Article
Chemistry, Multidisciplinary
Anup Dey, Jueun Jeon, Been Yoon, Yuce Li, Jae Hyung Park
Summary: In this study, a self-immolative polymeric prodrug (SPP) was developed, which could selectively degrade and generate large quantities of QMs in cancer cells. SPP self-assembled into nano-sized micelles, encapsulating an anticancer drug 2ME that produces intracellular ROS. The cascade-amplified prodrug SPP@2ME, when treated on cancer cells, rapidly releases 2ME at the ROS-rich intracellular environment, generating more ROS and triggering the degradation of more SPP chains, significantly amplifying oxidative stress and disrupting redox homeostasis in cancer cells.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Biochemistry & Molecular Biology
Agnese Petrini, Giovanni Ievoli, Francesca Migliorini, Maurizio Taddei, Sofia Siciliano
Summary: In this study, a general method for preparing benzylic N-acyl carbamates was developed to mask the amide group in important drugs such as Linezolid, Enzalutamide, or Tasimelteon with good to acceptable yields. These N-acyl carbamates showed stability in plasma, while qualitative analysis revealed that at pH 5.5, a classical 1,6-benzyl elimination mechanism occurred, releasing more than 80% of the drug within 24 hours.
Article
Chemistry, Medicinal
Adrian D. Hobson, Jianwen Xu, Christopher C. Marvin, Michael J. McPherson, Markus Hollmann, Michael Gattner, Kristina Dzeyk, Margaret M. Fettis, Agnieszka K. Bischoff, Lu Wang, Julia Fitzgibbons, Lu Wang, Paulin Salomon, Axel Hernandez Jr, Ying Jia, Hetal Sarvaiya, Christian A. Goess, Suzanne L. Mathieu, Ling C. Santora
Summary: To enable subcutaneous dosing, biotherapeutics need to have properties that allow high-concentration formulation and long-term stability in the formulation buffer. The introduction of drug-linkers in ADCs can increase hydrophobicity and aggregation, which are detrimental to subcutaneous dosing properties. This study demonstrates how the physicochemical properties of ADCs can be controlled by the drug-linker chemistry and prodrug chemistry, resulting in significantly improved solution stability. The use of an accelerated stress test in a minimal formulation buffer is crucial for achieving this optimization.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Selina Hollstein, Lamiaa M. A. Ali, Maeva Coste, Julian Vogel, Nadir Bettache, Sebastien Ulrich, Max von Delius
Summary: The increased importance of RNA-based therapeutics requires the development of next-generation stimuli-responsive systems for binding, transporting, and releasing RNA oligomers. In this study, we present triazolium-based amphiphiles capable of binding siRNA and enzyme-responsive release of the nucleic acid payload. These amphiphiles self-assemble into nanocarriers that can disintegrate in the presence of esterase. The molecular design includes a self-immolative linker anchored to the triazolium moiety, which acts as a positively-charged polar head group. Esterase triggers a cascade degradation of the linker, resulting in the release of the negatively-charged siRNA. This molecular design and approach are promising for various applications beyond this proof-of-principle study, thanks to efficient CuAAC click chemistry and mild esterase cleavage.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Patrick Keppel, Barbara Sohr, Walter Kuba, Marion Goldeck, Philipp Skrinjar, Jonathan C. T. Carlson, Hannes Mikula
Summary: Bond-cleavage reactions triggered by bioorthogonal tetrazine ligation have been used to chemically control the function of (bio)molecules and activate prodrugs. However, current methods for releasing phenols are limited. To address this issue, we developed a self-immolative linker that connects cleavable amines and phenols, allowing for controlled release of prodrugs.
Article
Biochemistry & Molecular Biology
Sabine Schuster, Eva Juhasz, Gabor Halmos, Ines Neundorf, Cesare Gennari, Gabor Mezo
Summary: The cleavable GnRH-III bioconjugates showed a growth inhibitory effect on GnRH receptor-expressing A2780 ovarian cancer cells. Furthermore, the antiproliferative activity of the non-cleavable GnRH-III-drug conjugates using cathepsin B-cleavable linker systems was significantly reduced.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Alberto Dal Corso, Margaux Frigoli, Martina Prevosti, Mattia Mason, Raffaella Bucci, Laura Belvisi, Luca Pignataro, Cesare Gennari
Summary: Amine-carbamate self-immolative (SI) spacers are practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a new pyrrolidine-carbamate SI spacer with a tertiary amine handle, which significantly accelerates the spacer cyclization and allows for the release of cytotoxic or immunostimulatory drugs at the treatment site. In silico analysis suggests a plausible mechanism for the superior efficacy of this advanced SI spacer compared to existing analogues.
