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Expert Opinion on Drug Metabolism &... May 2024Carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are among the most abundant hydrolases in humans, catalyzing the metabolism of numerous clinically important... (Review)
Review
INTRODUCTION
Carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are among the most abundant hydrolases in humans, catalyzing the metabolism of numerous clinically important medications, such as methylphenidate and clopidogrel. The large interindividual variability in the expression and activity of CES1 and CES2 affects the pharmacokinetics (PK) and pharmacodynamics (PD) of substrate drugs.
AREAS COVERED
This review provides an up-to-date overview of CES expression and activity regulations and examines their impact on the PK and PD of CES substrate drugs. The literature search was conducted on PubMed from inception to January 2024.
EXPERT OPINION
Current research revealed modest associations of CES genetic polymorphisms with drug exposure and response. Beyond genomic polymorphisms, transcriptional and posttranslational regulations can also significantly affect CES expression and activity and consequently alter PK and PD. Recent advances in plasma biomarkers of drug-metabolizing enzymes encourage the research of plasma protein and metabolite biomarkers for CES1 and CES2, which could lead to the establishment of precision pharmacotherapy regimens for drugs metabolized by CESs. Moreover, our understanding of tissue-specific expression and substrate selectivity of CES1 and CES2 has shed light on improving the design of CES1- and CES2-activated prodrugs.
Topics: Humans; Carboxylic Ester Hydrolases; Animals; Polymorphism, Genetic; Pharmaceutical Preparations; Prodrugs; Biomarkers; Carboxylesterase
PubMed: 38706437
DOI: 10.1080/17425255.2024.2348491 -
European Journal of Medicinal Chemistry Sep 2023In the last decades, inflammation has been recognized as being closely connected to cancer, and joint strategies encompassing chemotherapeutic and anti-inflammatory...
In the last decades, inflammation has been recognized as being closely connected to cancer, and joint strategies encompassing chemotherapeutic and anti-inflammatory agents have been extensively studied. In this work, a series of novel cisplatin and oxaliplatin-based Pt(IV) complexes comprising non-steroidal anti-inflammatory drugs (NSAIDs) and their carboxyl ester analogues as axial moieties were synthesized. Several of the cisplatin-based Pt(IV) complexes 22-30 showed increased cytotoxicity in the human cancer cell lines CH1/PA-1, SW480 and A549 compared to the Pt(II) drug. For the most potent complex 26, comprising two aceclofenac (AFC) moieties, the formation of Pt(II)-9-methylguanine (9-MeG) adducts after activation with ascorbic acid (AsA) was proven. Additionally, a significant inhibition of cyclooxygenase (COX) activity and prostaglandin E (PGE) production was observed, as well as increased cellular accumulation, depolarization of mitochondrial membranes, and strong proapoptotic potencies in SW480 cells. Overall, these systematic effects shown in vitro confer 26 as a potential anticancer agent combined with anti-inflammatory properties.
Topics: Humans; Cisplatin; Prodrugs; Platinum; Prostaglandin-Endoperoxide Synthases; Cell Line, Tumor; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 37295160
DOI: 10.1016/j.ejmech.2023.115515 -
BioDrugs : Clinical Immunotherapeutics,... Mar 2024We previously proposed that sacituzumab govitecan (SG, Trodelvy®) likely acts as a simple prodrug of systemic SN-38 as well as an antibody drug conjugate (ADC). In the...
We previously proposed that sacituzumab govitecan (SG, Trodelvy®) likely acts as a simple prodrug of systemic SN-38 as well as an antibody drug conjugate (ADC). In the present commentary, we assess whether a long-acting SN-38 prodrug, such as PLX038, might be efficacious in SG-resistant patients. We first describe possible mechanisms of action of SG, with new insights on pharmacokinetics and TROP2 receptor occupancy. We argue that SG is not an optimal conventional ADC and that the amount of systemic SN-38 spontaneously hydrolyzed from the ADC is so high it must have activity. Then, we describe the concept of time-over-target as related to the pharmacology of SG and PLX038 as SN-38 prodrugs. To be clear, we are not in any way suggesting that PLX038 or any SN-38 prodrug is superior to SG as an anticancer agent. Clearly, SG has the benefit over antigen-independent SN-38 prodrugs in that it targets cells with the TROP2 receptor. However, we surmise that PLX038 should be a more efficacious and less toxic prodrug of systemic SN-38 than SG. Finally, we suggest possible mechanisms of SG resistance and how PLX038 might perform in the context of each. Taken together, we argue that-contrary to many opinions-SG does not exclusively act as a conventional ADC, and propose that PLX038 may be efficacious in some settings of SG-resistance.
