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Biotechnology and Applied Biochemistry Feb 2024Suicide gene therapy involves introducing viral or bacterial genes into tumor cells, which enables the conversion of a nontoxic prodrug into a toxic-lethal drug. The... (Review)
Review
Suicide gene therapy involves introducing viral or bacterial genes into tumor cells, which enables the conversion of a nontoxic prodrug into a toxic-lethal drug. The application of the bacterial cytosine deaminase (bCD)/5-fluorocytosine (5-FC) approach has been beneficial and progressive within the current field of cancer therapy because of the enhanced bystander effect. The basis of this method is the preferential deamination of 5-FC to 5-fluorouracil by cancer cells expressing cytosine deaminase (CD), which strongly inhibits DNA synthesis and RNA function, effectively targeting tumor cells. However, the poor binding affinity of toward 5-FC compared to the natural substrate cytosine and/or inappropriate thermostability limits the clinical applications of this gene therapy approach. Nowadays, many genetic engineering studies have been carried out to solve and improve the activity of this enzyme. In the current review, we intend to discuss the biotechnological aspects of Escherichia coli CD, including its structure, functions, molecular cloning, and protein engineering. We will also explore its relevance in cancer clinical trials. By examining these aspects, we hope to provide a thorough understanding of E. coli CD and its potential applications in cancer therapy.
Topics: Humans; Cytosine Deaminase; Escherichia coli; Fluorouracil; Flucytosine; Genetic Therapy; Prodrugs
PubMed: 37743549
DOI: 10.1002/bab.2516 -
Nature Communications Dec 2023Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its...
Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its deep tissue penetration and low phototoxicity. However, most of the photocleavable groups cannot be directly activated by NIR light. Here, we report a upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis. We utilize a photosensitizer (PS) that can be activated via singlet-triplet (S-T) absorption and achieve photolysis of boron-dipyrromethene (BODIPY)-based prodrugs via triplet-triplet energy transfer. Using the strategy, NIR light can achieve green light-responsive photolysis with a single-photon process. A wide range of drugs and bioactive molecules are designed and demonstrated to be released under low-irradiance NIR light (100 mW/cm, 5 min) with high yields (up to 87%). Moreover, a micellar nanosystem encapsulating both PS and prodrug is developed to demonstrate the practicality of our strategy in normoxia aqueous environment for cancer therapy. This study may advance the development of photocleavable prodrugs and photoresponsive drug delivery systems for photo-activated therapy.
Topics: Prodrugs; Photolysis; Drug Delivery Systems; Photosensitizing Agents; Energy Transfer
PubMed: 38062051
DOI: 10.1038/s41467-023-43805-y -
Acta Biomaterialia Dec 2023Supramolecular organic frameworks (SOFs) have emerged as a promising class of organic porous materials with vast potential as nanocarriers for combination therapy. Here,...
Supramolecular organic frameworks (SOFs) have emerged as a promising class of organic porous materials with vast potential as nanocarriers for combination therapy. Here, we successfully construct an anionic flexible supramolecular organic framework (TPP-SOF) by leveraging multiple host-guest interactions. TPP-SOF is fabricated by the hierarchical orthogonal assembly between anionic water-soluble dimacrocyclic host (P5CD), porphyrin photosensitizers (TPP), and ROS-sensitive thioketal linked adamantane dimer (Ada-S-Ada). TPP-SOF exhibits pH-dependent activation of O production, which further facilitates the cleavage of Ada-S-Ada linker and promotes the disintegration of the framework. Moreover, leveraging electrostatic and hydrophobic interactions, the anionic TPP-SOF serves as an effective platform for loading cationic photosensitizer IR780 and chemotherapeutic prodrug PhenPt(IV), leading to the formation of supramolecular nanoparticles (IR780/Pt@TPP-SOF) for synergistic therapy. The obtained nanoparticles exhibit good stability, efficient generation of O, and photothermal performance. In vitro and in vivo studies indicate that IR780/Pt@TPP-SOF exhibits remarkable synergistic chemo/PDT/PTT effects under 808 and 660 nm light irradiation. This study showcases a deep insight for the development of SOFs and a new approach for delivering cationic drugs and constructing synergistic combination therapy systems. STATEMENT OF SIGNIFICANCE: In this work, a pH/ROS-responsive anionic flexible supramolecular organic framework, TPP-SOF, was innovatively designed by the hierarchical orthogonal assembly, to co-deliver cationic photosensitizer IR780 and prodrug PhenPt(IV) for synergistic cancer therapy. The drug-loaded TPP-SOF is termed IR780/Pt@TPP-SOF, in which the photoactivity of porphyrin within TPP-SOF could be activated under acidic conditions, the O generated by the photosensitizers could break the thioketal bonds in Ada-S-Ada, leading to the disassembly of the framework and releasing the drugs. This supramolecular drug delivery system displays good biocompatibility and exhibits remarkable synergistic chemo/PDT/PTT effects.
