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Bioconjugate Chemistry Dec 2023Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current...
Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current strategies often deliver either the prodrug or its complementary activator to the tumor with a monomechanism targeted mechanism, which cannot achieve the desired antitumor efficacy and safety profile. The orchestration of two distinct and orthogonal mechanisms should overcome the hierarchical heterogeneity of solid tumors to improve the delivery efficiency of both components simultaneously for bio-orthogonal prodrug therapies. We herein developed a dual-mechanism targeted bioorthogonal prodrug therapy by integrating two orthogonal, receptor-independent tumor-targeting strategies. We first employed the endogenous albumin transport system to generate the albumin-bound, bioorthogonal-caged doxorubicin prodrug with extended plasma circulation and selective accumulation at the tumor site. We then employed enzyme-instructed self-assembly (EISA) to specifically enrich the bioorthogonal activators within tumor cells. As each targeted delivery mode induced an intrinsic pharmacokinetic profile, further optimization of the administration sequence according to their pharmacokinetics allowed the spatiotemporally controlled prodrug activation on-target and on-demand. Taken together, by orchestrating two discrete and receptor-independent targeting strategies, we developed an all-small-molecule based bioorthogonal prodrug system for dual-mechanism targeted anticancer therapies to maximize therapeutic efficacy and minimize adverse drug reactions for chemotherapeutic agents.
Topics: Humans; Prodrugs; Doxorubicin; Neoplasms; Albumins; Cell Line, Tumor
PubMed: 37955377
DOI: 10.1021/acs.bioconjchem.3c00404 -
Clinical Cancer Research : An Official... Nov 2001The selective activation of prodrug(s) in tumor tissues by exogenous enzyme(s) for cancer therapy can be accomplished by several ways, including gene-directed enzyme... (Review)
Review
The selective activation of prodrug(s) in tumor tissues by exogenous enzyme(s) for cancer therapy can be accomplished by several ways, including gene-directed enzyme prodrug therapy (GDEPT), virus-directed enzyme prodrug therapy (VDEPT), and antibody-directed enzyme prodrug therapy (ADEPT). The central part of enzyme/prodrug cancer therapy is to deliver drug-activating enzyme gene or functional protein to tumor tissues, followed by systemic administration of a prodrug. Although each approach (GDEPT, VDEPT, and ADEPT) has been tested in clinical trials, there are some potential problems using the current delivery systems. In this article, disadvantages and advantages associated with each approach (GDEPT, VDEPT, and ADEPT) and future perspective for improving current systems are discussed.
Topics: Antibodies, Monoclonal; Enzymes; Female; Gene Transfer Techniques; Humans; Male; Models, Biological; Neoplasms; Prodrugs
PubMed: 11705842
DOI: No ID Found -
Archiv Der Pharmazie Sep 2022Reactive oxygen species (ROS) are known to trigger drug release from arylboronate-containing ROS-responsive prodrugs. In cancer cells, elevated levels of ROS can be...
Reactive oxygen species (ROS) are known to trigger drug release from arylboronate-containing ROS-responsive prodrugs. In cancer cells, elevated levels of ROS can be exploited for the selective activation of prodrugs via Baeyer-Villiger type oxidation rearrangement sequences. Here, we report a proof of concept to demonstrate that these cascades can as well be initiated by cold physical plasma (CPP). An analog of a recently reported fluorouracil prodrug based on the less toxic drug 5-fluorocytosine (5-FC) was synthesized with a view to laboratory safety reasons and used as a model compound to prove our hypothesis that CPP is suitable as a trigger for the prodrug activation. Although the envisioned oxidation and rearrangement with successive loss of boronic acid species could be achieved by plasma treatment, the anticipated spontaneous liberation of 5-FC was inefficient in the model case. However, the obtained results suggest that custom-tailored CPP-responsive prodrugs might become an evolving research field.