Topics: Humans; Irinotecan; Prodrugs; Antigens, Neoplasm; Neoplasms; Immunoconjugates; Camptothecin; Antibodies, Monoclonal, Humanized
PubMed: 38236523
DOI: 10.1007/s40259-024-00643-8 -
Acta Biomaterialia Oct 2023The clinical application of growth factors such as recombinant human bone morphogenetic protein-2 (rh-BMP-2), for functional bone regeneration remains challenging due to...
The clinical application of growth factors such as recombinant human bone morphogenetic protein-2 (rh-BMP-2), for functional bone regeneration remains challenging due to limited in vivo efficacy and adverse effects of previous modalities. To overcome the instability and short half-life of rh-BMP-2 in vivo, we developed a novel osteogenic supplement by fusing a protein transduction domain (PTD) with BMP-2, effectively creating a prodrug of BMP-2. In this study, we first created an improved PTD-BMP-2 formulation using lipid nanoparticle (LNP) micellization, resulting in downsizing from micrometer to nanometer scale and achieving a more even distribution. The micellized PTD-BMP-2 (mPTD-BMP-2) demonstrated improved distribution and aggregation profiles. As a prodrug of BMP-2, mPTD-BMP-2 successfully activated Smad1/5/8 and induced mineralization with osteogenic gene induction in vitro. In vivo pharmacokinetic analysis revealed that mPTD-BMP-2 had a much more stable pharmacokinetic profile than rh-BMP-2, with a 7.5-fold longer half-life. The in vivo BMP-responsive element (BRE) reporter system was also successfully activated by mPTD-BMP-2. In the in vivo rat tibia distraction osteogenesis (DO) model, micro-computed tomography (micro-CT) scan findings indicated that mPTD-BMP-2 significantly increased bone volume, bone surface, axis moment of inertia (MOI), and polar MOI. Furthermore, it increased the expression of osteogenesis-related genes, and induced bone maturation histologically. Based on these findings, mPTD-BMP-2 could be a promising candidate for the next-generation osteogenesis drug to promote new bone formation in DO surgery. STATEMENT OF SIGNIFICANCE: This study introduces micellized bone morphogenetic protein-2 (mPTD-BMP-2), a next-generation osteogenic supplement that combines protein transduction domain (PTD) and nano-sized micelle formulation technique to improve transduction efficiency and stability. The use of PTD represents a novel approach, and our results demonstrate the superiority of mPTD-BMP-2 over rh-BMP-2 in terms of in vivo pharmacokinetic profile and osteogenic potential, particularly in a rat tibial model of distraction osteogenesis. These findings have significant scientific impact and potential clinical applications in the treatment of bone defects that require distraction osteogenesis. By advancing the field of osteogenic supplements, our study has the potential to contribute to the development of more effective treatments for musculoskeletal disorders.
Topics: Rats; Humans; Animals; Tibia; Osteogenesis, Distraction; Prodrugs; X-Ray Microtomography; Bone Morphogenetic Proteins; Bone Morphogenetic Protein 2; Osteogenesis; Bone Morphogenetic Protein 7
PubMed: 37611691
DOI: 10.1016/j.actbio.2023.08.031 -
Journal of Medicinal Chemistry Feb 2024We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives - acting as potential prodrugs of d4T nucleotides: (i) the...
We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives - acting as potential prodrugs of d4T nucleotides: (i) the δ-phosph(on)ate is modified by two alkyl residues and ; (ii) the δ-phosph(on)ate is esterified covalently by one acyloxybenzyl moiety and a moiety and ; or (iii) the δ-phosphate of nucleoside tetraphosphate is masked by two prodrug groups and . We were able to prove the efficient release of d4T triphosphate (d4TTP, (i)), δ-monoalkylated d4T tetraphosphates ( and , (ii)), and d4T tetraphosphate (d4T4P, (iii)), respectively, by chemical or enzymatic processes. Surprisingly, δ-dialkylated d4T tetraphosphates, δ-monoalkylated d4T tetraphosphates, and d4T4P were substrates for HIV-RT. Remarkably, the antiviral activity of Tetraro-prodrug was improved by 7700-fold (SI 5700) as compared to the parent d4T in CEM/TK cells, denoting a successful cell membrane passage of these lipophilic prodrugs and an intracellular delivery of the nucleotide metabolites.
Topics: Anti-HIV Agents; Nucleosides; Stavudine; HIV-1; Nucleotides; Prodrugs
PubMed: 38345794
DOI: 10.1021/acs.jmedchem.3c02022 -
Biomaterials Aug 2023Insufficient immune stimulation and stubborn immune resistance are the critical factors limiting tumor immunotherapy. Here, we report a multifunctional nanoprodrug...
