Molecular Pharmaceutics最新文献

{"title":"Development of a Novel Engineered Antibody Format for PSMA-Targeted Radionuclide Therapy.","authors":"Nicholas L Fletcher, Zachary H Houston, Peter G Chandler, Eddie Yan, Rob Holgate, Michael Wheatcroft, Kristofer J Thurecht","doi":"10.1021/acs.molpharmaceut.4c01193","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01193","url":null,"abstract":"<p><p>Prostate cancer remains a prevalent and lethal malignancy across the globe. Despite ongoing advances in therapeutic approaches, these remain ineffective, and new treatments are drastically needed. Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is a well-developed approach for prostate cancer treatment; however, current small molecule and antibody carriers for molecular radiotherapy each have drawbacks in their biodistribution and consequent side effects as highlighted in current clinical trials. To address this, we developed an approach to bioengineer the well clinically validated antibody carrier HuJ591 to yield an engineered, full-length antibody construct that achieves the beneficial fast pharmacokinetic profile of small molecule carriers alongside the enhanced tumor targeting and reduced renal toxicity of antibody carriers. We report here a rational design process to produce a novel humanized PSMA-targeting antibody designed for the delivery of radiation with abrogated FcRn recycling that aims to reduce blood circulation time and minimize systemic exposure. We demonstrate that these IgG-based constructs retain the favorable properties of HuJ591, such as inherent protein stability, expression in systems compatible with industrial manufacture, and comparable, highly specific PSMA-binding characteristics. We then radiolabeled constructs with the diagnostic radionuclide ⁶⁴Cu as a surrogate for therapeutic radionuclide payloads and undertook a proof-of-concept preclinical imaging study to probe the resulting <i>in vivo</i> behaviors. This demonstrated the success of this design strategy to yield the intended <i>in vivo</i> and radiopharmaceutical characteristics, with the resulting construct being rapidly cleared from circulation over 3 days. Together, this study demonstrates the rational design of a novel targeting antibody platform for PSMA-expressing tumors with reduced systemic exposure. Such a platform is extremely promising for future radiotherapeutic delivery approaches, whereby effective tumor treatment can be achieved while mitigating potential hematologic toxicity observed with standard antibody delivery approaches.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile Salts Trigger Deformability in Liposomal Vesicles through Edge-Activating Action.","authors":"Deepak Kumar, Sanjay Tiwari","doi":"10.1021/acs.molpharmaceut.5c00129","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00129","url":null,"abstract":"<p><p>This study investigates how bile-salt-based edge activators (EAs) (sodium cholate, NaC; sodium deoxycholate, NaDC; and sodium taurocholate, NaTC) can influence the mechanical properties and deformability of liposomal vesicles. We have elucidated their effect on liposomes composed of l-α-phosphatidylcholine (SPC). Liposomes were formulated using thin-film hydration and characterized using scattering, spectroscopic, and atomic force microscopic (AFM) techniques. Our data show that bile salts can alter the hydrodynamic diameter (<i>D</i>_h), morphology, and mechanical characteristics of vesicles. Their effect on the deformability and Young's modulus of vesicles followed the order NaDC ≥ NaC > NaTC. Breakthrough events were noticed in the vesicles at specific depth levels during force-deformation and force-indentation experiments. Based on the lack of hysteresis in the approach-retract curve, we inferred that the vesicles attained elasticity at lower concentrations of NaDC. Hydrophobic interactions between phospholipids and bile salts were verified from Fourier-transformed infrared spectrophotometer (FTIR) experiments. Increase in bile salt concentration was accompanied by a red shift of the acyl chain (asymmetric stretching CH₂ and symmetric stretching CH₃) and phosphate groups. This shift suggests enhanced hydrogen bonding between liposomes and bile salts. The affinity of bile salts for the SPC molecule correlated with their relative hydrophobicity. We conclude that NaDC can indeed improve the mechanical properties of liposomes and their ability to penetrate biological barriers.