Review
Polymer Science
Alexander G. Gavriel, Mark R. Sambrook, Andrew T. Russell, Wayne Hayes
Summary: Interest in self-immolative chemistry has grown over the past decade, with more research groups using versatile linkers to control the release of compounds. These linkers are widely used in medicinal chemistry, analytical chemistry, and material science, and can be found in small molecules, dendritic and polymeric systems. This article reviews key literature in the field and highlights recent examples that show the advancements made in the past decade.
Article
Pharmacology & Pharmacy
Heba S. Abd-Ellah, Ramesh Mudududdla, Glen P. Carter, Jonathan B. Baell
Summary: Drug targeting is essential for delivering drugs to specific sites of action and optimizing their pharmacological effects while minimizing adverse effects. Current colonic drug delivery systems lack site specificity, and new approaches are needed. Amino-alkoxycarbonyloxymethyl (amino-AOCOM) ether prodrugs activated by pH-triggered intramolecular cyclisation-elimination reaction show potential for colonic delivery. Model compounds and mesalamine (Msl) prodrugs were evaluated under simulated gastrointestinal conditions, demonstrating stability and sustained release at colonic pH. This study provides proof of concept for cyclisation-activated prodrugs for colon delivery, but release characteristics may vary.
Article
Multidisciplinary Sciences
Min-Sik Lee, Courtney Dennis, Insia Naqvi, Lucas Dailey, Alireza Lorzadeh, George Ye, Tamara Zaytouni, Ashley Adler, Daniel S. Hitchcock, Lin Lin, Megan T. Hoffman, Aladdin M. Bhuiyan, Jaimie L. Barth, Miranda E. Machacek, Mari Mino-Kenudson, Stephanie K. Dougan, Unmesh Jadhav, Clary B. Clish, Nada Y. Kalaany
Summary: This study reveals the distinct dependence of pancreatic ductal adenocarcinoma (PDA) on de novo ornithine synthesis from glutamine, mediated by ornithine aminotransferase (OAT), which is required for tumor growth and polyamine synthesis. The reliance on OAT-mediated ornithine synthesis in PDA provides a potential therapeutic window for treating pancreatic cancer with minimal toxicity.
Article
Chemistry, Multidisciplinary
Yufei Cao, Jiale Si, Moujiang Zheng, Qinghao Zhou, Zhishen Ge
Summary: Radiotherapy is widely used in the treatment of various cancers and has the advantages of precise controllability and deep tissue penetration. However, it is limited by side effects and tumor hypoxia. The combination of radiotherapy and other modalities can improve therapeutic efficacy and reduce toxicity.
CHEMICAL COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Qi-Zhang Li, Zan-Wen Zuo, Ze-Rong Zhou, Yan Ji
Summary: Polyamine metabolism plays a crucial role in anticancer strategies, with combination therapies and effective use of natural active ingredients showing promising results. Polyamine metabolic enzymes are key therapeutic targets, and combination therapies may be more effective than monotherapies based on polyamine depletion.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Chemistry, Physical
Dina M. Silva, Ruy Liu, Anabela F. Goncalves, Andre da Costa, Andreia Castro Gomes, Raul Machado, Jitraporn Vongsvivut, Mark J. Tobin, Vitor Sencadas
Summary: The study successfully produced polymer-polymer core-shell microparticles through emulsion and spray drying, with suitable size for inhalation therapies. These microparticles have the potential to combine and release different drugs effectively, offering promising clinical applications.
JOURNAL OF COLLOID AND INTERFACE SCIENCE
(2021)
Article
Chemistry, Medicinal
Brooklynn Venteicher, Kasey Merklin, Huy X. Ngo, Huan-Chieh Chien, Keino Hutchinson, Jerome Campbell, Hannah Way, Joseph Griffith, Cesar Alvarado, Surabhi Chandra, Evan Hill, Avner Schlessinger, Allen A. Thomas
Summary: This study investigated the impact of connecting hydrophobic moieties and carbonyl groups on LAT1 transport activity, finding that meta-carboxyl l-phenylalanine esters had better LAT1 transport rates compared to acylated l-tyrosine analogues. However, as the size of the hydrophobic moiety increased, there was a decrease in LAT1 transport rate with a concomitant increase in potency of inhibition.
