast cells as well as Ce6 alone. However, the bCDsu-ss-Ce6 nanophotosensitizers showed an improved Ce6 uptake ratio, higher reactive oxygen species (ROS) production, and phototoxicity compared to those of Ce6 alone. GSH addition resulted in a higher Ce6 uptake ratio, ROS generation, and phototoxicity than Ce6 alone, indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive biological activity in vitro against HeLa human cervical cancer cells. In a tumor xenograft model using HeLa cells, the bCDsu-ss-Ce6 nanophotosensitizers efficiently accumulated in the tumor rather than in normal organs. In other words, the fluorescence intensity in tumor tissues was significantly higher than that of other organs, while Ce6 alone did not specifically target tumor tissue. These results indicated a higher anticancer activity of bCDsu-ss-Ce6 nanophotosensitizers, as demonstrated by their efficient inhibition of the growth of tumors in an in vivo animal tumor xenograft study.

Phyllanthi Tannin Loaded Solid Lipid Nanoparticles for Lung Cancer Therapy: Preparation, Characterization, Pharmacodynamics and Safety Evaluation

The objective of the present study was to develop PTF-loaded solid lipid nanoparticles (PTF-SLNs) and investigate their efficacy in treating lung cancer. The PTF-SLNs were prepared by the thin film hydration method and verified by FTIR and TEM. Their physicochemical properties were characterized by particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), drug loading (DL), etc. Then, the pharmacodynamic studies of PTF-SLNs were performed on Lewis lung cancer cells and tumor-bearing mice. Finally, the safety studies were assessed by organ index, serum biochemical indicators, and histopathological changes. The PTF-SLNs were characterized by around 50 nm sphere nanoparticles, sustained ideal stability, and controlled drug release effects. The pharmacodynamic evaluation results showed that PTF-SLNs had stronger anti-tumor efficacy than PTF. An in vitro study revealed a more obvious cytotoxicity and apoptosis effect. The IC 50 values of PTF and PTF-SLNs were 67.43 μg/mL and 20.74 μg/mL, respectively. An in vivo study showed that the tumor inhibition rates of 2 g/kg PTF and 0.4 g/kg PTF-SLNs were 59.97% and 64.55%, respectively. The safety preliminary study indicated that PTF-SLNs improve the damage of PTF to normal organs to a certain extent. This study provides a nanoparticle delivery system with phenolic herbal extract to improve anti-tumor efficacy in lung cancer.

Assessing dynamic metabolic heterogeneity in prostate cancer patients via total-body [68Ga]Ga-PSMA-11 PET/CT imaging: quantitative analysis of [68Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs.

This study aimed to quantitatively assess [68Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs in prostate cancer using the total-body [68Ga]Ga-PSMA-11 PET/CT and to characterize the dynamic metabolic heterogeneity of prostate cancer. Dynamic total-body [68Ga]Ga-PSMA-11 PET/CT scans were performed on ten prostate cancer patients. Manual delineation of volume-of-interests (VOIs) was performed on multiple normal organs displaying high [68Ga]Ga-PSMA-11 uptake, as well as pathological lesions. Time-to-activity curves (TACs) were generated, and the four compartment models including one-tissue compartmental model (1T1k), reversible one-tissue compartmental model (1T2k), irreversible two-tissue compartment model (2T3k) and reversible two-tissue compartmental model (2T4k) were fitted to each tissue TAC. Various rate constants, including K1 (forward transport rate from plasma to the reversible compartment), k2 (reverse transport rate from the reversible compartment to plasma), k3 (tracer binding on the PSMA-receptor and its internalization), k4 (the externalization rate of the tracer) and Ki (net influx rate), were obtained. The selection of the optimal model for describing the uptake of both lesions and normal organs was determined using the Akaike information criteria (AIC). Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for differentiating physiological and pathological [68Ga]Ga-PSMA-11 uptake. Both 1T1k and 1T2k models showed relatively high AIC values compared to the 2T3k and 2T4k models in both pathological lesions and normal organs. The kinetic behavior of pathological lesions was better described by the 2T3k model compared to the 2T4k model, while the normal organs were better described by the 2T4k model. Significant variations in kinetic metrics, such as K1, k2, and k3, and Ki, were observed among normal organs with high [68Ga]Ga-PSMA-11 uptake and pathological lesions. The high Ki value in normal organs was primarily determined by elevated K1 and low k3, rather than k2. Conversely, the high Ki value in pathological lesions, ranking second to the kidney and similar to salivary glands and spleen, was predominantly determined by the highest k3 value. Notably, k3 exhibited the highest performance in distinguishing between physiological and pathological [68Ga]Ga-PSMA-11 uptake, with an area under the curve (AUC) of 0.844 (95% CI, 0.773-0.915), sensitivity of 82.9%, and specificity of 74.1%. The k3 values showed better performance than SUVmean (AUC, 0.659), SUVmax (AUC, 0.637), and other kinetic parameter including K1 (AUC, 0.604), k2 (AUC, 0.634), and Ki (AUC, 0.651). Significant discrepancies in kinetic metrics were detected between pathological lesions and normal organs, despite their shared high uptake of [68Ga]Ga-PSMA-11. Notably, the k3 value exhibits a noteworthy capability to distinguish between pathological lesions and normal organs with elevated [68Ga]Ga-PSMA-11 uptake. This discovery implies that k3 holds promise as a prospective imaging biomarker for distinguishing between pathologic and non-specific [68Ga]Ga-PSMA-11 uptake in patients with prostate cancer.