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Delivery of Metabolically Resilient Glutathione: <i>In Vivo</i> Pharmacokinetic, Permeation, and Efficacy Studies.","authors":"Kiran D Bhilare, Prakashkumar Dobariya, Antonio Lee, Wei Xie, Jiashu Xie, Joyce Meints, Robert Vince, Michael K Lee, Swati S More","doi":"10.1021/acs.molpharmaceut.5c00382","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00382","url":null,"abstract":"<p><p>Nose-to-brain delivery is an attractive drug delivery strategy for the treatment of Alzheimer's disease (AD) as it offers direct penetration of drugs into the brain by surpassing the blood-brain barrier, while reducing the potential systemic side effects. We developed a glutathione analogue, ψ-GSH, that resists catabolism and reduces AD-related behavioral and pathological abnormalities <i>in vivo</i>. Although ψ-GSH is effective via intraperitoneal administration, limited oral availability hinders the clinical translation of ψ-GSH. In this study, we sought to evaluate if intranasal ψ-GSH administration can provide neuroprotection in an acute mouse model of AD-related pathology. The pharmacokinetic analysis confirmed brain delivery of the compound to levels 4-fold higher than those achieved by an efficacious systemic dose of ψ-GSH. Unaffected stability in simulated nasal fluid and mucosa further displayed the feasibility of this delivery method. Repeated intranasal administration of ψ-GSH prevented cognitive impairment induced by the intracerebroventricular injection of Aβ_1-42 without significant adverse effects. Biochemical and immunohistochemical analyses displayed the beneficial effect of the treatment on oxidative stress and inflammatory markers by engaging GSH-dependent mechanisms, mirroring the pharmacological effects of intraperitoneal ψ-GSH. Additionally, <i>in vitro</i> directional transport studies using a human nasal epithelial cell line showed directional brain transport of ψ-GSH, without compromising the integrity of tight junction proteins. Collectively, our results demonstrate intranasal delivery as a safe and effective alternative for brain delivery of ψ-GSH at pharmacologically relevant concentrations for the treatment of neurological conditions. The study supports future formulation studies for intranasal ψ-GSH administration and its efficacy evaluation in transgenic AD mouse models for preclinical advancement.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pH/GSH Dual-Responsive Janus-Type Au@H-MP@DOX MR Molecular Imaging Nanomotor for Combined Photothermal/Chemotherapeutic Treatment of Pancreatic Cancer.","authors":"Hao Zhang, Dan Xie, Meng Chen, Qiangqiang Yin, Guangyue Shi, Jialong He, Xiaoyang Yu, Qian Lu, Zhengji Wang, Jing Dong, Liguo Hao","doi":"10.1021/acs.molpharmaceut.5c00542","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00542","url":null,"abstract":"<p><p>Chemotherapy is a widely used cancer treatment modality, while the complex tumor microenvironment (TME) significantly impedes drug delivery and deep tissue penetration. An MR molecular imaging drug-loaded nanomotor has been developed to achieve deep tumor tissue penetration and imaging-guided drug delivery, enabling combined photothermal and chemotherapeutic treatment of pancreatic cancer. A Janus-type nanomotor (Au@H-MP NMs) was fabricated via magnetron sputtering for application in photothermal therapy. Doxorubicin (DOX) was loaded onto one hemisphere of the nanomotor, achieving combined photothermal and chemotherapeutic treatment. Additionally, the nanomotor exhibits dual responsiveness to pH and glutathione (GSH), facilitating the controlled release of DOX within deep tumor tissues. Studies confirmed the nanomotors excellent biosafety, strong photothermal conversion capability, and effective induction of apoptosis. Tumor tissue penetration was validated through in vitro migration and infiltration assays, while in vivo experiments demonstrated significant tumor suppression and enhanced drug accumulation. Moreover, MR imaging technology enables real-time monitoring of nanomotor dynamics. These findings suggest that the synthesized Janus-type MR molecular imaging nanomotor offers a promising strategy for multimodal treatment of pancreatic cancer with significant clinical potential.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cleavable PEGylation Enhances the Antitumor Efficacy of Small-Sized Antibody-Drug Conjugates.","authors":"Jiani Han, Keyuan Xu, Liu Yang, Yu Ding, Xi Wang, Dongming Yin, Jian Wang, Hongru Zhang, Zhangyong Hong","doi":"10.1021/acs.molpharmaceut.5c00090","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00090","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics. However, traditional ADCs are often limited by poor tumor penetration due to their large molecular size. While the use of small-sized antibody fragments or analogues can improve tumor permeability, this approach typically results in an extremely shortened blood circulation half-life, which diminishes the therapeutic benefits and brings other metabolic challenges. In addition, the expression of target antigens on normal tissues often leads to unnecessary on-target/off-tumor toxicity. To address these issues, we developed a novel tumor site-specific cleavable PEGylation strategy for small-sized ADC design. The small ADC molecule Z_HER2-MMAE was site-specifically PEGylated at its N-terminus with a 20 kDa polyethylene glycol (PEG) chain and a uPA (LSGRSDNH) cleavage sequence was inserted between them (PEG_20k-U-Z_HER2-MMAE). Our results showed that PEG_20k-U-Z_HER2-MMAE achieves a similar half-life extension (6.4 and 6.0 h) compared to the conventional PEG_20k-Z_HER2-MMAE, both