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Angewandte Chemie (International Ed. in... Feb 2024Although the clearance of senescent cells has been proven to slow down the aging process and promote anti-cancer chemotherapy, the development of senolytics remains...
Although the clearance of senescent cells has been proven to slow down the aging process and promote anti-cancer chemotherapy, the development of senolytics remains challenging. Herein, we report a senolytic strategy enabled by senescent cell-sensitive bioorthogonal tetrazine ligation. Our design is based on linking dihydrotetrazine (Tz) to a galactose (Gal) moiety that serves both as a recognition moiety for senescence-associated β-galactosidase and a caging group for the control of tetrazine activity. Gal-Tz enables efficient click-release of a fluorescent hemicyanine and doxorubicin from a trans-cyclooctene-caged prodrug to detect and eliminate senescent HeLa and A549 cells over non-senescent counterparts with a 16.44 senolytic index. Furthermore, we leverage the strategy for the selective activation and delivery of proteolysis-targeting chimeras (PROTACs) as senolytics. PROTAC prodrug TCO-ARV-771 can be selectively activated by Gal-Tz and delivered into senescent HeLa and A549 cells to induce the degradation of bromodomain-containing protein 4. Senolytic PROTACs may offer an efficient way for intervention on cell senescence thanks to their unique capacity to degrade target proteins in a sub-stoichiometric and catalytic fashion. The results of this study establish the bioorthogonal tetrazine ligation approach as a viable strategy for selective removal of senescent cells.
Topics: Humans; Cell Line, Tumor; Senotherapeutics; Heterocyclic Compounds; Prodrugs; Cellular Senescence
PubMed: 38233359
DOI: 10.1002/anie.202315425 -
AAPS PharmSciTech Jul 2023Albendazole is a broad-spectrum anthelmintic drug used for parasitic infections. In addition, due to its mechanism of action, it has been studied as an anticancer agent....
Albendazole is a broad-spectrum anthelmintic drug used for parasitic infections. In addition, due to its mechanism of action, it has been studied as an anticancer agent. However, poor and highly variable bioavailability are limiting factors for its use in systemic illnesses. The present study aimed to develop two parenteral formulations of albendazole and to compare its pharmacokinetic profile with the conventional oral administration. Parenteral formulations were developed using two different approaches: a phosphonooxymethylated prodrug and cosolvents. For the albendazole prodrug, once synthetized, its solubility and hydrolysis with alkaline phosphatase were evaluated. A factorial design of experiments was used for the cosolvent formulation. Stability and hemolytic activity were assessed. A pharmacokinetic study was performed on New Zealand rabbits. Both formulations were administered intravenously, and the prodrug was also administered intramuscularly. Results were compared with those obtained after the oral administration of albendazole. A 20,000-fold and 6000-fold increase in albendazole solubility was found with the prodrug and cosolvent formulations, respectively. Both parenteral formulations displayed higher albendazole plasma concentrations for the first 2 h compared with oral administration, even when the oral dose was doubled. The absolute bioavailability of oral albendazole was 15.5% while for the intramuscular administration of the prodrug was 102.6%. Both parenteral formulations showed a significant decrease in the formation of albendazole sulfoxide (ANOVA p<0.05) and allowed greater exposure to albendazole. Albendazole cosolvent parenteral formulation could be a promising option in systemic illnesses considering its ease of preparation and superb pharmacokinetic performance.
Topics: Animals; Rabbits; Albendazole; Prodrugs; Anthelmintics; Antineoplastic Agents; Biological Availability; Administration, Oral
PubMed: 37498473
DOI: 10.1208/s12249-023-02613-9 -
Journal of Medicinal Chemistry Dec 2023Time- and space-resolved drug delivery is highly demanded for cancer treatment, which, however, can barely be achieved with a traditional prodrug strategy. In recent... (Review)
Review
Time- and space-resolved drug delivery is highly demanded for cancer treatment, which, however, can barely be achieved with a traditional prodrug strategy. In recent years, the prodrug strategy based on a bioorthogonal bond cleavage chemistry has emerged with the advantages of high temporospatial resolution over drug activation and homogeneous activation irrespective of individual heterogeneity. In the past five years, tremendous progress has been witnessed in this field with one such bioorthogonal prodrug entering Phase II clinical trials. This Perspective aims to highlight these new advances (2019-2023) and critically discuss their pros and cons. In addition, the remaining challenges and potential strategic directions for future progress will also be included.
