Cancer Biotherapy and Radiopharmaceuticals最新文献

Background: Secondary upper limb lymphedema is easy to occur after breast cancer surgery, for which treatment is limited. 9-cis-retinoic acid (9-cisRA) has been demonstrated to increase lymphangiogenesis without enhancing tumor metastasis but has the disadvantages of poor water solubility, easy decomposition in light, unstable to heat, and short half-life. Methods: Based on this, 9-cisRA-Lip with a particle size of roughly 143 nm and high dispersibility was prepared by thin-film dispersion method and verified by Malvern Laser Particle Size Analyzer and electron microscopy. Results: In vitro, 9-cisRA-Lip demonstrated good biosafety and tumor safety, promoting the proliferation of L929 cells while having no effect on 4T1 and Human Umbilical Vein Endothelial (HUVEC) cells. Compared with 9-cisRA, 9-cisRA-Lip was more effective at encouraging mouse lymphatic endothelial cell (SVEC4-10) migration, proliferation, and tube formation. In vivo, 9-cisRA-Lip-Gel showed good slow-release effect, mice treated with 9-cisRA-Lip-Gel one-time local injection had considerably less tail edema than the control group from day 9 to day 39 postsurgery (p < 0.05). This may be attributed to the greater capacity of 9-cisRA-Lip to enhance the phosphorylation of FGFR3 (Fibroblast Growth Factor Receptor 3) at Tyr 724. Conclusions: 9-cisRA-Lip-Gel presents a potential treatment option for lymphedema following surgery.

Background: Methyltransferase-like 3 (METTL3) and HECT and RLD domain containing E3 ubiquitin protein ligase 4 (HERC4) have been studied in the field of oncology; howbeit, their roles and interaction in hepatocellular carcinoma (HCC) await elucidation. Methods: Initially, METTL3 and HERC4 expressions in normal and HCC samples were predicted employing the UALCAN database, and the targeting relationship between these two was explored via coimmunoprecipitation assay. Following the quantification on N6-methyladenosine (m⁶A) enrichment, the localization of METTL3 and HERC4 on HCC cells was visualized via immunofluorescence assay. The effects of METTL3 and HERC4 on HCC cells proliferation and migration were determined in vitro assays. METTL3 and HERC4 expressions were quantified via quantitative polymerase chain reaction, and those of metastasis-related proteins N-cadherin and vimentin were calculated with immunoblotting assay. Furthermore, the levels of angiogenic factors such as vascular endothelial growth factor and basic fibroblast growth factor were measured by enzyme-linked immunosorbent assay. Results: METTL3 and HERC4 expressed highly in HCC and their expressions were positively correlated with tumor grade. METTL3 overexpression enhanced the expression of HERC4 and promoted the proliferation and migration abilities of HCC cells. Specifically, METTL3 overexpression increased vimentin and N-cadherin expressions, while its silencing did conversely. Besides, HERC4 overexpression reversed the effects of METTL3 silencing on the proliferation and migration as well as the levels of angiogenic factors in HCC cells. Conclusion: This study reveals the upregulation of METTL3 and HERC4 expression in HCC and their role in HCC by enhancing the proliferation, migration, and angiogenesis potential of HCC cells.

Background: Hyaluronic acid (HA), as a critical ingredient of extracellular matrix (ECM) and synovial fluid, has attracted extensive attention in targeted tumor thearpy. The superiority of HA is reflected as its great biocompatibility, biodegradability and special binding ability to CD44 receptor. Moreover, CD44 receptor proteins are overexpressed in many kinds of tumor cells and cancer stem cells (CSCs). Therefore, HA is commonly used as ligands for the surface modification of versatile nanocarriers applied in various tumor therapy approaches. Methods: We reviewed a large amount of literature and summarized the unique properties of HA, the rationale for the use of HA as tumor-specific carrier for drug delivery, catabolism of HA coated nanocarriers and research achievements of frequently-used HA-modified organic and inorganic nanocarries. Results: We concluded the significant applications of HA coated nanocarriers in tumor Chemotherapy and chemoresistance, Combination therapy and Cancer theranostics. Conclusion: The application prospect of HA-coated nanocarriers will be more extensive for various targeting combination therapy and theranostics. was concluded so as to provide some potential thoughts for targeted tumor thearpy and even diagnosis.