representing about a 26-fold improvement compared to Z_HER2-MMAE. Importantly, PEG_20k-U-Z_HER2-MMAE exhibited significantly higher drug accumulation at the tumor site, leading to the complete eradication of NCI-N87 and SK-OV-3 tumors at a dose of 5.5 mg/kg. Additionally, it demonstrated a maximum tolerated dose (MTD) exceeding 35 mg/kg, while the noncleavable PEG_20k-Z_HER2-MMAE could only slow tumor growth. In addition, compared to Z_HER2-MMAE, the in vitro cytotoxic activity of PEG_20k-Z_HER2-MMAE or PEG_20k-U-Z_HER2-MMAE was reduced by about 50 times, with the latter expected to reduce the on-target/off-tumor side effects due to the specific activation by uPA at tumor sites. These data fully demonstrate the effectiveness and high safety of our tumor-specific cleavable PEGylation strategy, supporting the potential in the development of next-generation ADCs for cancer therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing siRNA Therapeutics Targeting HIF-1α: Computational Design, Screening, and Molecular Dynamics Simulation Studies.","authors":"Neeraj Kumar Shrivastava, Pratibha Verma, Garima Singh, Jyoti Singh, Anurag Kumar, Sneha Yadav, Archana Bharti Sonkar, Mohd Nazam Ansari, Abdulaziz S Saeedan, Yusuf Akhter, Sara A Aldossary, Gaurav Kaithwas","doi":"10.1021/acs.molpharmaceut.5c00104","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00104","url":null,"abstract":"<p><p>Hypoxia-inducible factor-1 alpha (HIF-1α) is an important transcription factor regulating glycolysis, angiogenesis, metastasis, and erythropoiesis under hypoxic conditions in solid tumors. Small interfering RNAs (siRNAs) have emerged as a promising therapeutic approach for solid tumors by selectively silencing target genes. This study explored siRNA-mediated degradation of HIF-1α by specifically targeting HIF-1α mRNA. We retrieved the HIF-1α gene sequence from the database and used various computational tools like siDirect and OligoWalk to get potential 19-21nts long siRNAs. Furthermore, these siRNAs were screened using parameters like sequence specificity, BLASTn, secondary structure formation, GC content, binding affinity between siRNA and mRNA, and thermodynamic properties. The potential siRNAs were further evaluated through molecular docking studies for interaction with the human Argonaute-2 protein (hAgo2), followed by molecular dynamics simulation studies. Post-MD studies revealed S4 (5'UAUAUGGUGAUGAUGUGGC3') as the most potential siRNA candidate against HIF-1α, based on root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and H-bond analysis. Molecular mechanics Poisson-Boltzmann surface area (MMPBSA) analysis was also performed to further validate the selected siRNA candidates, which further affirmed S4 (5'UAUAUGGUGAUGAUGUGGC3') as a potential candidate against HIF-1α.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclodextrin-Based Supramolecular Carrier for Cancer Proteinaceous Antigen.","authors":"Airi Obata, Reina Katanosaka, Toru Taharabaru, Ken-Ichi Arita-Morioka, Chihiro Motozono, Keiichi Motoyama, Taishi Higashi","doi":"10.1021/acs.molpharmaceut.5c00115","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00115","url":null,"abstract":"<p><p>Protein-based vaccines are gaining attention as a promising platform for vaccines because they are highly safe and induce humoral and cellular immunity. However, antigenic proteins have the disadvantages of low cell membrane permeability and easy degradability by endo/lysosomes. Therefore, the development of carriers that can overcome these challenges is essential. We recently developed a supramolecular carrier for the intracellular delivery of genome-editing molecules using cyclodextrin-based aminated polyrotaxanes (amino-PRX). The amino-PRX deformed its structure in response to the complicated shape and charge distribution of the genome-editing molecule, forming a complex with high efficiency. Moreover, by optimizing its structure, a second-generation amino-PRX (2G) possessing endosomal escape ability was constructed. Considering 2G deformability, it is applicable to antigenic proteins and could be an excellent antigen carrier. Therefore, here, we aimed to evaluate the utility of 2G as a protein-based cancer vaccine carrier. The results showed that 2G formed complexes with antigenic proteins efficiently. In addition, the 2G/antigenic protein complex activated immune cells with high efficiency and exhibited excellent antitumor effects. These results suggest that 2G is a promising protein-based cancer vaccine carrier.