Topics: Humans; Photosensitizing Agents; Photochemotherapy; Prodrugs; Reactive Oxygen Species; Polymers; Nanoparticles; Porphyrins; Hydrogen-Ion Concentration; Cell Line, Tumor; Neoplasms
PubMed: 37866724
DOI: 10.1016/j.actbio.2023.10.019 -
Biomedicine & Pharmacotherapy =... Aug 2023Mammalian carboxylesterase 1 enzymes can hydrolyze many xenobiotic chemicals and endogenous lipids. We here identified and characterized a mouse strain (FVB/NKI) in...
Mammalian carboxylesterase 1 enzymes can hydrolyze many xenobiotic chemicals and endogenous lipids. We here identified and characterized a mouse strain (FVB/NKI) in which three of the eight Ces1 genes were spontaneously deleted, removing Ces1c and Ces1e partly, and Ces1d entirely. We studied the impact of this Ces1c/d/e deficiency on drug and lipid metabolism and homeostasis. Ces1c/d/e mice showed strongly impaired conversion of the anticancer prodrug irinotecan to its active metabolite SN-38 in plasma, spleen and lung. Plasma hydrolysis of the oral anticancer prodrug capecitabine to 5-DFCR was also profoundly reduced in Ces1c/d/e mice. Our findings resolved previously unexplained FVB/NKI pharmacokinetic anomalies. On a medium-fat diet, Ces1c/d/e female mice exhibited moderately higher body weight, mild inflammation in gonadal white adipose tissue (gWAT), and increased lipid load in brown adipose tissue (BAT). Ces1c/d/e males showed more pronounced inflammation in gWAT and an increased lipid load in BAT. On a 5-week high-fat diet exposure, Ces1c/d/e deficiency predisposed to developing obesity, enlarged and fatty liver, glucose intolerance and insulin resistance, with severe inflammation in gWAT and increased lipid load in BAT. Hepatic proteomics analysis revealed that the acute phase response, involved in the dynamic cycle of immunometabolism, was activated in these Ces1c/d/e mice. This may contribute to the obesity-related chronic inflammation and adverse metabolic disease in this strain. While Ces1c/d/e deficiency clearly exacerbated metabolic syndrome development, long-term (18-week) high-fat diet exposure overwhelmed many, albeit not all, observed phenotypic differences.
Topics: Animals; Female; Male; Mice; Carboxylic Ester Hydrolases; Inflammation; Irinotecan; Lipids; Mammals; Metabolic Syndrome; Obesity; Prodrugs
PubMed: 37267638
DOI: 10.1016/j.biopha.2023.114956 -
Journal of Controlled Release :... Jan 2024To reduce recurrence rate after transurethral resection of bladder tumor, long-term intravesical instillations of Bacillus Calmette-Guérin (BCG) and/or chemotherapeutic...
To reduce recurrence rate after transurethral resection of bladder tumor, long-term intravesical instillations of Bacillus Calmette-Guérin (BCG) and/or chemotherapeutic drugs is the standard treatment for non-muscle invasive bladder carcinoma. However, the main challenges of intravesical therapy, such as short retention time and poor permeability of drugs in the bladder, often require frequent and high-dose administrations, leading to significant adverse effects and financial burden for patients. Aiming at addressing these challenges, we developed a novel approach, in which the cell-penetrating peptide modified oxaliplatin prodrug liposomes and a low-dose BCG were co-delivered via a viscous chitosan solution (LRO-BCG/CS). LRO-BCG/CS addressed these challenges by significantly improving the retention capability and permeability of chemotherapy agents across the bladder wall. Then, oxaliplatin triggered the immunogenic cell death, and the combination of BCG simultaneously further activated the systemic anti-tumor immune response in the MB49 orthotopic bladder tumor model. As a result, LRO-BCG/CS demonstrated superior anti-tumor efficacy and prolonged the survival time of tumor-bearing mice significantly, even at relatively low doses of oxaliplatin and BCG. Importantly, this combinational chemo-immunotherapy showed negligible side effects, offering a promising and well-tolerated therapeutic strategy for bladder cancer patients.