Article
Biochemistry & Molecular Biology
Ahmed K. Aladhami, Christian A. Unger, Shannon L. Ennis, Diego Altomare, Hao Ji, Marion C. Hope, Kandy T. Velazquez, Reilly T. Enos
Summary: Macrophage-derived TNF-alpha does not play a significant role in the development of obesity, but can reduce TNF-alpha gene expression and circulating levels in adipose tissue, as well as modulate specific signaling pathway gene expression.
Review
Pharmacology & Pharmacy
Jatin Machhi, Farah Shahjin, Srijanee Das, Milankumar Patel, Mai Mohamed Abdelmoaty, Jacob D. Cohen, Preet Amol Singh, Ashish Baldi, Neha Bajwa, Raj Kumar, Lalit K. Vora, Tapan A. Patel, Maxim D. Oleynikov, Dhruvkumar Soni, Pravin Yeapuri, Insiya Mukadam, Rajashree Chakraborty, Caroline G. Saksena, Jonathan Herskovitz, Mahmudul Hasan, David Oupicky, Suvarthi Das, Ryan F. Donnelly, Kenneth S. Hettie, Linda Chang, Howard E. Gendelman, Bhavesh D. Kevadiya
Summary: This article summarizes the treatment and vaccine development during the COVID-19 pandemic, focusing on the role played by nanocarrier delivery.
ADVANCED DRUG DELIVERY REVIEWS
(2021)
Article
Nanoscience & Nanotechnology
Ling Ding, Siyuan Tang, Ao Yu, Anlin Wang, Weimin Tang, Huizhen Jia, David Oupicky
Summary: Pancreatic cancer progression relies on the nervous tumor microenvironment. This study utilized cationic perfluorocarbon nanoemulsions to deliver therapeutic siRNA and silence nerve growth factor (NGF) expression in orthotopic pancreatic tumors. The nanoemulsions achieved deep tumor penetration, enhanced NGF gene silencing, and effectively suppressed tumor growth in vivo and in vitro compared to control polycation/siRNA polyplexes. Delivery of NGF siRNA using nanoemulsion is a promising treatment approach for pancreatic cancer by targeting the tumor-neuronal interactions.
ACS APPLIED MATERIALS & INTERFACES
(2022)
Review
Biotechnology & Applied Microbiology
Raj Kumar, Keshaw Ram Aadil, Kunal Mondal, Yogendra Kumar Mishra, David Oupicky, Seeram Ramakrishna, Ajeet Kaushik
Summary: Neurodegenerative disorders are prevalent among the aging population, causing memory loss and motor coordination issues, leading to significant socio-economic burdens. Nano-biotechnology-based approaches offer effective and personalized alternatives for managing these diseases.
CRITICAL REVIEWS IN BIOTECHNOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Weimin Tang, Yi Chen, Hee-Seong Jang, Yu Hang, Chinmay M. Jogdeo, Jing Li, Ling Ding, Chuhan Zhang, Ao Yu, Fei Yu, Kirk W. Foster, Babu J. Padanilam, David Oupicky
Summary: This study introduces a siRNA carrier designed for injured kidneys in AKI, showing potential to enhance therapeutic effects and improve kidney function. By inhibiting CXCR4 and p53 simultaneously, the PCX/sip53 polyplexes can selectively deliver therapeutic siRNA in AKI, reducing renal damage.
JOURNAL OF CONTROLLED RELEASE
(2022)
Article
Chemistry, Multidisciplinary
Ling Ding, Siyuan Tang, Weimin Tang, Deanna D. Mosley, Ao Yu, Diptesh Sil, Svetlana Romanova, Kristina L. Bailey, Daren L. Knoell, Todd A. Wyatt, David Oupicky
Summary: This study reports a method using PFOB nanoemulsions to improve the delivery efficiency of siRNA in the treatment of pulmonary fibrosis. The results show that the nanoemulsions can effectively treat pulmonary fibrosis and inhibit the progression of the disease.
Article
Biochemistry & Molecular Biology
Weimin Tang, Sudipta Panja, Chinmay M. Jogdeo, Siyuan Tang, Ao Yu, David Oupicky
Summary: This study investigates the impact of charge and hydrophilicity of polymers on their accumulation in injured kidneys and demonstrates that polymers with hydroxyl group modification show the least accumulation. These findings provide important guidance for the development of targeted drug carriers for AKI therapy.