Insufficient immune stimulation and stubborn immune resistance are the critical factors limiting tumor immunotherapy. Here, we report a multifunctional nanoprodrug platform with self-driven indoximod (IND) release and oxidative stress amplification. The aim is to awaken immune responses and block the indoleamine 2,3-dioxygenase (IDO) pathway through a combination of ferroptosis, photothermal therapy, and immunotherapy. This nanosystem improved the delivery efficiency of IND due to click chemistry linked ROS responsive prodrug and self-driven drug release. Meanwhile, the tactic of simultaneously increasing ROS and eliminating GSH amplified oxidative stress and strengthened ferroptosis, which further enhanced immunogenicity along with polydopamine-based photothermal therapy. IDO immunization combined with ferroptosis as well as photothermal therapy not only stimulated immune response, but also reversed immune suppression with enhanced immune memory. Therefore, primary tumor, distant tumor, and cancer metastasis were inhibited. This study provides a perspective on immunotherapeutics for cancer treatment.
Topics: Ferroptosis; Reactive Oxygen Species; Prodrugs; Immunotherapy; Cell Line, Tumor
PubMed: 37196407
DOI: 10.1016/j.biomaterials.2023.122157 -
Chemistry & Biodiversity May 2024Curcumin is a diverse natural pharmacological agent involved in various signal transduction mechanisms. Therapeutically, this potent molecule faces different challenges... (Review)
Review
Curcumin is a diverse natural pharmacological agent involved in various signal transduction mechanisms. Therapeutically, this potent molecule faces different challenges and issues related to low bioavailability due to its poor aqueous solubility, less permeability, faster elimination and clearance. Experts in synthetic chemistry and pharmaceuticals are continuously sparing their efforts to overcome these pharmacokinetic challenges by using different structural modification strategies and developing novel drug delivery systems. In this mini-review article, we are focusing on development of curcumin derivatives by different possible routes like conjugation with biomolecules, natural polymers, synthetic polymers, natural products, metal conjugates and co- administration with natural metabolic inhibitors. In addition to that, it was also focused on the preparation of modified formulations such as micelles, microemulsions, liposomes, complexes with phospholipids, micro and nanoemulsions, solid lipid nanoparticles, nano lipid carriers, biopolymer nanoparticles and microgels to improve the pharmacokinetic properties of the curcumin without altering its pharmacodynamics activity. This review helps to understand the problems associated with curcumin and different strategies to improve its pharmacokinetic profile.
Topics: Curcumin; Humans; Biological Availability; Prodrugs; Drug Compounding; Animals; Nanoparticles
PubMed: 38401117
DOI: 10.1002/cbdv.202302030 -
ACS Nano Jul 2023Rational design of multifunctional nanomedicines has revolutionized the therapeutic efficacy of cancers. Herein, we have constructed the functional nucleic acids...
Rational design of multifunctional nanomedicines has revolutionized the therapeutic efficacy of cancers. Herein, we have constructed the functional nucleic acids (FNAs)-engineered nanoplatforms based on the concept of a bio-barcode (BBC) for synergistic targeted therapy of multidrug-resistant (MDR) cancer. In this study, the platinum(IV) prodrug is synthesized to covalently link two kinds of FNAs at a rational ratio to fabricate three-dimensional BBC-like DNA nanoscaffolds, accompanied by the one-pot encapsulation of ZnO nanoparticles (NPs) through electrostatic interaction. The multivalent AS1411 aptamers equipped in ZnO@BBCs facilitate specific and efficient endocytosis into MDR human lung adenocarcinoma cells (A549/DDP). In response to the intracellular environment of A549/DDP cells, such as the lysosome-acidic pH and overexpressed GSH, the ZnO NPs are degraded into Zn ions for generating reactive oxygen species (ROS), while the Pt(IV) prodrugs are reduced into Pt(II) active species by glutathione (GSH), followed by the release of therapeutic DNAzymes for chemotherapy and gene therapy. In particular, the designed system plays an important role in remodeling the intracellular environment to reverse cancer MDR. On the one hand, the depletion of GSH promotes the downregulation of glutathione peroxidase 4 (GPX4) for amplifying oxidative stress and increasing lipid peroxidation (LPO), resulting in the activation of ferroptosis. On the other hand, the silence of early growth response protein 1 (Egr-1) mRNA by Zn-dependent DNAzymes directly inhibits the proliferation and migration of MDR cells, which further suppresses the P-glycoprotein (P-gp)-mediated drug efflux. Thus, the proposed nanoplatforms show great promise for the development of versatile therapeutic tools and personalized nanomedicines for MDR cancers.