Topics: Humans; Mice; Animals; BCG Vaccine; Oxaliplatin; Liposomes; Prodrugs; Urinary Bladder Neoplasms; Administration, Intravesical; Immunotherapy; Adjuvants, Immunologic; Neoplasm Recurrence, Local
PubMed: 38042374
DOI: 10.1016/j.jconrel.2023.11.050 -
Journal of Inorganic Biochemistry Nov 2023Two cobalt(III) complexes containing different β-ketoesters, namely [Co(L1)(pyen)](ClO)·HO (1) and [Co(L2)(pyen)](ClO) (2)...
Two cobalt(III) complexes containing different β-ketoesters, namely [Co(L1)(pyen)](ClO)·HO (1) and [Co(L2)(pyen)](ClO) (2) (pyen = N,N'-bis(pyridin-2-ylmethyl)ethylenediamine; L1 = methylacetoacetate; L2 = ethyl 4-chloroacetoacetate) have been prepared and investigated as prototypes of bioreductive prodrugs. The presence of β-ketoester and pyen ligands in 1 and 2, as well as the perchlorate counterions, was supported by IR spectroscopy and CHN elemental analysis. The composition molecular structure of both complexes was confirmed by NMR spectroscopy and ESI mass spectrometry. Structural information was also obtained for 2via X-ray diffraction analysis. The redox properties indicate that 1 and 2 are suitable for reduction under biological conditions. Investigation of DNA-interacting suggest that 1 and 2 bind DNA via electrostatic forces. Both complexes may be employed as possible platforms for the delivery of biologically active compounds, since their reaction with ascorbic acid in PBS at pH 6.2 and 7.4 at 37°C results in the release of the β-ketoester ligands upon Co(III)/Co(II) reduction.
Topics: Cobalt; Ligands; Molecular Structure; Prodrugs; Crystallography, X-Ray
PubMed: 37562318
DOI: 10.1016/j.jinorgbio.2023.112345 -
International Journal of Molecular... Jan 2024Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks,... (Review)
Review
Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying medical conditions can impair the progression through the stages of wound healing, resulting in the development of chronic, non-healing wounds. Great progress has been made in developing wound dressings and improving surgical techniques, yet challenges remain in finding effective therapeutics that directly promote healing. This review examines the current understanding of the pro-healing effects of targeted pharmaceuticals, re-purposed drugs, natural products, and cell-based therapies on the various cell types present in normal and chronic wounds. Overall, despite several promising studies, there remains only one therapeutic approved by the United States Food and Drug Administration (FDA), Becaplermin, shown to significantly improve wound closure in the clinic. This highlights the need for new approaches aimed at understanding and targeting the underlying mechanisms impeding wound closure and moving the field from the management of chronic wounds towards resolving wounds.
Topics: Humans; Wound Healing; Prodrugs; Bandages; Becaplermin; Inflammation
PubMed: 38279304
DOI: 10.3390/ijms25021304 -
Bioconjugate Chemistry Sep 2023Most cancer patients rarely benefit from monodrug therapy because of both cancer complexity and tumor environment. One of the main reasons for this failure is...
