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Current Drug Discovery Technologies Sep 2006Skin as a route for drug delivery has been extensively investigated. However, because of the predominant barrier function of stratum corneum in skin, the clinical... (Review)
Review
Skin as a route for drug delivery has been extensively investigated. However, because of the predominant barrier function of stratum corneum in skin, the clinical application is limited. One strategy to solve this problem of drug permeation via skin is the use of prodrugs. Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to its parent active drug. Prodrugs can enhance dermal/transdermal drug delivery via different mechanisms, including increased skin partitioning, increased aqueous solubility, and reduced crystallization, etc. Besides the prodrug itself, the optimization of vehicle is important as well. The prodrug partitioning between skin and vehicle as well as prodrug-vehicle interaction may influence the enhancing efficacy on skin permeation. This review explores the synthesis and enhancing mechanisms of prodrugs for topical drug delivery. The prodrugs categorized by the therapeutic use of the parent drugs, including anticancer drugs, analgesics, anti-inflammatory drugs and vitamins, are systemically introduced in this review.
Topics: Animals; Drug Delivery Systems; Drug Design; Humans; Models, Anatomic; Models, Biological; Molecular Structure; Prodrugs; Skin; Skin Absorption
PubMed: 17311566
DOI: 10.2174/157016306780136772 -
Chemical Society Reviews Jun 2024Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with... (Review)
Review
Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with traditional drug-loaded nanocarriers in which drugs are just physically entrapped (, burst release, poor drug loadings). In the past few years, reversible-deactivation radical polymerization (RDRP) techniques have been extensively used to design tailor-made polymer prodrug nanocarriers. This synthesis strategy has received a lot of attention due to the possibility of fine tuning their structural parameters (, polymer nature and macromolecular characteristics, linker nature, physico-chemical properties, functionalization, ), to achieve optimized drug delivery and therapeutic efficacy. In particular, adjusting the nature of the drug-polymer linker has enabled the easy synthesis of stimuli-responsive polymer prodrugs for efficient spatiotemporal drug release. In this context, this review article will give an overview of the different stimuli-sensitive polymer prodrug structures designed by RDRP techniques, with a strong focus on the synthesis strategies, the macromolecular architectures and in particular the drug-polymer linker, which governs the drug release kinetics and eventually the therapeutic effect. Their biological evaluations will also be discussed.
Topics: Prodrugs; Polymerization; Drug Carriers; Humans; Polymers; Nanoparticles; Drug Liberation; Free Radicals
PubMed: 38775004
DOI: 10.1039/d2cs01060g -
Chembiochem : a European Journal of... Aug 2019Intramolecular N-to-O and O-to-N acyl migrations have been known for a century. Recent decades have witnessed a considerable number of applications of such chemical... (Review)
Review
Intramolecular N-to-O and O-to-N acyl migrations have been known for a century. Recent decades have witnessed a considerable number of applications of such chemical transformations in the fields of medicinal chemistry and peptide chemistry. The former has been focused on employing the isoacyl-mediated prodrug approach to improve the physicochemical properties of insoluble drug candidates. The latter involves multiple directions, including establishing new peptide segment ligation methods; facilitating sterically hindered amide-bond coupling; and enabling the synthesis, handling and investigation of difficult sequences. Notably, most of these cases can be achieved in a traceless manner. These successes are mainly attributed to the unique chemical and biophysical properties of the isoacyl structural motif. This review will summarize the historical achievements and highlight the recent advances in this topic.
Topics: Acylation; Chemistry, Pharmaceutical; Molecular Structure; Peptides; Prodrugs
PubMed: 31144418
DOI: 10.1002/cbic.201900260 -
Physical Chemistry Chemical Physics :... Jun 2023Octahedral Pt complexes are considered highly promising candidates for overcoming some shortcomings of clinically approved Pt drugs. Pt compounds, owing to their... (Review)
Review
Octahedral Pt complexes are considered highly promising candidates for overcoming some shortcomings of clinically approved Pt drugs. Pt compounds, owing to their inertia, appear to be capable of resisting premature aquation and undesired binding to essential plasma proteins and have shown remarkable potential for both oral administration and for reducing side effects. Additionally, their pharmacological properties can be finely tuned by choosing appropriate axial ligands. The reduction inside the cell by biological reducing agents to the correponding active cytotoxic Pt species, accompanied by the loss of the axial ligands, is considered an essential step of their mechanism and has been extensively studied. However, a detailed understanding of the mechanism by which Pt prodrugs are activated, which should be highly beneficial for their proper design, is lacking, and many contradictory results continue to be collected. In the hope of contributing to the advancement of knowledge in this field, this perspective focuses on the insights gained from computational studies carried out with the aim of finding answers to the many still open questions concerning the reduction of Pt complexes in biological environments.
