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https://read.qxmd.com/read/34109794/prodrug-delivery-using-dual-targeting-nanoparticles-to-treat-breast-cancer-brain-metastases
#1
Xiufeng Ju, Haiyan Chen, Tongtong Miao, Jiang Ni, Liang Han
Brain metastases from breast cancer are the most frequent brain metastasis in women, which are often difficult to be surgically removed due to the multifocal and infiltrative intracranial growth patterns. Cytotoxic drugs have potent anti-breast cancer properties. However, owing to the toxic side effects and the blood-brain barrier (BBB), these drugs cannot be fully and aggressively exploited with systemic administration and hence have very limited application for brain metastases. In this study, hyaluronidase-activated prodrug hyaluronic-doxorubicin ( h DOX) was assembled by the BBB and metastatic breast cancer dual-targeting nanoparticles (NPs), which were constructed based on transcytosis-targeting peptide and hyaluronic acid co-modified poly(lactic-co-glycolic acid)-poly( ε -carbobenzoxy-l-lysine)...
June 10, 2021: Molecular Pharmaceutics
https://read.qxmd.com/read/34089981/development-of-lc-hrms-methods-for-evaluation-of-metabolic-conversion-of-5-fluorocytosine-at-gdept-procedure
#2
Pavel Skvara, Erika Durinikova, Kateřina Grabicová, Erika Mordacikova, Miroslava Matuskova, Andrea Vojs Stanova
Gene-directed enzyme/prodrug therapy represents one of the experimental treatment approaches. The system based on conversion of nontoxic prodrug 5-fluorocytosine to chemotherapeutic 5-fluorouracil by cytosine deaminase or fusion cytosine deaminase::uracil phosphoribosyl transferase belongs to the most frequently used. The detailed analysis of 5-fluorocytosine, 5-fluorouracil and its metabolites enables to understand various responses of tumour cells to treatment as well as mechanisms of resistance. A fast, sensitive and accurate methods based on liquid chromatography with high-resolution mass spectrometry (LC-HRMS) for the identification and quantification of 5-fluorocytosine, 5-fluorouracil and its major metabolites were developed...
May 24, 2021: Journal of Pharmaceutical and Biomedical Analysis
https://read.qxmd.com/read/34069171/gene-directed-enzyme-prodrug-therapy-by-dendrimer-like-mesoporous-silica-nanoparticles-against-tumor-cells
#3
Vicente Candela-Noguera, Gema Vivo-Llorca, Borja Díaz de Greñu, María Alfonso, Elena Aznar, Mar Orzáez, María Dolores Marcos, Félix Sancenón, Ramón Martínez-Máñez
We report herein a gene-directed enzyme prodrug therapy (GDEPT) system using gated mesoporous silica nanoparticles (MSNs) in an attempt to combine the reduction of side effects characteristic of GDEPT with improved pharmacokinetics promoted by gated MSNs. The system consists of the transfection of cancer cells with a plasmid controlled by the cytomegalovirus promoter, which promotes β-galactosidase (β-gal) expression from the bacterial gene lacZ (CMV-lacZ). Moreover, dendrimer-like mesoporous silica nanoparticles (DMSNs) are loaded with the prodrug doxorubicin modified with a galactose unit through a self-immolative group (DOXO-Gal) and modified with a disulfide-containing polyethyleneglycol gatekeeper...
May 14, 2021: Nanomaterials
https://read.qxmd.com/read/34068264/combination-of-mesenchymal-stem-cell-delivered-oncolytic-virus-with-prodrug-activation-increases-efficacy-and-safety-of-colorectal-cancer-therapy
#4
Chun-Te Ho, Mei-Hsuan Wu, Ming-Jen Chen, Shih-Pei Lin, Yu-Ting Yen, Shih-Chieh Hung
Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection...
May 13, 2021: Biomedicines
https://read.qxmd.com/read/34058372/stimulus-responsive-liposomes-for-biomedical-applications
#5
REVIEW
Antonia I Antoniou, Sabrina Giofrè, Pierfausto Seneci, Daniele Passarella, Sara Pellegrino
Liposomes are amphipathic lipidic supramolecular aggregates that are able to encapsulate and carry molecules of both hydrophilic and hydrophobic nature. They have been widely used as in vivo drug delivery systems for some time because they offer features such as synthetic flexibility, biodegradability, biocompatibility, low immunogenicity, and negligible toxicity. In recent years, the chemical modification of liposomes has paved the way to the development of smart liposome-based drug delivery systems, which are characterized by even more tunable and disease-directed features...