Topics: Prodrugs; Drug Delivery Systems
PubMed: 38085596
DOI: 10.1021/acs.jmedchem.3c01459 -
European Journal of Pharmaceutics and... Oct 2023The establishment of latent cellular and anatomical viral reservoirs is a major obstacle to achieving a cure for people infected by HIV. Mesenteric lymph nodes (MLNs)...
The establishment of latent cellular and anatomical viral reservoirs is a major obstacle to achieving a cure for people infected by HIV. Mesenteric lymph nodes (MLNs) are one of the most important anatomical reservoirs of HIV. Suboptimal levels of antiretroviral (ARVs) drugs in these difficult-to-penetrate viral reservoirs is one of the limitations of current antiretroviral therapy (ART) regimens. This study aimed to design and assess highly lipophilic ester prodrugs of dolutegravir (DTG) formulated with long-chain triglyceride (LCT) for delivery of DTG to the viral reservoir in mesenteric lymph and MLNs. A number of alkyl ester prodrugs of DTG were designed based on the predicted affinity to chylomicrons (CM), and the six most promising prodrugs were selected and synthesised. The synthesised prodrugs were further assessed for their intestinal lymphatic transport potential and biotransformation in biorelevant media in vitro and ex vivo. DTG and the most promising prodrug (prodrug 5) were then assessed in pharmacokinetic and biodistribution studies in rats. Although oral administration of 5 mg/kg of unmodified DTG (an allometrically scaled dose from humans) with or without lipids achieved concentrations above protein binding-adjusted IC (PA-IC) (64 ng/mL) in most tissues, the drug was not selectively targeted to MLNs. The combination of lipophilic ester prodrug and LCT-based formulation approach improved the targeting selectivity of DTG to MLNs 4.8-fold compared to unmodified DTG. However, systemic exposure to DTG was limited, most likely due to poor intestinal absorption of the prodrug following oral administration. In vitro lipolysis showed a good correlation between micellar solubilisation of the prodrug and systemic exposure to DTG in rats in vivo. Thus, it is prudent to include in vitro lipolysis in the early assessment of orally administered drugs and prodrugs in lipidic formulations, even when intestinal lymphatic transport is involved in the absorption pathway. Further studies are needed to clarify the underlying mechanisms of low systemic bioavailability of DTG following oral administration of the prodrug and potential ways to overcome this limitation.
Topics: Humans; Rats; Animals; Prodrugs; Esters; Tissue Distribution; Intestines; Triglycerides; Administration, Oral
PubMed: 37634824
DOI: 10.1016/j.ejpb.2023.08.015 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Feb 2024Traditional antibody drug conjugates (ADC) combine monoclonal antibodies with cytotoxic drugs to accurately strike cancer cells, but there are still many shortcomings in... (Review)
Review
Traditional antibody drug conjugates (ADC) combine monoclonal antibodies with cytotoxic drugs to accurately strike cancer cells, but there are still many shortcomings in stability, targeting, efficacy, and safety. Novel ADC, such as bi-specific, site-specific, dual-payload, and pro-drug type ADC, can be optimized by simultaneously binding 2 different antigens or epitopes, selecting more stable linkers, coupling with specific amino acid sites of antibodies, carrying different drug payloads, and adopting prodrug strategies, while retaining the characteristics of traditional ADC. Significantly improving the stability, targeting, efficacy and safety of drugs can better meet the needs of clinical treatment. Novel ADC will play a more important role in cancer treatment in the future. Discussing the progress of novel ADC in cancer treatment and analyzing their advantages and challenges can provide theoretical support for the development of anti-cancer strategies and provide directions for drug research and development.
Topics: Humans; Neoplasms; Immunoconjugates; Antibodies, Monoclonal; Antineoplastic Agents; Prodrugs
PubMed: 38755726
DOI: 10.11817/j.issn.1672-7347.2024.230418 -
European Journal of Medicinal Chemistry Jan 2024The development of new antiviral agents such as nucleoside analogues or acyclic nucleotide analogues (ANPs) and prodrugs thereof is an ongoing task. We report on the...
