エピガロカテキン ガレート ジョホウセイ オ ユウスル ステント コーティング ザイリョウ ト シテ ノ ポリ ( L - ラクチド - co - イプシロン - カプロラクトン ) ジョウ ニ オケル ケッカン ヘイカツキン サイボウ ト ケッショウバン ノ キョドウ

京都大学0048新制・課程博士博士(医科学)甲第13739号医科博第3号新制||医科||1(附属図書館)UT51-2008-C655京都大学大学院医学研究科医科学専攻(主査)教授 前川 平, 教授 坂口 志文, 教授 吉原 博幸学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Nano-Delivery of Immunogenic Cell Death Inducers and Immune Checkpoint Blockade Agents: Single-Nanostructure Strategies for Enhancing Immunotherapy

Cancer immunotherapy has revolutionized oncology by harnessing the patient’s immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically ‘cold’ tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers and advanced drug delivery systems represents a promising solution. This review discusses the development and application of various nanocarriers, including polymeric nanoparticles, liposomes, peptide-based nanoparticles, and inorganic nanoparticles, designed to deliver ICD inducers and ICBs effectively. These nanocarriers improve therapeutic outcomes by converting cold tumors into hot tumors, thus enhancing immune responses and reducing systemic toxicity. By focusing on single-nanoparticle systems that co-deliver both ICD inducers and ICBs, this review highlights their potential in achieving higher drug concentrations at tumor sites, improving pharmacokinetics and pharmacodynamics, and facilitating clinical translation. Future research should aim to optimize these nanocarrier systems for better in vivo performance and clinical applications, ultimately advancing cancer immunotherapy

Perspectives for Improving the Tumor Targeting of Nanomedicine via the EPR Effect in Clinical Tumors

Over the past few decades, the enhanced permeability and retention (EPR) effect of nanomedicine has been a crucial phenomenon in targeted cancer therapy. Specifically, understanding the EPR effect has been a significant aspect of delivering anticancer agents efficiently to targeted tumors. Although the therapeutic effect has been demonstrated in experimental models using mouse xenografts, the clinical translation of the EPR effect of nanomedicine faces several challenges due to dense extracellular matrix (ECM), high interstitial fluid pressure (IFP) levels, and other factors that arise from tumor heterogeneity and complexity. Therefore, understanding the mechanism of the EPR effect of nanomedicine in clinics is essential to overcome the hurdles of the clinical translation of nanomedicine. This paper introduces the basic mechanism of the EPR effect of nanomedicine, the recently discussed challenges of the EPR effect of nanomedicine, and various strategies of recent nanomedicine to overcome the limitations expected from the patients’ tumor microenvironments

Emerging Albumin-Binding Anticancer Drugs for Tumor-Targeted Drug Delivery: Current Understandings and Clinical Translation

Albumin has shown remarkable promise as a natural drug carrier by improving pharmacokinetic (PK) profiles of anticancer drugs for tumor-targeted delivery. The exogenous or endogenous albumin enhances the circulatory half-lives of anticancer drugs and passively target the tumors by the enhanced permeability and retention (EPR) effect. Thus, the albumin-based drug delivery leads to a potent antitumor efficacy in various preclinical models, and several candidates have been evaluated clinically. The most successful example is Abraxane, an exogenous human serum albumin (HSA)-bound paclitaxel formulation approved by the FDA and used to treat locally advanced or metastatic tumors. However, additional clinical translation of exogenous albumin formulations has not been approved to date because of their unexpectedly low delivery efficiency, which can increase the risk of systemic toxicity. To overcome these limitations, several prodrugs binding endogenous albumin covalently have been investigated owing to distinct advantages for a safe and more effective drug delivery. In this review, we give account of the different albumin-based drug delivery systems, from laboratory investigations to clinical applications, and their potential challenges, and the outlook for clinical translation is discussed. In addition, recent advances and progress of albumin-binding drugs to move more closely to the clinical settings are outlined.N

Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy

Prodrugs are bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which improve cancer selectivity to reduce toxicities of anticancer drugs. However, such approaches have been challenged by poor therapeutic efficacy attributed to a short half-life and low tumor targeting. Herein, we propose cathepsin B-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug, Al-ProD, that consists of a albumin-binding maleimide group, cathepsin B-cleavable peptide (FRRG), and doxorubicin. The Al-ProD binds to in situ albumin, and albumin-bound Al-ProD indicates high tumor accumulation with prolonged half-life, and selctively releases doxorubicin in cathepsin B-overexpressed tumor cells, inducing a potent antitumor efficacy. Concurrently, toxicity of Al-ProD toward normal tissues with innately low cathepsin B expression is significantly reduced by maintaining an inactive state, thereby increasing the safety of chemotherapy. This study offers a promising approach for effective and safe chemotherapy, which may open new avenues for drug design and translational medicine