Introduction: Prostate-specific membrane antigen (PSMA) is a target for diagnostic positron emission tomography (PET)-tracers and radiopharmaceutical therapy (RPT), for example, [¹⁷⁷Lu]Lu-PSMA-617, in prostate cancer. This autoradiography study investigates [¹⁷⁷Lu]Lu-PSMA-617 intratumoral distribution over time, compared with PSMA expression, proliferation (Ki67), and [⁶⁸Ga]Ga-PSMA-11, [¹⁸F]F-PSMA-1007, [¹⁸F]-fluorodeoxyglucose, and [¹⁸F]-fluorocholine distribution. Mice with LNCaP, 22Rv1, or PC-3 PIP xenografts got [¹⁷⁷Lu]Lu-PSMA-617 i.v. Sacrificed 1 h p.i. if coinjected with diagnostic tracers, otherwise at 20 min, 1-2, 12, 24, 48, 72 h, or 2-3 weeks p.i. Cryosectioned tumors imaged by autoradiography, adjacent sections Ki67 or PSMA stained. Results: Heterogeneous distribution of [¹⁷⁷Lu]Lu-PSMA-617 was seen 20 min p.i., with visible overlap between tumor cells, Ki67, PSMA, and radioactivity at 1-2 h p.i. Strongest Ki67-correlation at 48 h, which became negative at 72 h and beyond with some Ki67+/PSMA+ low radioactivity areas. Uptake in necrotic tissue was only observed at 2-3 weeks p.i. PSMA-targeted tracers distributed identically to [¹⁷⁷Lu]Lu-PSMA-617 whereas other tracers only had some overlap. Conclusion: Regrowth of the tumor post-[¹⁷⁷Lu]Lu-PSMA-617 administration creates Ki67+/PSMA+ areas that have no radioactivity uptake and need additional therapy fractions. The identical intratumoral distribution of [¹⁷⁷Lu]Lu-PSMA-617 and PSMA-targeted PET-tracers indicate that these will reveal the areas inside the tumor targeted by RPT at least at 1 h p.i.

Background: Chemotherapy based on oxaliplatin (OXA) is the first-line treatment for advanced colorectal cancer (CRC), and acquired resistance to OXA is the main reason for clinical treatment failure in CRC. Methods: To search for compounds that can reverse OXA resistance, we screened a small molecule inhibitor drug library and identified a drug, Raddeanin A (RA), that enhanced the anticancer effect of OXA. Using human CRC cell lines, CRC organoid models, and in vivo subcutaneous tumorigenic studies, we determined that RA inhibits the proliferation of CRC cells by promoting apoptosis and inducing cell cycle arrest. Results: We constructed OXA-resistant CRC cell lines and demonstrated that RA enhances the sensitivity of these cells to OXA. Further experiments showed that the mechanism by which RA enhanced the anticancer effects of OXA in CRC was by inhibiting the activation of the WNT/β-catenin signaling pathway. Conclusions: Because RA has been shown to be biocompatible in animal models, there is a possibility that RA could be developed as a sensitizer for resistant cancer cells or as a novel lead compound to enhance the therapeutic efficacy of OXA in resistant CRCs.

Objective: This study aims to comprehensively evaluate the efficacy and safety of bronchial arterial chemoembolization (BACE) in the treatment of advanced nonsmall cell lung cancer (NSCLC) through a meta-analysis of single-group rate, providing evidence-based guidance for clinical treatment. Materials and Methods: A systematic search was conducted in PubMed, the Cochrane Library, Embase, and Web of Science databases for relevant studies up to January 15, 2024. Inclusion criteria encompassed single-arm or multi-arm studies of nonrandomized controlled trials, observational studies, and single-arm studies in English language, focusing on NSCLC patients treated with BACE. Data extraction, quality assessment, and statistical analysis were performed following predefined protocols. Results: In total, 172 articles were initially retrieved, with 11 studies meeting the inclusion criteria. The included studies comprised 510 patients. Meta-analysis revealed significant heterogeneity among studies for median progression-free survival (PFS), median overall survival (OS), objective response rate, and disease control rate. The combined median PFS was 6.87 months (95% confidence interval [CI] 5.30-8.44), and the combined median OS was 13.68 months (95% CI 10.69-16.67). Subgroup analysis based on intervention measures demonstrated varying efficacy outcomes. Adverse reactions associated with BACE were generally mild, with no reports of grade 3 or higher adverse events. Conclusion: BACE emerges as a promising treatment modality for advanced NSCLC, exhibiting favorable efficacy and safety profiles.