Topics: Cell Line, Tumor; Flucytosine; Plasma Gases; Prodrugs; Reactive Oxygen Species; Structure-Activity Relationship
PubMed: 35621706
DOI: 10.1002/ardp.202200061 -
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 -
Current Topics in Medicinal Chemistry 2011There is a great emphasis on research to discover methods aimed at enhancing the efficacy of drugs and reducing their toxicity and unwanted side effects. Prodrugs are... (Review)
Review
There is a great emphasis on research to discover methods aimed at enhancing the efficacy of drugs and reducing their toxicity and unwanted side effects. Prodrugs are biologically inactive compounds that are converted to actual drug molecule, through biotransformation, that combine with the receptors to produce the biological action. Prodrugs can thus be considered as drugs containing specialized nontoxic protective groups utilized in a transient manner to alter or eliminate the undesirable properties of the parent drug molecule. Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most of the drugs for cardiovascular diseases have low oral bioavailability, short duration of action, first pass metabolism and variable lipohilicities. Out of the need to overcome these limitations, various prodrugs have been designed for antihypertensive agents. This review extensively focuses on various strategies used for design and development of prodrugs for the various classes of antihypertensives, emphasizing on the details regarding the need for prodrug synthesis for each class, structure, type of modification and goal achieved. It also provides an insight into the major advances in the field of antihypertensive prodrug research.
Topics: Animals; Antihypertensive Agents; Drug Design; Humans; Hypertension; Molecular Structure; Prodrugs
PubMed: 21671866
DOI: 10.2174/156802611797183285 -
Current Pharmaceutical Design 2009Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to the parent active drug inside the body.... (Review)
Review
Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to the parent active drug inside the body. Prodrugs can enhance the therapeutic efficacy and/or reduce adverse effects via different mechanisms, including increased solubility, improved permeability and bioavailability, prolonged half-life, and tissue-targeted delivery. Besides the prodrug itself, optimization of vehicles and other enhancement techniques is important as well. Strategies to improve the oral bioavailability and achieve tumor-specific targeting have been the most important developments in prodrug design during the last 5 years. This review describes recent developments in orally administered and tumor-targeted prodrugs. Pharmacokinetic and pharmacodynamic evaluations of these prodrugs are systematically introduced in this review.
Topics: Animals; Antineoplastic Agents; Biological Availability; Chemistry, Pharmaceutical; Drug Delivery Systems; Drug Design; Humans; Neoplasms; Permeability; Prodrugs; Solubility
PubMed: 19601825
DOI: 10.2174/138161209788682523 -
Journal of Controlled Release :... Oct 2017Unsaturated fatty acids (UFAs), with the distinct advantages of good biocompatibility and innate tumor-targeting effect, have been widely investigated for the rational... (Review)
Review
Unsaturated fatty acids (UFAs), with the distinct advantages of good biocompatibility and innate tumor-targeting effect, have been widely investigated for the rational design of chemotherapy agent-unsaturated fatty acid (CA-UFA) prodrugs in cancer therapy. Among them, several CA-UFA prodrugs have successfully entered clinical trials and are promising prospects for potential clinical applications. In addition, CA-UFA prodrug-based nanoparticulate drug delivery systems (nano-DDS), which integrate the advantages of CA-UFA prodrugs and nano-DDS, have been emerging as versatile nano-carriers for the efficient delivery of chemotherapeutics. In this paper, we review the advanced drug delivery strategies based on UFA conjugates and focus on the recent advances in CA-UFA prodrugs and the emerging CA-UFA prodrug-based nano-DDS. First, we discuss the rational design of CA-UFA prodrugs in response to the multiple obstacles in chemotherapy, with particular emphasis on the latest progress in both preclinical studies and clinical trials. Moreover, the emerging CA-UFA prodrug-based nano-DDS are also addressed. Finally, the prospects and potential challenges of CA-UFA prodrug-based drug delivery strategies in chemotherapy are highlighted.
