Molecular Pharmaceutics最新文献

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Exploring the Relationships between Targeted Structures and Antitumor Activities of Nuclear-Targeted Polypeptide-Functionalized Platinum(IV) Prodrugs 探讨核靶向多肽功能化铂(IV)前药的靶向结构与抗肿瘤活性的关系。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-17 DOI: 10.1021/acs.molpharmaceut.5c01110
Ruihan Li, , , Xuan Yin, , , Chuanke Chong, , , Yan Li, , , Qingqiang Yao, , , Yanling Mu*, , and , Chunyu Zhang*, 
{"title":"Exploring the Relationships between Targeted Structures and Antitumor Activities of Nuclear-Targeted Polypeptide-Functionalized Platinum(IV) Prodrugs","authors":"Ruihan Li,&nbsp;, ,&nbsp;Xuan Yin,&nbsp;, ,&nbsp;Chuanke Chong,&nbsp;, ,&nbsp;Yan Li,&nbsp;, ,&nbsp;Qingqiang Yao,&nbsp;, ,&nbsp;Yanling Mu*,&nbsp;, and ,&nbsp;Chunyu Zhang*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c01110","DOIUrl":"10.1021/acs.molpharmaceut.5c01110","url":null,"abstract":"<p >Polypeptides as drug delivery vehicles can achieve the targeted therapeutic effects of first-line platinum drugs in clinical practice, providing an important method to solve problems such as the high systemic toxicity of first-line platinum drugs. In this work, we employ a rational molecular conjugation strategy to design and synthesize two platinum(IV) prodrugs. The first, s-CisPt(IV)-TAT, is linked to a single nuclear-targeting polypeptide, while the second, d-CisPt(IV)-TAT, is conjugated with two of these polypeptides. Interestingly, despite the higher degree of functionalization, disubstituted d-CisPt(IV)-TAT exhibits lower reactivity and cytotoxicity than its monosubstituted counterpart. This counterintuitive result suggests that overloading with multiple ligands may reduce cellular uptake, thereby compromising therapeutic efficacy. Furthermore, both constructs are shown to induce apoptosis via DNA damage pathways, confirming their mechanism of action. These results underscore the importance of precisely tuning the ligand density in drug carriers. Our work provides valuable insights into the structure–activity relationships governing platinum prodrugs and highlights the need for a balance between functional density and biological performance in the design of next-generation polypeptide-conjugated chemotherapeutics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6349–6356"},"PeriodicalIF":4.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079160","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}
引用次数: 0
A Comparative Study of Flash Nanoprecipitation and Sequential Nanoprecipitation: Impact of Formulation Parameters on Drug-Loaded Nanoparticle Formation 纳米闪蒸沉淀法与顺序沉淀法的对比研究:配方参数对载药纳米颗粒形成的影响。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-17 DOI: 10.1021/acs.molpharmaceut.5c00835
Nouha El Amri, , , Amy McKinstry, , , Rachel E. Pollard, , , Parker K. Lewis, , and , Nathalie M. Pinkerton*, 
{"title":"A Comparative Study of Flash Nanoprecipitation and Sequential Nanoprecipitation: Impact of Formulation Parameters on Drug-Loaded Nanoparticle Formation","authors":"Nouha El Amri,&nbsp;, ,&nbsp;Amy McKinstry,&nbsp;, ,&nbsp;Rachel E. Pollard,&nbsp;, ,&nbsp;Parker K. Lewis,&nbsp;, and ,&nbsp;Nathalie M. Pinkerton*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00835","DOIUrl":"10.1021/acs.molpharmaceut.5c00835","url":null,"abstract":"<p >Flash NanoPrecipitation (FNP) is a well-established method for forming core–shell drug-loaded nanoparticles that has demonstrated effectiveness for encapsulating highly hydrophobic compounds. However, certain formulation challenges persist, including size limitations and reduced encapsulation efficiency for moderately hydrophobic drugs. Sequential NanoPrecipitation (SNaP) is a novel nanoparticle synthesis process that relies on the same assembly principle as FNP, while decoupling the core formation and stabilization. Through a systematic comparison using drugs with varying hydrophobicity, we demonstrate complementary capabilities