Article
Engineering, Biomedical
Weimin Tang, Sudipta Panja, Chinmay M. Jogdeo, Siyuan Tang, Ling Ding, Ao Yu, Kirk W. Foster, Del L. Dsouza, Yashpal S. Chhonker, Heather Jensen-Smith, Hee-Seong Jang, Erika I. Boesen, Daryl J. Murry, Babu Padanilam, David Oupicky
Summary: This study demonstrates the synthesis of a novel siRNA carrier, C-CS, which shows potential for targeted delivery to injured kidneys. The C-CS/siRNA nanoparticles effectively accumulate and deliver therapeutic siRNAs to injured kidneys through CXCR4 binding, providing a new approach for AKI therapy.
Article
Biochemistry & Molecular Biology
Diptesh Sil, Sudipta Panja, Chinmay M. Jogdeo, Raj Kumar, Ao Yu, Cassandra E. Holbert, Ling Ding, Jackson R. Foley, Tracy Murray Stewart, Robert A. Casero, David Oupicky
Summary: The PG11047 analogs HPGs showed enhanced anticancer activity in various cancer cell lines, with the ability to self-assemble and form nanoparticles.
Article
Pharmacology & Pharmacy
Chuhan Zhang, Yu Hang, Weimin Tang, Diptesh Sil, Heather C. Jensen-Smith, Robert G. Bennett, Benita L. McVicker, David Oupicky
Summary: This study developed dual-functioning nanoparticles for the effective delivery of antifibrotic RNA and CXCR4 inhibitor, which shows promise for improving the treatment of alcohol-associated liver disease. The nanoparticles were able to significantly silence miR-155 expression and reduce liver damage in a model.
Article
Engineering, Biomedical
Huizhen Jia, Ling Ding, Ao Yu, Weimin Tang, Siyuan Tang, Chuhan Zhang, David Oupicky
Summary: Crosstalk between Kupffer cells (KCs) and hepatic stellate cells (HSCs) is important in liver fibrosis, and inhibiting this crosstalk can reverse alcohol-associated liver disease (AALD) fibrosis. In this study, a multifunctional nanosystem was designed to block the crosstalk by downregulating miR-155 expression in KCs and inhibiting CXCR4 signaling in activated HSCs. The combination of these inhibitions improved antifibrosis effects in an AALD fibrosis mouse model.
BIOACTIVE MATERIALS
(2023)
Article
Pharmacology & Pharmacy
Zheng-Hong Peng, Chinmay M. Jogdeo, Jing Li, Ying Xie, Yazhe Wang, Yuri M. Sheinin, Jindrich Kopecek, David Oupicky
Summary: Significant progress has been made in nanomedicine for cancer treatment, but there is relatively less research on managing tumor metastasis. This study introduces a polymeric conjugate P-DOX-iRGD that not only inhibits primary tumor growth but also substantially inhibits pulmonary metastasis in a breast cancer mouse model. Furthermore, treatment with P-DOX-iRGD reduces splenomegaly and liver hematopoiesis caused by breast cancer.
Article
Medicine, Research & Experimental
Rubayat Khan, Sudipta Panja, Ling Ding, Siyuan Tang, Weimin Tang, Ekta Kapoor, Robert G. Bennett, David Oupicky
Summary: Polymeric HCQ (PCQ) has shown to efficiently inhibit cancer cell migration and colony formation, and has strong antimetastatic activity in a pancreatic cancer model, suggesting its potential as an adjuvant therapy for pancreatic cancer.
MOLECULAR PHARMACEUTICS
(2022)
Review
Engineering, Biomedical
Chinmay M. Jogdeo, Sudipta Panja, Shrey Kanvinde, Ekta Kapoor, Kasturi Siddhanta, David Oupicky
Summary: Combination therapy is effective in cancer and inflammatory diseases, and lipid-based codelivery systems have attracted attention due to their low toxicity, biocompatibility, and ease of formulation scale-up.
ADVANCED HEALTHCARE MATERIALS
(2023)
Review
Biotechnology & Applied Microbiology
Shrey Kanvinde, Tanmay Kulkarni, Suyash Deodhar, Deep Bhattacharya, Aneesha Dasgupta
Summary: The paper reviews the application of non-viral vectors in nucleic acid therapy and discusses their current applications as well as the regulatory landscape for the commercial translation of gene therapy.