Topics: Animals; Antineoplastic Agents; Fatty Acids, Unsaturated; Humans; Nanoparticles; Neoplasms; Prodrugs
PubMed: 28844757
DOI: 10.1016/j.jconrel.2017.08.034 -
Biomaterials Science Oct 2023Although immunotherapy has achieved great success in the treatment of a variety of tumors, its efficacy for glioblastoma (GBM) is still limited. Both the...
Although immunotherapy has achieved great success in the treatment of a variety of tumors, its efficacy for glioblastoma (GBM) is still limited. Both the immunosuppressive tumor microenvironment (TME) and poor penetration of immunotherapeutic agents into tumors contributed to the poor anti-glioma immunity. Herein, we develop an injectable prodrug-loaded hydrogel delivery system with sono-activatable properties for sonodynamic therapy (SDT)-triggered immunomodulation for GBM treatment. The prodrug alginate hydrogels (APN), which contain semiconducting polymer nanoparticles (SPNs) and the NLG919 prodrug linked by singlet oxygen (O)-cleavable linkers, are formed coordination of alginate solution with Ca in the TME. SPNs serve as sonosensitizers to produce O upon ultrasound (US) irradiation for SDT. The generated O not only induce immunogenic cell death, but also break O-cleavable linkers to precisely activate the NLG919 prodrug. Antitumor immunity is significantly amplified due to the reversal of immunosuppression mediated by indolamine 2,3-dioxygenase-dependent tryptophan metabolism. This smart prodrug hydrogel platform potently inhibits tumor growth in orthotopic glioma-bearing mice. Collectively, this work provides a sono-activatable hydrogel platform for precise sono-immunotherapy against GBM.
Topics: Mice; Animals; Glioblastoma; Prodrugs; Polymers; Neoplasms; Glioma; Nanoparticles; Immunotherapy; Alginates; Hydrogels; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37623749
DOI: 10.1039/d3bm00585b -
Journal of Medicinal Chemistry Dec 2016Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their... (Review)
Review
Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their development as drug molecules has been hindered by the inherent poor druglike properties of the monophosphate and monophosphonate groups. These include inefficient cellular uptake and poor in vivo stability, with this latter drawback being most relevant to monophosphates than monophosphonates. To address these limitations, numerous monophosphate and monophosphonate prodrug strategies have been developed and applied in the discovery of nucleoside monophosphate and monophosphonate prodrugs that can treat viral infections and cancer. The approval of sofosbuvir, a nucleoside monophosphate prodrug, highlighted the success to be had by employing these prodrug technologies in the discovery of nucleotide therapeutics. In this Miniperspective, we discuss the different key monophosphate and monophosphonate nucleoside prodrugs that entered clinical development, some of which may in the future be approved to treat various human diseases.
Topics: Humans; Neoplasms; Nucleosides; Phosphates; Prodrugs; Virus Diseases
PubMed: 27559756
DOI: 10.1021/acs.jmedchem.6b00523 -
Chembiochem : a European Journal of... Nov 2021Chemotherapy is the primary treatment modality employed in the clinic for the treatment of cancer. Despite proven clinical success, adverse side effects are one of the... (Review)
Review
Chemotherapy is the primary treatment modality employed in the clinic for the treatment of cancer. Despite proven clinical success, adverse side effects are one of the drawbacks of this approach. The prodrug strategy has emerged as an alternative approach with the aim of alleviating these drawbacks. Prodrug activation is typically achieved by either endogenous or exogenous triggers. Exogenous triggers like light are appealing as they are independent of inherent patient and/or cancer-type variations. However, tissue penetration depth remains the Achilles' heel of this approach. In this context, usage of X-rays as the external trigger with infinite tissue penetration depth opens up exciting prospects in prodrug activation strategies.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Cell Survival; Humans; Molecular Structure; Neoplasms; Prodrugs; X-Rays
PubMed: 34406685
DOI: 10.1002/cbic.202100373