May 28, 2021: Drug Discovery Today
https://read.qxmd.com/read/34033459/ceria-nanozyme-and-phosphate-prodrugs-drug-synthesis-through-enzyme-mimicry
#6
Raoul Walther, Tin H Huynh, Pere Monge, Anne Sofie Fruergaard, Aref Mamakhel, Alexander N Zelikin
Nanozymes can mimic the activities of diverse enzymes, and this ability finds applications in analytical sciences and industrial chemistry, as well as in biomedical applications. Among the latter, prodrug conversion mediated by nanozymes is investigated as a step toward site-specific drug synthesis, to achieve localized therapeutic effects. In this work, we investigated a ceria nanozyme as a mimic to phosphatase, to mediate conversion of phosphate prodrugs into corresponding therapeutics. To this end, the substrate scope of ceria as a phosphatase mimic was analyzed using a broad range of natural phosphor(di)esters and pyrophosphates...
May 25, 2021: ACS Applied Materials & Interfaces
https://read.qxmd.com/read/34029662/enzyme-gsh-dual-responsive-biodegradable-nanohybrid-for-spatiotemporally-specific-photodynamic-and-hypoxia-augmented-therapy-against-tumors
#7
Di Cheng, Yuejia Ji, Bin Wang, Tongxia Jin, Yufang Xu, Xuhong Qian, Weiping Zhu
Photodynamic therapy (PDT) efficacy has been severely limited by the hypoxia in tumor microenvironment. A multitherapy modality was developed, integrating the advantages of each therapy and a nanocarrier: PDT and PDT-induced hypoxia-activated chemotherapy. Following PDT-induced hypoxia augmented in the periphery of the tumors, chemotherapy was locally activated. To this end, new indocyanine green (IR820) and a hypoxia-activated prodrug tirapazamine (TPZ) were loaded in glutathione (GSH) decomposable mesoporous organic silica nanoparticles (GMONs), tethered by hyaluronic acid (HA)...
May 23, 2021: International Journal of Pharmaceutics
https://read.qxmd.com/read/34020248/effects-of-firibastat-in-combination-with-enalapril-and-hydrochlorothiazide-on-blood-pressure-and-vasopressin-release-in-hypertensive-doca-salt-rats
#8
Yannick Marc, Reda Hmazzou, Nadia De Mota, Fabrice Balavoine, Catherine Llorens-Cortes
In the brain, aminopeptidase A (APA) generates angiotensin III, one of the effector peptides of the brain renin-angiotensin system (RAS), exerting tonic stimulatory control over blood pressure (BP) in hypertensive rats. Oral administration of firibastat, an APA inhibitor prodrug, in hypertensive rats, inhibits brain APA activity, blocks brain angiotensin III formation and decreases BP. In this study, we evaluated the efficacy of firibastat in combination with enalapril, an angiotensin I-converting enzyme inhibitor, and hydrochlorothiazide (HCTZ), in conscious hypertensive deoxycorticosterone acetate (DOCA)-salt rats, which display high plasma arginine-vasopressin levels, low circulating renin levels and resistance to treatment by systemic RAS blockers...
May 19, 2021: Biomedicine & Pharmacotherapy
https://read.qxmd.com/read/34006134/stem-cells-for-the-treatment-of-glioblastoma-a-20-year-perspective
#9
Anda-Alexandra Calinescu, McKenzie C Kauss, Zain Sultan, Wajd N Al-Holou, Sue K O'Shea
Glioblastoma, the deadliest form of primary brain tumor, remains a disease without cure. Treatment resistance is in large part attributed to limitations in the delivery and distribution of therapeutic agents. Over the last 20 years, numerous preclinical studies have demonstrated the feasibility and efficacy of stem cells as antiglioma agents, leading to the development of trials to test these therapies in the clinic. In this review we present and analyze these studies, discuss mechanisms underlying their beneficial effect and highlight experimental progress, limitations and the emergence of promising new therapeutic avenues...