The development of new antiviral agents such as nucleoside analogues or acyclic nucleotide analogues (ANPs) and prodrugs thereof is an ongoing task. We report on the synthesis of three types of lipophilic triphosphate analogues of (R)-PMPA and dialkylated diphosphate analogues of (R)-PMPA. A highly selective release of the different nucleotide analogues ((R)-PMPA-DP, (R)-PMPA-MP, and (R)-PMPA) from these compounds was achieved. All dialkylated (R)-PMPA-prodrugs proved to be very stable in PBS as well as in CEM/0 cell extracts and human plasma. In primer extension assays, both the monoalkylated and the dialkylated (R)-PMPA-DP derivatives acted as (R)-PMPA-DP as a substrate for HIV-RT. In contrast, no incorporation events were observed using human polymerase γ. The dialkylated (R)-PMPA-compounds exhibited significant anti-HIV efficacy in HIV-1/2 infected cells (CEM/0 and CEM/TK). Remarkably, the dialkylated (R)-PMPA-MP derivative 9a showed a 326-fold improved activity as compared to (R)-PMPA in HIV-2 infected CEM/TK cells as well as a very high SI of 14,000. We are convinced that this study may significantly contribute to advancing antiviral agents developed based on nucleotide analogues in the future.
Topics: Humans; Tenofovir; Anti-HIV Agents; Organophosphonates; Adenine; HIV-2; Nucleotides; Prodrugs
PubMed: 38086193
DOI: 10.1016/j.ejmech.2023.116020 -
Journal of Medicinal Chemistry Jul 2023Proteolysis-targeting chimera (PROTAC) technology represents a novel and promising modality for targeted protein degradation with transformative implications for the... (Review)
Review
Proteolysis-targeting chimera (PROTAC) technology represents a novel and promising modality for targeted protein degradation with transformative implications for the clinical management of various diseases. Despite notable advantages, the possibility of on-target off-tumor toxicity in healthy cells represents a critical challenge to clinical applications in cancer treatment. Researchers are currently exploring strategies to enhance targeted degradation activity in a cell-selective manner to minimize undesirable side effects. In this Perspective, we highlight innovative approaches for prodrug-based PROTACs (pro-PROTACs) that facilitate tumor-targeted release. The development of such approaches may further expand the range of potential applications of PROTAC technology within drug development.
Topics: Humans; Neoplasms; Drug Development; Drug-Related Side Effects and Adverse Reactions; Prodrugs; Proteolysis; Proteolysis Targeting Chimera; Ubiquitin-Protein Ligases
PubMed: 37317568
DOI: 10.1021/acs.jmedchem.3c00302 -
Current Opinion in Chemical Biology Aug 2023Reactive sulfur species (RSS), such as HS, hydrogen polysulfide (HS, n ≥ 2), and hydropersulfides (RSSH, n ≥ 1), are known to mediate diverse signaling pathways... (Review)
Review
Reactive sulfur species (RSS), such as HS, hydrogen polysulfide (HS, n ≥ 2), and hydropersulfides (RSSH, n ≥ 1), are known to mediate diverse signaling pathways and possess a plethora of exciting therapeutic opportunities. Historically, due to the rapid inter-conversion among those species in vivo, the biological differences of distinct sulfur species were often overlooked. These species were considered to enrich the global sulfur pool in almost an equal fashion. However, advancement in this field has revealed that sulfur species at different oxidation states result in different pharmacological effects including scavenging reactive oxygen species (ROS), activating ion channels, and exhibiting analgesic effects. Here, we summarize recent advances in studying the biological and pharmacological differences of distinct sulfur species; discuss this phenomenon from the view of chemical properties and sulfur signaling pathways; and lay out a roadmap to transforming such new knowledge into general principles in developing sulfur-based therapeutics.