between these techniques. We showed that for the high hydrophobicity drugs such as β-carotene, both SNaP and FNP performed effectively. In the case of cinnarizine, a moderately hydrophobic drug that requires the use of hydrophobic ion pairing, good encapsulation efficiency was observed for the case of SNaP, while no encapsulation was observed with FNP. For ibuprofen, a water-soluble analgesic, low encapsulation efficiency was observed with SNaP, and no loading was observed with FNP. Release studies with itraconazole nanoparticles revealed that SNaP-produced nanoparticles exhibited approximately 50% slower release rates compared to FNP over 48 h. Additionally, SNaP enabled access to a broader size range and successful nanoparticle formation at lower solid concentrations. These findings establish SNaP as a valuable complement to FNP, particularly for applications requiring larger nanoparticles, encapsulation of moderately hydrophobic compounds, or modified release kinetics. Together, these nanoprecipitation approaches provide formulators with expanded capabilities for developing polymeric nanoparticle drug delivery systems.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6108–6119"},"PeriodicalIF":4.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.molpharmaceut.5c00835","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Choline-Retinoic Acid Ionic Liquid [Cho][Ra] as Potential Adjuvant to Enhance Humoral, Cellular, and Mucosal Immune Responses of SARS-CoV-2 RBD Antigen 胆碱-维甲酸离子液体[Cho][Ra]作为潜在佐剂增强SARS-CoV-2 RBD抗原的体液、细胞和粘膜免疫应答
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-17 DOI: 10.1021/acs.molpharmaceut.5c00470
Hongyu Zhu, , , Sen Yang, , , Jingyang Zhao, , , Liuyang Wang, , , Chenghao Gao, , , Yanan Sheng, , , Xuan Lin, , , Zhiguo Su, , , Kiichi Sato*, , , Zhongyu Hu*, , and , Songping Zhang*, 
{"title":"Choline-Retinoic Acid Ionic Liquid [Cho][Ra] as Potential Adjuvant to Enhance Humoral, Cellular, and Mucosal Immune Responses of SARS-CoV-2 RBD Antigen","authors":"Hongyu Zhu,&nbsp;, ,&nbsp;Sen Yang,&nbsp;, ,&nbsp;Jingyang Zhao,&nbsp;, ,&nbsp;Liuyang Wang,&nbsp;, ,&nbsp;Chenghao Gao,&nbsp;, ,&nbsp;Yanan Sheng,&nbsp;, ,&nbsp;Xuan Lin,&nbsp;, ,&nbsp;Zhiguo Su,&nbsp;, ,&nbsp;Kiichi Sato*,&nbsp;, ,&nbsp;Zhongyu Hu*,&nbsp;, and ,&nbsp;Songping Zhang*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00470","DOIUrl":"10.1021/acs.molpharmaceut.5c00470","url":null,"abstract":"<p >All-trans retinoic acid (Ra) has been demonstrated to enhance the establishment of systemic and intestinal immunity for codelivered antigens; however, the extremely poor water solubility of Ra significantly limits its application in vaccines. Herein, leveraging the advantages of ionic liquids in modifying the physicochemical properties of small-molecule drugs, we synthesized a novel ionic liquid composed of choline and retinoic acid ([Cho][Ra]). Compared to Ra, [Cho][Ra] exhibited an 18165-fold increase in solubility at pH 7.4 and an acid-responsive Ra release behavior. The [Cho][Ra] was then formulated with the SARS-CoV-2 RBD antigen, and its adjuvant effects were comprehensively evaluated. The <i>in vitro</i> cellular studies indicated that at 50 μg Ra equivalent dose, the [Cho][Ra]@RBD showed significantly higher than RBD along in activation of BMDC and the expression of gut homing molecules, including C–C motif chemokine receptor 9 (CCR9, 10.55 folds), α4β7 integrin (13.29 folds), and lymph node migration molecule CCR7 (82.68 folds). Animal experiments showed that compared to RBD alone, [Cho][Ra]@RBD promoted the establishment of mucosal immunity in the intestines in mice at the early stage following subcutaneous immunization and elicited higher serum antibody levels. Furthermore, compared to RBD and Alum@RBD, [Cho][Ra]@RBD enhanced the formation of CD4<sup>+</sup> T<sub>CM</sub> and CD8<sup>+</sup> T<sub>CM</sub> cells, indicating stronger cellular immune responses. In summary, [Cho][Ra] showed potential adjuvant effects in enhancing the humoral and cellular immune responses, as well as in the establishment of intestinal mucosal immunity for RBD antigen without the need for delivery system, thereby offering promising prospects for applying Ra in vaccines.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"5898–5913"},"PeriodicalIF":4.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074105","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}