May 19, 2021: CNS Oncology
https://read.qxmd.com/read/34000969/biochemical-profiling-of-anti-hiv-prodrug-elsulfavirine-elpida-%C3%A2-and-its-active-form-vm1500a-against-a-panel-of-twelve-human-carbonic-anhydrase-isoforms
#10
Claudiu T Supuran, Alessio Nocentini, Elena Yakubova, Nikolay Savchuk, Stanislav Kalinin, Mikhail Krasavin
The non-nucleoside reverse transcriptase inhibitor VM1500A is approved for the treatment of HIV/AIDS in its N -acyl sulphonamide prodrug form elsulfavirine (Elpida® ). Biochemical profiling against twelve human carbonic anhydrase (CA, EC 4.2.1.1) isoforms showed that while elsulfavirine was a weak inhibitor of all isoforms, VM1500A potently and selectively inhibited human (h) h CA VII isoform, a proven target for the therapy of neuropathic pain. The latter is a common neurologic complication of HIV infection and we hypothesise that by using Elpida® in patients may help alleviate this debilitating symptom...
December 2021: Journal of Enzyme Inhibition and Medicinal Chemistry
https://read.qxmd.com/read/33986267/a-cytokine-receptor-masked-il2-prodrug-selectively-activates-tumor-infiltrating-lymphocytes-for-potent-antitumor-therapy
#11
Eric J Hsu, Xuezhi Cao, Benjamin Moon, Joonbeom Bae, Zhichen Sun, Zhida Liu, Yang-Xin Fu
As a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate...
May 13, 2021: Nature Communications
https://read.qxmd.com/read/33966624/self-immolative-linkers-in-prodrugs-and-antibody-drug-conjugates-in-cancer-treatment
#12
Veera V Shivaji R Edupuganti, Joel D A Tyndall, Allan B Gamble
BACKGROUND: The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxicity continues to be challenging. Anti-cancer prodrug and antibody-drug-conjugate (ADC) strategies that can specifically and efficiently deliver cytotoxic compounds to cancer cells have been used to overcome some of the challenges. Key to the success of many of these strategies is a self-immolative linker, which after activation can release the drug payload. Various types of triggerable self-immolative linkers are used in prodrugs and ADCs to improve their efficacy and safety...
May 8, 2021: Recent Patents on Anti-cancer Drug Discovery
https://read.qxmd.com/read/33948381/quantitative-evaluation-and-comparison-of-two-prodrug-activating-suicide-gene-therapies-on-oral-squamous-cell-carcinoma
#13
Naining Xu, Honglei Tian, Chun Po Fung, Yuntao Lin, Guang Zhu, Yuehong Shen, Hongyu Yang
Prodrug-activating suicide gene therapy (PA suicide gene therapy for short) for cancer is to introduce cancer cells with suicide genes. The enzyme encoded by suicide gene is not toxic but is able to kill cancer cells by converting a non-toxic prodrug into a toxic compound. This approach is a promising cancer gene therapy that could reduce non-specific toxicity to normal tissue. However, there is no quantitative method to evaluate efficacy of suicide gene therapy in preclinical study. The aim of this study is to develop a new method to quantitatively evaluate and compare prodrug-activating suicide gene therapies...
2021: American Journal of Cancer Research
https://read.qxmd.com/read/33918536/the-yfko-nitroreductase-from-bacillus-licheniformis-on-gold-coated-superparamagnetic-nanoparticles-towards-a-novel-directed-enzyme-prodrug-therapy-approach
#14
Patrick Ball, Robert Hobbs, Simon Anderson, Emma Thompson, Vanessa Gwenin, Christopher Von Ruhland, Christopher Gwenin
The bacterial nitroreductase NfnB has been the focus of a great deal of research for its use in directed enzyme prodrug therapy in combination with the nitroreductase prodrug CB1954 with this combination of enzyme and prodrug even entering clinical trials. Despite some promising results, there are major limitations to this research, such as the fact that the lowest reported Km for this enzyme far exceeds the maximum dosage of CB1954. Due to these limitations, new enzymes are now being investigated for their potential use in directed enzyme prodrug therapy...
April 9, 2021: Pharmaceutics
https://read.qxmd.com/read/33913699/nonclinical-evaluation-of-antibacterial-oxazolidinones-contezolid-and-contezolid-acefosamil-with-low-serotonergic-neurotoxicity
#15
Wen Wang, Kate M Voss, Jinqian Liu, Mikhail F Gordeev
Linezolid, the principal oxazolidinone antibiotic for therapy of Gram-positive infections, is limited by its myelosuppression and monoamine oxidase (MAO) inhibition, with the latter manifested as serotonergic neurotoxicity. The oral oxazolidinone contezolid and its injectable prodrug contezolid acefosamil are developed to overcome the above limitations. Serotonergic profiles for contezolid in vitro and for orally administered contezolid acefosamil in rodents are reported. Contezolid exhibited 2- and 148-fold reduction over linezolid reversible inhibition of MAO-A and MAO-B human enzyme isoforms...