Background: Antimicrobial peptides (AMPs) such as UBI-29-41 offer a distinctive approach for precise detection due to their unique interactions with bacteria and makes them promising candidates for specific and selective imaging. The study was aimed to corroborate the in-house manual synthesis of ⁶⁸Ga-NOTA-UBI-29-41, evaluate its uptake in patients with suspected infection, and estimate of patient-specific dosimetry to ensure optimal clinical application. Materials and Methods: ⁶⁸Ga-NOTA-UBI-29-41 was synthesized by using a variable amount of UBI-29-41 (60-90 μg) to 555 MBq of Ga-68 in 0.05 M Hydrochloric acid (HCl) and heating the reaction sample for 12 min at 90°C at pH: 3.5-4 to obtain the radiopeptide with high yield and high radiochemical purity (RCP). ⁶⁸Ga-NOTA-UBI-29-41 positron emission tomography/Computed tomography (CT) scans at variable timepoints were done to evaluate its biodistribution and maximum uptake time. Furthermore, patient-specific dosimetric estimation was done using the HERMES software. Results: A total of 5 μg/37 MBq (5 μg/mCi) of NOTA-UBI-29-41 for 12 min at 90°C were the optimal parameters to obtain 88%-90% of yield and 98%-99 % of RCP. ⁶⁸Ga-NOTA-UBI-29-41 showed expeditious blood clearance and high renal excretion. The optimal time for imaging of infection with ⁶⁸Ga-NOTA-UBI-29-41 was found to be at 60 min postinjection (n = 8). The critical organ was the urinary bladder, receiving an average dose of 138.02 ± 45.92 µSv/MBq, followed by 53.81 ± 13.72 µSv/MBq for kidneys with a mean effective dose of 1.52 ± 0.64 mSv. Conclusion: The protocol for in-house manual labeling of ⁶⁸Ga-NOTA-UBI-29-41 was reproducible, providing high yield and RCP. ⁶⁸Ga-NOTA-UBI-29-41 administration was found to be safe and nontoxic. The favorable biodistribution and the first-in-human patient-specific dosimetry ensure optimal clinical application.

Reporting of diagnostic nuclear images in clinical cancer management is generally qualitative. Theranostic treatment with ¹⁷⁷Lu radioligands for prostate cancer and neuroendocrine tumors is routinely given as the same arbitrary fixed administered activity to every patient. Nuclear oncology, as currently practiced with ¹⁷⁷Lu-prostate-specific membrane antigen and ¹⁷⁷Lu peptide receptor radionuclide therapy, cannot, therefore, be characterized as personalized precision medicine. The evolution of artificial intelligence (AI) could change this "one-size-fits-all" approach to theranostics, through development of a symbiotic relationship with physicians. Combining quantitative data collection, collation, and analytic computing power of AI algorithms with the clinical expertise, empathy, and personal care of patients by their physician envisions a new paradigm in theranostic reporting for molecular imaging and radioligand treatment of cancer. Human-AI interaction will facilitate the compilation of a comprehensive, integrated nuclear medicine report. This holistic report would incorporate radiomics to quantitatively analyze diagnostic digital imaging and prospectively calculate the radiation absorbed dose to tumor and critical normal organs. The therapy activity could then be accurately prescribed to deliver a preordained, effective, tumoricidal radiation absorbed dose to tumor, while minimizing toxicity in the particular patient. Post-therapy quantitative imaging would then validate the actual dose delivered and sequential pre- and post-treatment dosimetry each cycle would allow individual dose prescription and monitoring over the entire course of theranostic treatment. Furthermore, the nuclear medicine report would use AI analysis to predict likely clinical outcome, predicated upon AI definition of tumor molecular biology, pathology, and genomics, correlated with clinical history and laboratory data. Such synergistic comprehensive reporting will enable self-assurance of the nuclear physician who will necessarily be deemed personally responsible and accountable for the theranostic clinical outcome. Paradoxically, AI may thus be expected to enhance the practice of phronesis by the nuclear physician and foster a truly empathic trusting relationship with the cancer patient.