引用次数: 0
Cinnamaldehyde-Containing Organoarsenic Prodrug with Synergistic Anticancer Activity via Redox Dyshomeostasis 含肉桂醛的有机砷前药通过氧化还原失衡具有协同抗癌活性。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-15 DOI: 10.1021/acs.molpharmaceut.5c00778
Hui Xiong, , , Jingxue Yan, , , Jun Zhang, , , Yuhang Jiang, , , Xiaoqin Chi*, , , Hongyu Lin*, , and , Jinhao Gao, 
{"title":"Cinnamaldehyde-Containing Organoarsenic Prodrug with Synergistic Anticancer Activity via Redox Dyshomeostasis","authors":"Hui Xiong,&nbsp;, ,&nbsp;Jingxue Yan,&nbsp;, ,&nbsp;Jun Zhang,&nbsp;, ,&nbsp;Yuhang Jiang,&nbsp;, ,&nbsp;Xiaoqin Chi*,&nbsp;, ,&nbsp;Hongyu Lin*,&nbsp;, and ,&nbsp;Jinhao Gao,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00778","DOIUrl":"10.1021/acs.molpharmaceut.5c00778","url":null,"abstract":"<p >The severe occurrence and mortality of cancer and the gradually increasing failure rate of traditional chemotherapeutic agents call for the search for alternative strategies for cancer therapy. Herein, we report the development of a small-molecule prodrug TAO-CA by conjugating a trivalent organoarsenical (TAO) with a natural product cinnamaldehyde (CA) via an acetal linkage. This prodrug is able to be activated under the mildly acidic environment of the tumor to release the two parent drugs for simultaneously inhibiting the activity of thioredoxin reductase (TrxR) and reducing the cellular level of glutathione (GSH), resulting in intracellular redox dyshomeostasis and consequent cancer cell apoptosis for effective inhibition of tumor growth. The mechanism and efficacy of this prodrug have been validated by a series of <i>in vitro</i> and <i>in vivo</i> experiments, demonstrating the promising potential of our strategy, the integration of the prodrug approach, and synergistic redox dyshomeostasis induction for effective cancer therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6083–6091"},"PeriodicalIF":4.5,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062936","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}
引用次数: 0
Development of a Dual-Modal PET/NIR-II Probe of Urofollitropin for Enhanced Follicle-Stimulating Hormone Receptor-Targeted Imaging in Diverse Tumors 双模PET/NIR-II尿卵泡素探针在不同肿瘤促卵泡激素受体靶向成像中的应用
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-15 DOI: 10.1021/acs.molpharmaceut.5c00961
Yu Sun, , , Chunrong Qu, , , Kun Qian, , , Xiao Zhang, , , Jun Zhao*, , , Hao Chen*, , and , Zhen Cheng*, 
{"title":"Development of a Dual-Modal PET/NIR-II Probe of Urofollitropin for Enhanced Follicle-Stimulating Hormone Receptor-Targeted Imaging in Diverse Tumors","authors":"Yu Sun,&nbsp;, ,&nbsp;Chunrong Qu,&nbsp;, ,&nbsp;Kun Qian,&nbsp;, ,&nbsp;Xiao Zhang,&nbsp;, ,&nbsp;Jun Zhao*,&nbsp;, ,&nbsp;Hao Chen*,&nbsp;, and ,&nbsp;Zhen Cheng*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00961","DOIUrl":"10.1021/acs.molpharmaceut.5c00961","url":null,"abstract":"<p >The overexpression of follicle-stimulating hormone receptor (FSHR) in diverse tumors, with low or no expression in normal tissues, makes it a promising target for cancer diagnosis and therapy. Urofollitropin (uFSH), a highly purified form of FSH extracted from the urine of postmenopausal women, is widely used in treating infertility or hypogonadotropic hypogonadism through specifically binding to FSHR expressed on ovaries or granulosa cells in the clinic. Given the specific binding between uFSH and FSHR, the uFSH-derived probe may serve as a potential tool for diagnosing diverse tumors. Therefore, in the present study, using uFSH as