Therapeutic Potential of Prodrugs Towards Targeted Drug Delivery

Mishra, Abhinav; Chandra, Suresh; Tiwari, Ruchi; Srivastava, Ashish; Tiwari, Gaurav

doi:10.2174/1874104501812010111

Cited by 36 publications

(21 citation statements)

References 36 publications

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“…Numerous enzyme-prodrug systems have been considered in various reviews (see [17][18][19]). Several of these systems are now in preclinical and clinical trials, including the most extensively studied systems of the herpes simplex virus thymidine kinase gene (HSVtk), with ganciclovir (GCV) as a prodrug, and the cytosine deaminase gene (CD) of Escherichia coli and yeast, which converts the prodrug antifungal agent 5-fluorocytosine (5-FC)-which features low toxicity-into the antineoplastic antimetabolite toxic 5-fluorouracil (5-FU) (See Supplementary Table S1).…”

Section: Gdept: Why Good Intentions Do Not Lead To Paradise In Suicide Cancer Gene Therapymentioning

confidence: 99%

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

Alekseenko

Kuzmich

Kondratyeva

et al. 2021

IJMS

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Gene-directed enzyme prodrug gene therapy (GDEPT) theoretically represents a useful method to carry out chemotherapy for cancer with minimal side effects through the formation of a chemotherapeutic agent inside cancer cells. However, despite great efforts, promising preliminary results, and a long period of time (over 25 years) since the first mention of this method, GDEPT has not yet reached the clinic. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. The advent of checkpoint immunotherapy has yielded new highly promising avenues of study in cancer therapy. For such therapy, it seems reasonable to use combinations of different immunomodulators alongside traditional methods, such as chemotherapy and radiotherapy, as well as GDEPT. In this review, we focused on non-viral gene immunotherapy systems combining the intratumoral production of toxins diffused by GDEPT and immunomodulatory molecules. Special attention was paid to the applications and mechanisms of action of the granulocyte-macrophage colony-stimulating factor (GM–CSF), a cytokine that is widely used but shows contradictory effects. Another method to enhance the formation of stable immune responses in a tumor, the use of danger signals, is also discussed. The process of dying from GDEPT cancer cells initiates danger signaling by releasing damage-associated molecular patterns (DAMPs) that exert immature dendritic cells by increasing antigen uptake, maturation, and antigen presentation to cytotoxic T-lymphocytes. We hypothesized that the combined action of this danger signal and GM–CSF issued from the same dying cancer cell within a limited space would focus on a limited pool of immature dendritic cells, thus acting synergistically and enhancing their maturation and cytotoxic T-lymphocyte attraction potential. We also discuss the problem of enhancing the cancer specificity of the combined GDEPT–GM–CSF–danger signal system by means of artificial cancer specific promoters or a modified delivery system.

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Section: Gdept: Why Good Intentions Do Not Lead To Paradise In Suicide Cancer Gene Therapymentioning

confidence: 99%

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

Alekseenko

Kuzmich

Kondratyeva

et al. 2021

IJMS

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“…In a first step, tumours are transduced to express a gene encoding for the prodrug-activating enzyme. In a second step, a non-toxic prodrug is delivered systemically and subsequently converted in situ to a cytotoxic derivative by the expressed enzyme 2 . In this way, GDEPT achieves high concentration of cytotoxic compounds locally, minimising systemic side effects associated with conventional cancer chemotherapy 3 .…”

Section: Introductionmentioning

confidence: 99%

Repurposing ¹⁸F-FMISO as a PET tracer for translational imaging of nitroreductase-based gene directed enzyme prodrug therapy

Garibay¹,

Jalón²,

Stigen³

et al. 2021

Theranostics

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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. Methods: The efficacy with which 18 F-FMISO could be used to report NfsB NTR activity in vivo was investigated using the MDA-MB-231 mammary carcinoma xenograft model. For validation, subcutaneous xenografts of cells constitutively expressing NTR were imaged using 18 F-FMISO PET/CT and fluorescence imaging with CytoCy5S, a validated fluorescent NTR substrate. Further, examination of the non-invasive functionality of 18 F-FMISO PET/CT in reporting NfsB NTR activity in vivo was assessed in metastatic orthotopic NfsB NTR expressing xenografts and metastasis confirmed by bioluminescence imaging. 18 F-FMISO biodistribution was acquired ex vivo by an automatic gamma counter measuring radiotracer retention to confirm in vivo results. To assess the functional imaging of NTR-based GDEPT with 18 F-FMISO, PET/CT was performed to assess both gene transduction and cytotoxicity effects of prodrug therapy (CB1954) in subcutaneous models. Results: 18 F-FMISO retention was detected in NTR + subcutaneous xenografts, displaying significantly higher PET contrast than NTR - xenografts ( p < 0.0001). Substantial 18 F-FMISO retention was evident in metastases of orthotopic xenografts ( p < 0.05). Accordingly, higher 18 F-FMISO biodistribution was prevalent ex vivo in NTR + xenografts. 18 F-FMISO NfsB NTR PET/CT imaging proved useful for monitoring in vivo NTR transduction and the cytotoxic effect of prodrug therapy. Conclusions: 18 F-FMISO NfsB NTR PET/CT imaging offered significant contrast between NTR + and NTR - tumours and effective resolution of metastatic progression. Furthermore, 18 F-FMISO NfsB NTR PET/CT imaging proved efficient in monitoring the two steps of GDEPT, in vivo NfsB NTR transduction and response to CB1954 prodrug therapy. These results support the repurposing of ...

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“…The chemical approach in which the parent drug is linked to a linker and the targeted drug approach such as virus-directed enzyme prodrug therapy (VDEPT), antibody-directed enzyme prodrug therapy (ADEPT), and gene-directed enzyme prodrug therapy (GDEPT) are the main two prodrug approaches [ 101 , 102 , 103 , 104 ]. The two main classes of the prodrugs’ chemical approach are (1) the carrier-linked prodrugs, which can be classified into bipartite prodrugs, where the carrier is linked to the parent drug directly; tripartite prodrugs, where the carrier is attached to the parent drug through spacer links; and mutual prodrugs, which consist of two drugs that are linked together chemically and act as promoiety to the other, and (2) bioprecursors, which are inactive substances without a carrier and converted rapidly to the active parent drug after metabolic reactions ( Figure 4 ) [ 105 , 106 , 107 , 108 ].…”

Section: The Prodrug Approachmentioning

confidence: 99%

Enzyme Models—From Catalysis to Prodrugs

Breijyeh

2021

Molecules

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Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.

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Therapeutic Potential of Prodrugs Towards Targeted Drug Delivery

Cited by 36 publications

References 36 publications

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

Repurposing ¹⁸F-FMISO as a PET tracer for translational imaging of nitroreductase-based gene directed enzyme prodrug therapy

Enzyme Models—From Catalysis to Prodrugs

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Therapeutic Potential of Prodrugs Towards Targeted Drug Delivery

Cited by 36 publications

References 36 publications

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

Repurposing 18F-FMISO as a PET tracer for translational imaging of nitroreductase-based gene directed enzyme prodrug therapy

Enzyme Models—From Catalysis to Prodrugs

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Product

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Repurposing ¹⁸F-FMISO as a PET tracer for translational imaging of nitroreductase-based gene directed enzyme prodrug therapy