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Analysis of mRNA Degradation Kinetics Using Chromatographic and Electrophoretic Methods.","authors":"Caio H N Barros, Manuel Alfaro, Agota Csiki-Fejer, Bakul Bhatnagar, Serguei Tschessalov, Steven Ferguson, Sutapa Barua, Ramin Darvari, Elizabeth M Topp","doi":"10.1021/acs.molpharmaceut.4c01543","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01543","url":null,"abstract":"<p><p>The effects of temperature and lipid nanoparticle (LNP) encapsulation on mRNA chemical stability were assessed for two model mRNA (EGFP mRNA, 996 nt; Fluc mRNA, 1929 nt) using capillary electrophoresis (CE) and ion pair reversed phase high performance liquid chromatography (IP-RP-HPLC) to measure mRNA integrity. The apparent degradation rates for unencapsulated (\"naked\") mRNA were method-dependent for Fluc mRNA, with rates up to 50% greater when measured using CE compared to IP-RP-HPLC. This discrepancy is attributed to differences in mass resolution, separation mechanisms and/or linearity of the two methods and was not observed for EGFP mRNA. The apparent reaction order for naked mRNA degradation varied with storage temperature, being zero-order at 35 °C and first-order at 50 °C. Encapsulation of mRNA using LNPs slowed mRNA degradation by up to 9-fold relative to naked mRNA controls stored under the same conditions. Encapsulation also induced changes in thermal unfolding patterns. Overall, the results show the benefits and limitations of each analytical method for determining mRNA degradation kinetics and the effects of temperature and LNP encapsulation on mRNA stability.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Green-Reduced Biodegradable Core-Shell Smart-Responsive MOFs for Photothermal-Enhanced Chemo-Chemodynamic in Tumor Catalysis Therapy.","authors":"Liqun Wei, Yi-Mei Zhang, Xiao-Le Yin, Xuan Zhang, Bing Zhang, Jimin Fan, Zhihuan Zhao, Min Xu","doi":"10.1021/acs.molpharmaceut.5c00328","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00328","url":null,"abstract":"<p><p>Metal-organic frameworks (MOFs) have been widely developed for the treatment of malignant tumors due to their high porosity, ease of functionalization, and smart-responsive degradation. Herein, a core-shell nanocomposite PAZDH (HA@DOX-PDA@Bio-Ag/ZIF-8) based on polydopamine (PDA)-coated green-reduced silver nanoparticles (Bio-Ag NPs) loaded on zeolite imidazolium framework-8 (ZIF-8) is designed, which can trigger near-infrared light (NIR)-enhanced chemodynamic reaction and chemotherapy for effective tumor treatment. Due to the targeting of the shell to the CD44 receptor, which is overexpressed in tumor cells, PAZDH NPs can actively aggregate at the tumor site. Subsequently, based on the pH-sensitive degradation of the core, this nanocomposite can release Bio-Ag NPs and doxorubicin (DOX) in a smart-responsive manner. Moreover, Bio-Ag NPs prepared by the green-reduced method using plant extract have a particle size of 40 nm, which can easily enter the tumor cells by endocytosis and induce apoptosis by catalyzing the production of cytotoxic ·OH from H₂O₂ enriched in the TME. Importantly, the high temperature generated by PTT can promote the release of DOX and accelerate the generation rate of ·OH, enabling photothermal-enhanced chemo-chemodynamic therapy. The PAZDH NPs can efficiently induce tumor ablation and inhibit solid tumors by up to 91.72%. In conclusion, this study provides a promising strategy for the development of smart-responsive MOFs in the field of tumor treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photo-Activated PROTACs for Targeted BRD4 Degradation and Synergistic Photodynamic Therapy in Bladder Cancer.","authors":"Ke Wang, Mingzhu Zhang, Cheng Huang, Jishuang Zhang, Yinan Hua, Xinlu Qin, Yongming Deng, Shaohua Wei, Lin Zhou","doi":"10.1021/acs.molpharmaceut.5c00271","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00271","url":null,"abstract":"<p><p>Proteolysis-targeting chimera (PROTAC) drugs rely on the formation of a ternary complex consisting of the target protein, the drug, and a ubiquitin-protein ligase (E3 ubiquitin ligase). However, some cancer patients may not exhibit sufficient expression of both the target protein and the E3 ligase in tumor tissues, leading to potential off-target effects when treated with conventional PROTACs. In this study, we have developed a photoactivated PROTAC strategy that employs the photosensitizer monosubstituted amino phthalocyanine (ZnPc) and the bromine domain protein 4 (BRD4) ligand (JQ1) as core components. A series of highly active compounds were designed and the most effective and safe candidate (ZnPc-O₃-JQ1), was identified. Upon activation by light, ZnPc-O₃-JQ1 generates reactive oxygen species (ROS) that degrade BRD4. The degradation of BRD4 results in downregulation of hypoxia-inducible factor-1α (HIF-1α), thereby counteracting the treatment resistance induced by tumor hypoxia during photodynamic therapy (PDT). Furthermore, to mitigate oxidative stress caused by ROS, cells upregulate cystine/glutamate antiporter system (Xc^- system, SLC7A11) to enhance glutathione (GSH) synthesis. However, downregulation of HIF-1α inhibits GSH synthesis by inhibiting glutamate-cysteine ligase (GCL, the key enzyme in the de novo synthesis of GSH), disrupting the antioxidant defense system. This photo-PROTAC strategy enables a mutually synergistic effect between PDT and PROTAC, providing a new avenue for the design of safer and more efficient PROTAC drugs, photosensitizers, and combination therapies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}