the precursor, we developed a dual-modal PET/NIR-II probe named <sup>64</sup>Cu-NODAGA-uFSH-CH1055 and studied its binding specificity to FSHR in diverse cancers <i>in vitro</i> and <i>in vivo</i>. <i>In vitro</i> cell assays revealed significantly lower fluorescence in the blocking group than in the unblocking group in U87-MG, HT-29, 143B, and PC-3 tumor cells (<i>p</i> &lt; 0.05). Both <i>in vivo</i> PET/CT and NIR-II imaging demonstrated clear tumor visualization. The U87-MG tumors had the highest radioactive uptake (1.80% ± 0.23% ID/g), followed by HT-29 (1.25% ± 0.23% ID/g), 143B (0.98% ± 0.02% ID/g), and PC-3 (0.75% ± 0.11% ID/g) (<i>p</i> = 0.024). The same fluorescence signal intensity trend in diverse tumors was found in the NIR-II images, which was consistent with the FSHR expression detected by Western blotting. Both i<i>n vitro</i> and <i>in vivo</i> assays showed the specific FSHR-targeting capability of <sup>64</sup>Cu-NODAGA-uFSH-CH1055 in diverse tumors, indicating that the uFSH-based dual-modal probe has the potential for the noninvasive visualization of various tumors through PET/CT and NIR-II imaging.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6228–6236"},"PeriodicalIF":4.5,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068601","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}
引用次数: 0
Computation Simulation of Nanoparticle Endocytosis: Do Individual Particles Synergize with Each Other for Cell Entry? 纳米颗粒内吞作用的计算模拟:单个颗粒是否相互协同进入细胞?
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-15 DOI: 10.1021/acs.molpharmaceut.5c00834
Yiqin Li, , , Nianwu Wang, , and , Hong-Bo Pang*, 
{"title":"Computation Simulation of Nanoparticle Endocytosis: Do Individual Particles Synergize with Each Other for Cell Entry?","authors":"Yiqin Li,&nbsp;, ,&nbsp;Nianwu Wang,&nbsp;, and ,&nbsp;Hong-Bo Pang*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00834","DOIUrl":"10.1021/acs.molpharmaceut.5c00834","url":null,"abstract":"<p >After decades of research, nanomaterials have been widely used in various applications, including biomedical materials as therapies themselves or drug carriers. In such cases, cell entry is a crucial step, which has been extensively studied. However, one fundamental and yet long-overlooked question is whether there is any synergy among individual nanoparticles (NPs) in this process. We previously reported the bystander uptake of NPs, a synergistic phenomenon in which NPs facilitate each other for cell entry. Moreover, we then harnessed molecular dynamics simulation, a method that has been used to study NP–cell interactions, to elicit the biophysical basis of bystander uptake. This review provides a brief overview of current nanotechnology for intracellular delivery, the underlying endocytic pathway, and the use of molecular dynamics simulation on NP–cell interaction. Our emphasis is then on the bystander uptake system and its translational applications and the recent advance in understanding its mechanism with computational simulation and biophysics. These efforts may provide novel insights on the synergy among individual NPs during cell encounter and endocytosis and open new avenues to understand NP uptake with computation simulation and biophysical perspective.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"5791–5800"},"PeriodicalIF":4.5,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062870","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}
引用次数: 0
Enhancement of Targeted and Antitumor Effects of M1 Macrophages Based on Bioorthogonal Reactions 基于生物正交反应增强M1巨噬细胞靶向和抗肿瘤作用。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-15 DOI: 10.1021/acs.molpharmaceut.5c00856
Xin Ding, , , Yang Zhang, , , Songshen Chu, , , Song Huang, , , Jiajia Wang*, , and , Xia Li*, 