April 29, 2021: Chemical Research in Toxicology
https://read.qxmd.com/read/33897898/repurposing-18-f-fmiso-as-a-pet-tracer-for-translational-imaging-of-nitroreductase-based-gene-directed-enzyme-prodrug-therapy
#16
Gorka Ruiz de Garibay, Elvira García de Jalón, Endre Stigen, Kjetil B Lund, Mihaela Popa, Ben Davidson, Mireia Mayoral Safont, Cecilie B Rygh, Heidi Espedal, Torill M Barrett, Bengt Erik Haug, Emmet McCormack
Nitroreductases (NTR) are a family of bacterial enzymes used in gene directed enzyme prodrug therapy (GDEPT) that selectively activate prodrugs containing aromatic nitro groups to exert cytotoxic effects following gene transduction in tumours. The clinical development of NTR-based GDEPT has, in part, been hampered by the lack of translational imaging modalities to assess gene transduction and drug cytotoxicity, non-invasively. This study presents translational preclinical PET imaging to validate and report NTR activity using the clinically approved radiotracer, 18 F-FMISO, as substrate for the NTR enzyme...
2021: Theranostics
https://read.qxmd.com/read/33896106/nir-ii-absorbing-semiconducting-polymer-triggered-gene-directed-enzyme-prodrug-therapy-for-cancer-treatment
#17
Xun Zhang, Yanqing Yang, Tianyi Kang, Jun Wang, Guang Yang, Yuming Yang, Xiangwei Lin, Lidai Wang, Kai Li, Jie Liu, Jen-Shyang Ni
Exploration of facile strategies for precise regulation of target gene expression remains highly challenging in the development of gene therapies. Especially, a stimuli-responsive nanocarrier integrated with ability of noninvasive remote control for treating wide types of cancers is rarely developed. Herein, a NIR-II absorbing semiconducting polymer (PBDTQ) is employed to remotely activate the heat-inducible heat-shock protein 70 (HSP70) promoter under laser irradiation, further realizing regulation of gene-directed enzyme prodrug therapy (GDEPT) for cancer treatment in mild hyperthermia...
April 25, 2021: Small
https://read.qxmd.com/read/33871122/an-amphiphilic-pegylated-peptide-dendron-gemcitabine-prodrug-based-nanoagent-for-cancer-therapy
#18
Ning Li, Zhenyu Duan, Lili Wang, Chunhua Guo, Hu Zhang, Zhongwei Gu, Qiyong Gong, Kui Luo
An amphiphilic peptide dendrimer conjugated with gemcitabine (GEM), PEGylated dendron-Gly-Phe-Leu-Gly-GEM (PEGylated dendron-GFLG-GEM), is developed as a nano-prodrug for breast cancer therapy. The self-assembled behavior is observed under a transmission electron microscopy and dynamic light scattering. The negatively charged surface and hydrodynamic size of the amphiphilic nanosized prodrug supported that the prodrug can maintain the stability of GEM during circulation and accumulate in the tumor tissue. Drug release assays are conducted to monitor the release of GEM from this nanodrug delivery system in response to the tumor microenvironment, and these assays confirm that GEM released from the nanocarrier is identical to free GEM...
April 19, 2021: Macromolecular Rapid Communications
https://read.qxmd.com/read/33844553/virus-derived-peptides-for-hepatic-enzyme-delivery
#19
Anna Pratsinis, Philipp Uhl, Jan Stephan Bolten, Patrick Hauswirth, Susanne Heidi Schenk, Stephan Urban, Walter Mier, Dominik Witzigmann, Jörg Huwyler
Recently, a lipopeptide derived from the hepatitis B virus (HBV) large surface protein has been developed as an HBV entry inhibitor. This lipopeptide, called MyrcludexB (MyrB), selectively binds to the sodium taurocholate cotransporting polypeptide (NTCP) on the basolateral membrane of hepatocytes. Here, the feasibility of coupling therapeutic enzymes to MyrB was investigated for the development of enzyme delivery strategies. Hepatotropic targeting shall enable enzyme prodrug therapies and detoxification procedures...
April 12, 2021: Molecular Pharmaceutics
https://read.qxmd.com/read/33818688/role-of-bempedoic-acid-in-clinical-practice
#20
REVIEW
Christie M Ballantyne, Harold Bays, Alberico L Catapano, Anne Goldberg, Kausik K Ray, Joseph J Saseen
Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment...
April 5, 2021: Cardiovascular Drugs and Therapy
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