Topics: Humans; Drug Resistance, Multiple; DNA, Catalytic; Zinc Oxide; Drug Resistance, Neoplasm; Prodrugs; Nanoparticles; Lung Neoplasms; Cell Line, Tumor
PubMed: 37458477
DOI: 10.1021/acsnano.3c02009 -
Advanced Materials (Deerfield Beach,... Mar 2024Pyroptosis, an emerging mechanism of programmed cell death, holds great potential to trigger a robust antitumor immune response. Platinum-based chemotherapeutic agents...
Pyroptosis, an emerging mechanism of programmed cell death, holds great potential to trigger a robust antitumor immune response. Platinum-based chemotherapeutic agents can induce pyroptosis via caspase-3 activation. However, these agents also enhance cyclooxygenase-2 (COX-2) expression in tumor tissues, leading to drug resistance and immune evasion in pancreatic cancer and significantly limiting the effectiveness of chemotherapy-induced pyroptosis. Here, an amphiphilic polymer (denoted as PHDT-Pt-In) containing both indomethacin (In, a COX-2 inhibitor) and platinum(IV) prodrug (Pt(IV)) is developed, which is responsive to glutathione (GSH). This polymer self-assemble into nanoparticles (denoted as Pt-In NP) that can disintegrate in cancer cells due to the GSH responsiveness, releasing In to inhibit the COX-2 expression, hence overcoming the chemoresistance and amplifying cisplatin-induced pyroptosis. In a pancreatic cancer mouse model, Pt-In NP significantly inhibit tumor growth and elicit both innate and adaptive immune responses. Moreover, when combined with anti-programmed death ligand (α-PD-L1) treatment, Pt-In NP demonstrate the ability to completely suppress metastatic tumors, transforming "cold tumors" into "hot tumors". Overall, the sustained release of Pt(IV) and In from Pt-In NP amplifies platinum-drug-induced pyroptosis to elicit long-term immune responses, hence presenting a generalizable strategy for pancreatic cancer.
Topics: Animals; Mice; Prodrugs; Platinum; Cyclooxygenase 2; Pyroptosis; Cisplatin; Nanoparticles; Polymers; Pancreatic Neoplasms; Cell Line, Tumor
PubMed: 38092007
DOI: 10.1002/adma.202310456 -
Biomedicine & Pharmacotherapy =... Oct 2023Patients receiving high-dose methotrexate (HDMTX) for malignancies are exposed to diverse complications, including nephrotoxicity, hepatotoxicity, mucositis,... (Review)
Review
Patients receiving high-dose methotrexate (HDMTX) for malignancies are exposed to diverse complications, including nephrotoxicity, hepatotoxicity, mucositis, myelotoxicity, neurological symptoms, and death. Glucarpidase is a recombinant carboxypeptidase G2 (CPG2) that converts MTX into nontoxic metabolites. In this study, the role of vector type, gene optimization, orientation, and host on the expression of CPG2 is investigated. The effectiveness of various therapeutic regimens containing glucarpidase is classified and perspectives on the dose adjustment based on precision medicine are provided. Conjugation with cell-penetrating peptides, human serum albumin, and polymers such as PEG and dextran for delivery, higher stability, and production of the biobetter variants of CPG2 is highlighted. Conjugation of CPG2 to F(ab՜) or scFv antibody fragments against tumor-specific antigens and the corresponding prodrugs for tumor-targeted drug delivery using the antibody-directed enzyme prodrug therapy (ADEPT) is communicated. Trials to reduce the off-target effects and the possibility of repeated ADEPT cycles by adding pro-domains sensitive to tumor-overexpressed proteases, antiCPG2 antibodies, CPG2 mutants with immune-system-unrecognizable epitopes, and protective polymers are reported. Intracellular cpg2 gene expression by gene-directed enzyme prodrug therapy (GDEPT) and the concerns regarding the safety and transfection efficacy of the GDEPT vectors are described. A novel bifunctional platform using engineered CAR-T cell micropharmacies, known as Synthetic Enzyme-Armed KillER (SEAKER) cells, expressing CPG2 to activate prodrugs at the tumor niche is introduced. Taken together, integrated data in this review and recruiting combinatorial strategies in novel drug delivery systems define the future directions of ADEPT, GDEPT, and SEAKER cell therapy and the placement of CPG2 therein.
Topics: Humans; Methotrexate; gamma-Glutamyl Hydrolase; Prodrugs; Antidotes; Neoplasms; Antibodies; Polymers
PubMed: 37579696
DOI: 10.1016/j.biopha.2023.115292