{"title":"Enhancement of Targeted and Antitumor Effects of M1 Macrophages Based on Bioorthogonal Reactions","authors":"Xin Ding,&nbsp;, ,&nbsp;Yang Zhang,&nbsp;, ,&nbsp;Songshen Chu,&nbsp;, ,&nbsp;Song Huang,&nbsp;, ,&nbsp;Jiajia Wang*,&nbsp;, and ,&nbsp;Xia Li*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00856","DOIUrl":"10.1021/acs.molpharmaceut.5c00856","url":null,"abstract":"<p >Chimeric antigen receptor macrophages (CAR-Ms), which are genetically engineered, have application prospects in solid tumor therapy because of the prominent role of macrophages in the tumor microenvironment. Recently, non-natural sugar metabolic labeling based on bioorthogonal reactions has emerged as a research hotspot in targeted tumor therapy. In this study, 4T1 cells and M1 macrophages were incubated with Ac<sub>4</sub>GalBCN and Ac<sub>4</sub>ManNAz, respectively, to equip the cell surfaces with –BCN and –N<sub>3</sub> groups. These modifications enhanced the proximity between these two kinds of cells and promoted phagocytosis and cytokine release. Moreover, compared to other groups, the bioorthogonal labeling group exhibited heightened tumor-targeted effects and antitumor phagocytic activity against 4T1 cells in vivo. Addition of the small-molecule inhibitor RRx-001 further improved the synergistic effect on phagocytosis and immune cell phenotypes in tumors. In summary, our study highlights the metabolic labeling strategy as a potent approach to promote M1 macrophage-mediated antitumor responses within the tumor environment, providing a novel means for the development of therapeutic strategies tailored for solid tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6151–6162"},"PeriodicalIF":4.5,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062946","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}
引用次数: 0
Targeting Subcellular Organelles in Breast Cancer with Enzyme Induced Self-Assembly: Stimulated Response with Eyes-Absence Enzymes (EYA) 用酶诱导的自组装靶向乳腺癌亚细胞细胞器:眼缺失酶(EYA)的刺激反应。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-14 DOI: 10.1021/acs.molpharmaceut.5c00546
Emily Carney, , , Robert Powell, , , Ananya Kumar, , and , Neda Habibi*, 
{"title":"Targeting Subcellular Organelles in Breast Cancer with Enzyme Induced Self-Assembly: Stimulated Response with Eyes-Absence Enzymes (EYA)","authors":"Emily Carney,&nbsp;, ,&nbsp;Robert Powell,&nbsp;, ,&nbsp;Ananya Kumar,&nbsp;, and ,&nbsp;Neda Habibi*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00546","DOIUrl":"10.1021/acs.molpharmaceut.5c00546","url":null,"abstract":"<p >Self-assembly of short peptides induced by enzymes is an emerging pathway to overcome drug resistance in cancer. However, specific targeting requires optimal precursor design and understanding of subcellular interactions. In our study, we synthesized six short peptides by modifying the N-terminal motif with fluorenylmethyloxycarbonyl (Fmoc), diphenyalanine (FF), arginylglycylaspartic acid (RGD), naphthyl (Nap), and 4-nitrobenz-2-oxa-1,3-diazole (NBD) motifs and including C terminal activation groups of tyrosine phosphate (pTyr) and threonine phosphate (pThr). We utilized the tyrosine phosphatase activity of Eye Absent Enzyme (EYA) to induce self-assembly of short peptides in breast cancer cells. The subcellular interaction of P1–P6 on DNA, mitochondria, and the cell membrane were evaluated in MDA-MB-231 (receptor-negative), MCF-7 (receptor-positive), and MCF10 (nontumorigenic epithelial breast) cells. Being dephosphorylated by EYA, the peptide transformed from monomers to assembled, which was confirmed by UV absorption shift and released phosphate. Studying protein expression showed that EYA2 is expressed in breast cancer cells but is absent in normal epithelial breast cells. The peptide/assemblies first aggregate on the cell membrane, then enter the cells, and accumulate in nuclei. Fmoc–FF–pTyr and RGD–FF–pTyr demonstrated significant binding affinity for phosphatidylserine on the surface of apoptotic cells. Among these, Fmoc–FF–pTyr effectively induced DNA damage and triggered apoptosis in cancer cells while remaining nontoxic to normal cells at optimal concentrations (10 μM). Peptides containing Nap groups selectively accumulated in the mitochondria of MCF-7 and MDA-MB-231 cells, enhancing the effectiveness of the doxorubicin treatments. These results demonstrate the critical role of EISA precursor in modulating phosphatase induced pathways by EYA’s in breast cancer and the importance of considering these properties in nanotherapeutic design.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"5914–5927"},"PeriodicalIF":4.5,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062955","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}