Most cancer patients rarely benefit from monodrug therapy because of both cancer complexity and tumor environment. One of the main reasons for this failure is insufficient accumulation of the optimal dose at the tumorous site. Our investigation implies a promising strategy to engineer prodrug nanoparticles (NPs) of bortezomib (BTZ) and selenium (Se) using sialic acid (SAL) as a ligand to improve breast cancer therapy. BTZ was conjugated with SAL and HPMA (-2-hydroxypropyl methacrylamide) to prepare a prodrug conjugate; BTZ-SAL-HPMA (BSAL-HP) and then fabricated into prodrug NPs with Se (Se_BSAL-HP prodrug NPs). The self-assembly of prodrug NPs functionalized with Se showed size (204.13 ± 0.02 nm) and zeta potential (-31.0 ± 0.11 mV) in dynamic light scattering (DLS) experiments and spherical shape in TEM and SEM analysis. Good stability and low pH drug release profile were characterized by Se_BSAL-HP prodrug NPs. The tumor-selective boronate-ester-based prodrug NPs of BTZ in combination with Se endowed a synergistic effect against cancer cells. Compared to prodrug conjugate, Se_BSAL-HP prodrug NPs exhibited higher cell cytotoxicity and enhanced cellular internalization with significant changes in mitochondria membrane potential (MMP). Elevated apoptosis was observed in the (G2/M) phase of the cell cycle for Se_BSAL-HP prodrug NPs (2.7-fold) higher than BTZ. studies were performed on Sprague-Dawley rats and resulted in positive trends. The increased therapeutic activity of Se_BSAL-HP prodrug NPs inhibited primary tumor growth and showed 43.05 fold decrease in tumor volume than the control in 4T1 tumor bearing mice. The surprising and remarkable outcomes for Se_BSAL-HP prodrug NPs were probably due to the ROS triggering effect of boronate ester and selenium given together.
Topics: Rats; Animals; Mice; Rats, Sprague-Dawley; Selenium; Prodrugs; N-Acetylneuraminic Acid; Bortezomib; Neoplasms; Esters
PubMed: 37603704
DOI: 10.1021/acs.bioconjchem.3c00210 -
Viruses Nov 2023Antiretroviral Therapy (ART) is an effective treatment for human immunodeficiency virus (HIV) which has transformed the highly lethal disease, acquired immunodeficiency... (Review)
Review
Antiretroviral Therapy (ART) is an effective treatment for human immunodeficiency virus (HIV) which has transformed the highly lethal disease, acquired immunodeficiency syndrome (AIDS), into a chronic and manageable condition. However, better methods need to be developed for enhancing patient access and adherence to therapy and for improving treatment in the long term to reduce adverse effects. From the perspective of drug discovery, one promising strategy is the development of anti-HIV prodrugs. This approach aims to enhance the efficacy and safety of treatment, promoting the development of more appropriate and convenient systems for patients. In this review, we discussed the use of the prodrug approach for HIV antiviral agents and emphasized nucleoside reverse transcriptase inhibitors. We comprehensively described various strategies that are used to enhance factors such as water solubility, bioavailability, pharmacokinetic parameters, permeability across biological membranes, chemical stability, drug delivery to specific sites/organs, and tolerability. These strategies might help researchers conduct better studies in this field. We also reported successful examples from the primary therapeutic classes while discussing the advantages and limitations. In this review, we highlighted the key trends in the application of the prodrug approach for treating HIV/AIDS.
Topics: Humans; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Prodrugs; Nucleosides; Acquired Immunodeficiency Syndrome; HIV Infections; HIV; HIV Reverse Transcriptase
PubMed: 38005911
DOI: 10.3390/v15112234 -
Journal of Medicinal Chemistry Jul 2023In this article, we report , a new class of heterobimetallic Ir(III)-Pt(IV) conjugates as multifunctional potent anticancer theranostic agents. In the designed...
In this article, we report , a new class of heterobimetallic Ir(III)-Pt(IV) conjugates as multifunctional potent anticancer theranostic agents. In the designed construction, the octahedral Pt(IV) prodrug is tethered to the cancer cell targeting biotin ligand through one of the axial sites and the other axial site of Pt(IV) center is attached to multifunctional Ir(III) complexes that possess organelle-targeting capabilities with excellent anticancer and imaging properties. The conjugates preferentially accumulate within the mitochondria of cancer cells, and subsequently, Pt(IV) is reduced to Pt(II) species that concomitantly releases both the Ir(III) complex and biotin from its axial sites. The conjugates demonstrate potent anticancer activity in various 2D monolayer cancer cells, including the cisplatin-resistant cells in the nanomolar concentrations and 3D multicellular tumor spheroids. The mechanistic investigation of conjugates suggests that the loss of MMP, generation of ROS, and caspase-3-mediated apoptosis are responsible for cell death.
Topics: Platinum; Iridium; Precision Medicine; Biotin; Antineoplastic Agents; Prodrugs; Cell Line, Tumor
PubMed: 37387570
DOI: 10.1021/acs.jmedchem.3c00336