Impact of glucose metabolism on PD-L1 expression in sorafenib-resistant hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide. Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein that binds to programmed cell death-1 (PD-1), which is expressed in activated T cells and other immune cells and has been employed in cancer therapy, including HCC. Recently, PD-L1 overexpression has been documented in treatment-resistant cancer cells. Sorafenib is a multikinase inhibitor and the only FDA-approved treatment for advanced HCC. However, several patients exhibit resistance to sorafenib during treatment. This study aimed to assess the effect of glucose deprivation on PD-L1 expression in HCC cells. We used PD-L1-overexpressing HepG2 cells and IFN-γ-treated SK-Hep1 cells to explore the impact of glycolysis on PD-L1 expression. To validate the correlation between PD-L1 expression and glycolysis, we analyzed data from The Cancer Genome Atlas (TCGA) and used immunostaining for HCC tissue analysis. Furthermore, to modulate PD-L1 expression, we treated HepG2, SK-Hep1, and sorafenib-resistant SK-Hep1R cells with rapamycin. Here, we found that glucose deprivation reduced PD-L1 expression in HCC cells. Additionally, TCGA data and immunostaining analyses confirmed a positive correlation between the expression of hexokinase II (HK2), which plays a key role in glucose metabolism, and PD-L1. Notably, rapamycin treatment  decreased the expression of PD-L1 and HK2 in both high PD-L1-expressing HCC cells and sorafenib-resistant cells. Our results suggest that the modulation of PD-L1 expression by glucose deprivation may represent a strategy to overcome PD-L1 upregulation in patients with sorafenib-resistant HCC

Sustained and Long-Term Release of Doxorubicin from PLGA Nanoparticles for Eliciting Anti-Tumor Immune Responses

Immunogenic cell death (ICD) is a powerful trigger eliciting strong immune responses against tumors. However, traditional chemoimmunotherapy (CIT) does not last long enough to induce sufficient ICD, and also does not guarantee the safety of chemotherapeutics. To overcome the disadvantages of the conventional approach, we used doxorubicin (DOX) as an ICD inducer, and poly(lactic-co-glycolic acid) (PLGA)-based nanomedicine platform for controlled release of DOX. The diameter of 138.7 nm of DOX-loaded PLGA nanoparticles (DP-NPs) were stable for 14 days in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Furthermore, DOX was continuously released for 14 days, successfully inducing ICD and reducing cell viability in vitro. Directly injected DP-NPs enabled the remaining of DOX in the tumor site for 14 days. In addition, repeated local treatment of DP-NPs actually lasted long enough to maintain the enhanced antitumor immunity, leading to increased tumor growth inhibition with minimal toxicities. Notably, DP-NPs treated tumor tissues showed significantly increased maturated dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs) population, showing enhanced antitumor immune responses. Finally, the therapeutic efficacy of DP-NPs was maximized in combination with an anti-programmed death-ligand 1 (PD-L1) antibody (Ab). Therefore, we expect therapeutic efficacies of cancer CIT can be maximized by the combination of DP-NPs with immune checkpoint blockade (ICB) by achieving proper therapeutic window and continuously inducing ICD, with minimal toxicities

Tumor-Specific Monomethyl Auristatin E (MMAE) Prodrug Nanoparticles for Safe and Effective Chemotherapy

A prodrug is bioreversible medication that is specifically converted to the active drugs by enzymes overexpressed in the tumor microenvironment, which can considerably reduce the chemotherapy-induced side effects. However, prodrug strategies usually have low antitumor efficacy compared to free drugs by delayed drug release. This is because they need time to be activated by enzymatic cleavage and they also cannot be fully recovered to the active drugs. Therefore, highly potent anticancer drug should be considered to expect a sufficient antitumor efficacy. Herein, we propose tumor-specific monomethyl auristatin E (MMAE) prodrug nanoparticles for safe and effective chemotherapy. The cathepsin B-specific cleavable FRRG peptide and MMAE are chemically conjugated via one-step simple synthetic chemistry. The resulting FRRG-MMAE molecules form stable nanoparticles without any additional carrier materials by hydrophobic interaction-derived aggregations. The FRRG-MMAE nanoparticles efficiently accumulate within the tumor tissues owing to the enhanced permeability and retention (EPR) effect and inhibit the tubulin polymerization by releasing free MMAE in the cathepsin B-overexpressed tumor cells. In contrast, FRRG-MMAE nanoparticles maintain a non-toxic inactive state in the normal tissues owing to innately low cathepsin B expression, thereby reducing MMAE-related severe toxicity. Collectively, this study provides a promising approach for safe and effective chemotherapy via MMAE-based prodrug nanoparticles, which may open new avenues for advanced drug design for translational nanomedicine

Astrocytic scar restricting glioblastoma via glutamate–MAO-B activity in glioblastoma-microglia assembloid

Abstract Background Glial scar formation is a reactive glial response confining injured regions in a central nervous system. However, it remains challenging to identify key factors formulating glial scar in response to glioblastoma (GBM) due to complex glia-GBM crosstalk. Methods Here, we constructed an astrocytic scar enclosing GBM in a human assembloid and a mouse xenograft model. GBM spheroids were preformed and then co-cultured with microglia and astrocytes in 3D Matrigel. For the xenograft model, U87-MG cells were subcutaneously injected to the Balb/C nude female mice. Results Additional glutamate was released from GBM-microglia assembloid by 3.2-folds compared to GBM alone. The glutamate upregulated astrocytic monoamine oxidase-B (MAO-B) activity and chondroitin sulfate proteoglycans (CSPGs) deposition, forming the astrocytic scar and restricting GBM growth. Attenuating scar formation by the glutamate–MAO-B inhibition increased drug penetration into GBM assembloid, while reducing GBM confinement. Conclusions Taken together, our study suggests that astrocytic scar could be a critical modulator in GBM therapeutics. Graphical Abstrac