引用次数: 0
Self-Assembling Antioxidant Nanoparticles Increase Survival and Reduce Disease Symptoms of Severe Malaria 自组装抗氧化纳米颗粒增加生存并减少严重疟疾的疾病症状。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-13 DOI: 10.1021/acs.molpharmaceut.5c00419
Toru Yoshitomi, , , Kyoko Hayashi, , , Tamasa Araki, , , Takeshi Annoura, , and , Yukio Nagasaki*, 
{"title":"Self-Assembling Antioxidant Nanoparticles Increase Survival and Reduce Disease Symptoms of Severe Malaria","authors":"Toru Yoshitomi,&nbsp;, ,&nbsp;Kyoko Hayashi,&nbsp;, ,&nbsp;Tamasa Araki,&nbsp;, ,&nbsp;Takeshi Annoura,&nbsp;, and ,&nbsp;Yukio Nagasaki*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00419","DOIUrl":"10.1021/acs.molpharmaceut.5c00419","url":null,"abstract":"<p >Severe infectious diseases trigger a rapid increase in cytokines, known as a cytokine storm, accompanied by an excessive rise in reactive oxygen species (ROS), leading to severe damage to tissues and cells. While antioxidants have been used to eliminate ROS, conventional low-molecular-weight (LMW) antioxidants fail to effectively mitigate oxidative stress in infectious diseases due to rapid metabolism, excretion, and potential disruption of the redox balance within normal cells. We developed a novel self-assembling antioxidant nanoparticle, termed a redox nanoparticle (RNP), designed to prevent rapid metabolism and excretion. Furthermore, due to its nanoscale size and poly(ethylene glycol) shell, RNP exhibits limited entry into normal cells, preserving the intracellular redox balance. This study evaluates the impact of RNP on oxidative stress associated with infectious diseases, utilizing a <i>Plasmodium berghei</i>-induced malaria model in mice. After intraperitoneal administration, RNP was absorbed into the bloodstream and remained in circulation for over 24 h. In the malaria model, we observed that once the threshold of erythrocyte parasite infection was exceeded, ROS levels in the blood dramatically increased in untreated infected mice, causing lethal damage. The administration of LMW TEMPOL resulted in only a marginal reduction in ROS, whereas RNP significantly decreased ROS levels, leading to a marked improvement in disease severity and survival. Moreover, the RNP suppressed the oxidation and fragility of erythrocyte membranes caused by infection. These findings highlight the potential of RNP as a breakthrough therapeutic agent for malaria and other infectious diseases characterized by excessive oxidative stress.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"5879–5886"},"PeriodicalIF":4.5,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051308","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}
引用次数: 0
Voices in Molecular Pharmaceutics: Meet Dr. Awesh K. Yadav, Who Advances Treatment for Cancer and Neurological Disorders. 分子药剂学的声音:认识Awesh K. Yadav博士,他推动了癌症和神经系统疾病的治疗。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-09-12 DOI: 10.1021/acs.molpharmaceut.5c01304
Awesh K Yadav
{"title":"Voices in <i>Molecular Pharmaceutics</i>: Meet Dr. Awesh K. Yadav, Who Advances Treatment for Cancer and Neurological Disorders.","authors":"Awesh K Yadav","doi":"10.1021/acs.molpharmaceut.5c01304","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c01304","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038848","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}
引用次数: 0
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