Topics: Prodrugs; Ligands; Antineoplastic Agents; Reducing Agents; Cell Line, Tumor
PubMed: 37259840
DOI: 10.1039/d3cp01150j -
Chemical Communications (Cambridge,... Dec 2022A tumor-targeting therapy strategy is urgently needed to increase the accumulation of drugs in tumors and reduce the side effects in normal tissues. Herein, we developed...
A tumor-targeting therapy strategy is urgently needed to increase the accumulation of drugs in tumors and reduce the side effects in normal tissues. Herein, we developed an esterase-activatable curcumin prodrug Cur-RGD for tumor-targeting therapy. Armed with the tumor-targeting RGD peptide and esterase-triggered drug release, this prodrug Cur-RGD can efficiently improve the therapeutic effect of curcumin in tumors.
Topics: Humans; Curcumin; Prodrugs; Esterases; Oligopeptides; Neoplasms; Nanoparticles; Drug Carriers; Antineoplastic Agents; Cell Line, Tumor
PubMed: 36373630
DOI: 10.1039/d2cc03952d -
International Journal of Molecular... Feb 2022Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to...
Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A (PLA) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA.
Topics: Cyclosporine; Humans; Inflammatory Bowel Diseases; Phospholipases A2; Phospholipids; Prodrugs
PubMed: 35269813
DOI: 10.3390/ijms23052673 -
Current Oncology Reports Jan 2000The prodrug strategy has its own particular real and theoretic obstacles. Clinical strategies and research efforts have tried to approach these problems. The bystander... (Review)
Review
The prodrug strategy has its own particular real and theoretic obstacles. Clinical strategies and research efforts have tried to approach these problems. The bystander effect, whereby nontransduced cells are affected by simple proximity to those that have received the novel gene, has enabled many prodrug systems to be more efficient than anticipated. Several prodrug gene therapy systems have been developed, including the HSVtk/GCV and CD/5-FC systems. Preclinical work serves as the foundation for clinical trials examining the use of prodrug gene therapy systems. At least 21 prodrug gene therapy trials have been approved for patient enrollment in the United States and Europe. Recent work has demonstrated the success of prodrug gene therapy, which might lead to combination therapies using vector transfer of both prodrug/suicide as well as immune-enhancing genes to tumors.
Topics: Clinical Trials as Topic; Combined Modality Therapy; Genetic Therapy; Humans; Neoplasms; Prodrugs; Research Design
PubMed: 11122820
DOI: 10.1007/s11912-000-0006-z -
Annals of the New York Academy of... Jun 1999
Review
Topics: Adenocarcinoma; Animals; Biotransformation; Genetic Therapy; Humans; Pancreatic Neoplasms; Prodrugs
PubMed: 10415876
DOI: 10.1111/j.1749-6632.1999.tb09535.x -
Theranostics 2022Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly...
Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer.
Topics: Doxorubicin; Glucuronidase; Humans; Neoplasms; Prodrugs
PubMed: 35832083
DOI: 10.7150/thno.69168 -
Angewandte Chemie (International Ed. in... May 2021An emerging approach in the field of targeted drug delivery is the establishment of abiotic metal-triggered prodrug mechanisms that can control the release of bioactive...
An emerging approach in the field of targeted drug delivery is the establishment of abiotic metal-triggered prodrug mechanisms that can control the release of bioactive drugs. Currently, the design of prodrugs that use abiotic metals as a trigger relies heavily on uncaging strategies. Here, we introduce a strategy based on the gold-catalyzed activation of a phenanthridinium-based prodrug via hydroamination under physiological conditions. To make the prodrug strategy biocompatible, a gold artificial metalloenzyme (ArM) based on human serum albumin, rather than the free gold metal complex, was used as a trigger for prodrug activation. The albumin-based gold ArM protected the catalytic activity of the bound gold metal even in the presence of up to 1 mM glutathione in vitro. The drug synthesized via the gold ArM exerted a therapeutic effect in cell-based assays, highlighting the potential usefulness of the gold ArM in anticancer applications.
Topics: A549 Cells; Amination; Catalysis; Cell Survival; Cyclization; Glutathione; Gold; Humans; Metalloproteins; Phenanthridines; Prodrugs; Serum Albumin
PubMed: 33719151
DOI: 10.1002/anie.202100369