Objectives: We compared the value of the semiquantitative parameters of ⁶⁸Ga-labeled FAP inhibitor (⁶⁸Ga-FAPI)-04 positron emission tomography/computed tomography (PET/CT) and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) in diagnosing primary malignant and benign diseases. Materials and Methods: ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 PET/CT images of 80 patients were compared. Semiquantitative parameters, including maximum standardized uptake value (SUV_max), mean SUV (SUV_mean), peak SUV (SUV_peak), peak SUV by lean body mass (SUL_peak), metabolic tumor volume (or tumor volume of FAPI; FAPI-TV), and TLG (or total lesion activity of FAPI; FAPI-TLA), were automatically obtained using the IntelliSpace Portal image processing workstation with a threshold of 40% SUV_max. The liver blood pool was measured as the background, and the tumor-to-background ratio (TBRliver) was calculated. Results: In all malignant lesions, FAPI-TV and FAPI-TLA were higher in ⁶⁸Ga-FAPI-04 PET/CT than in ¹⁸F-FDG. In the subgroup analysis, ⁶⁸Ga-FAPI-04 had higher FAPI-TV and FAPI-TLA and lower SUV_max than ¹⁸F-FDG had in group A, including gynecological tumor, esophageal, and colorectal cancers. However, six semiquantitative parameters were higher in group B (the other malignant tumors). For the benign diseases, SUV_max, SUV_mean, SUV_peak, and SUL_peak were lower in ⁶⁸Ga-FAPI-04 PET/CT than in ¹⁸F-FDG. ⁶⁸Ga-FAPI-04 PET/CT showed a lower liver background and a higher TBRliver than ¹⁸F-FDG did. ⁶⁸Ga-FAPI-04 PET/CT had higher accuracy, sensitivity, and specificity than ¹⁸F-FDG had. Conclusion: More accurate semiquantitative parameters and lower abdominal background in ⁶⁸Ga-FAPI-04 PET/CT make it more competitive in the differential diagnosis of malignant and benign diseases than in ¹⁸F-FDG.

Introduction: The expression of alpha-five beta-three (αVβ3) integrins is upregulated in various malignancies undergoing angiogenesis. The development of integrin antagonists as diagnostic probes makes the αVβ3 integrin a suitable candidate for targeting tumor angiogenesis. The goal of this study was to optimize the radiolabeling and evaluate the potential of conjugated integrin antagonist carbamate (IAC), a peptidomimetic, as a theranostic radiopharmaceutical for targeting tumor angiogenesis. Methodology: Radiolabeling of DOTAGA [2,2',2"-{10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl} triacetic-acid]-IAC with [⁶⁸Ga]Ga, [¹⁷⁷Lu]Lu, and [²²⁵Ac]Ac was optimized. The binding affinity (K_d) of DOTAGA-IAC for the αVβ3 receptor and cancer cell lines was quantified. The biodistribution studies were conducted in healthy Wistar rats. Dosimetry analysis was performed on [¹⁷⁷Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [⁶⁸Ga]Ga-DOTAGA-IAC and [¹⁸F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [⁶⁸Ga]Ga-DOTAGA-IAC and [¹⁸F]FDG in these patients. Results: Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). K_d and B_max measurements were 15.02 nM and 417 fmol for αVβ3 receptor protein: 115.7 nM and 295.3 fmol for C6 glioma cells. Biodistribution studies in rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [¹⁷⁷Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq. The dynamic study in patients revealed the optimal imaging time to be 30-35 mins postadministration. Out of the cohort, [⁶⁸Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUV_max) of 3.94 ± 0.58 compared with [¹⁸F]FDG (SUV_max 13.8 ± 6.53). Conclusion: The study demonstrates that DOTAGA-IAC exhibits strong binding to αVβ3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The outcomes from the pilot study suggest the potential of [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. While recognizing the theranostic potential of DOTAGA-IAC for αVβ3 integrin-expressing tumors, further clinical investigations are warranted to comprehensively assess therapeutic efficacy.