Topics: Hydrogen Sulfide; Prodrugs; Sulfides; Sulfur
PubMed: 37279623
DOI: 10.1016/j.cbpa.2023.102329 -
Expert Opinion on Drug Delivery May 2024The prodrug approach has been thought to be a simple solution to improve brain drug delivery for decades. Nevertheless, it still comes as a surprise that there is... (Review)
Review
INTRODUCTION
The prodrug approach has been thought to be a simple solution to improve brain drug delivery for decades. Nevertheless, it still comes as a surprise that there is relatively little success in the field. The best example anti-parkinsonian drug levodopa has been serendipitously discovered to be a transporter-utilizing brain-delivered prodrug rather than a rationally developed one.
AREAS COVERED
The lack of success can mainly be explained by the insufficient understanding of the role of membrane proteins that can facilitate drug delivery at dynamic barriers, such as the blood-brain barrier (BBB), but also by the sparse knowledge of prodrug bioconverting enzymes in the brain. This review summarizes the current status of the prodrug attempts that have been developed in the past to improve brain drug delivery.
EXPERT OPINION
With the expandingly improved analytical and computational technologies, it is anticipated that enhanced brain drug delivery will be eventually achieved for most of the central nervous system (CNS) acting drugs. However, this requires that carrier-mediated (pro)drug delivery methods are implemented in the very early phases of the drug development processes and not as a last step to survive a problematic investigational drug candidate.
Topics: Prodrugs; Humans; Drug Delivery Systems; Blood-Brain Barrier; Animals; Brain; Drug Development; Central Nervous System Agents; Drug Carriers
PubMed: 38738934
DOI: 10.1080/17425247.2024.2355180 -
Acta Biomaterialia Aug 2023Prodrug assembled nanoparticles integrate the merits of both prodrug and nanoparticle, which significantly improve pharmacokinetic parameters, enhance tumorous...
Prodrug assembled nanoparticles integrate the merits of both prodrug and nanoparticle, which significantly improve pharmacokinetic parameters, enhance tumorous accumulation and decrease adverse effects, while they are challenged by disassembly upon dilution in blood, masking the superiority of nanoparticles (NPs). Herein, a reversibly "double locked" hydroxycamptothecin (HCPT) prodrug nanoparticle decorated with cyclic RGD peptide (cRGD) is developed for safe and efficient chemotherapy of orthotopic lung cancer in mice. HCPT prodrug is constructed from acetal (ace)-linked cRGD-PEG-ace-HCPT-ace-acrylate polymer, which is self-assembled into the nanoparticles with "the first lock" of HCPT. Then the nanoparticles undergo the in situ UV-crosslinking of the acrylate residues for constructing "the second lock" of HCPT. The obtained "double locked" nanoparticles (T-DLHN) with simple and well-defined construction are demonstrated to possess extremely high stability against 100-fold dilution and acid-triggered "unlock" including de-crosslinking and liberation of the pristine HCPT. In an orthotopic lung tumor of mouse model, T-DLHN reveals a prolonged circulation time of about 5.0 h, superb lung tumor-homing capacity with tumorous drug uptake of about 7.15%ID/g, resulting in significantly boosted anti-tumor activity and reduced adverse effects. Hence, these nanoparticles utilizing "double lock" and acid-triggered "unlock" strategies represent a unique and promising nanoplatform for safe and efficient drug delivery. STATEMENT OF SIGNIFICANCE: Prodrug assembled nanoparticles have the unique properties of the well-defined structure, systemic stability, improved pharmacokinetics, passive targeting and decreased adverse effects. However, prodrug assembled NPs would disassemble against extensive dilution in the blood circulation when intravenously injected into the body. Herein, we have designed a cRGD-directed reversibly "double-locked" HCPT prodrug nanoparticle (T-DLHN) for safe and efficient chemotherapy of orthotopic A549 human lung tumor xenografts. Upon intravenous injection, T-DLHN can overcome the shortcoming of disassembly against extensive dilution, prolong the circulation time due to the "double locked" configuration and then mediate targeted drug delivery into the tumors. After uptaken into the cells, T-DLHN undergoes concurrent de-crosslinking and liberation of HCPT under acidic condition for enhanced chemotherapeutic efficacy with negligible adverse effects.
Topics: Humans; Mice; Animals; Prodrugs; Cell Line, Tumor; Camptothecin; Drug Delivery Systems; Lung Neoplasms; Nanoparticles
PubMed: 37220820
DOI: 10.1016/j.actbio.2023.05.030