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International Journal of Pharmaceutics Sep 2019Water solubility has been identified as a critical parameter and the main responsible by affecting poor performance of oral drug delivery. Poorly soluble drugs can... (Review)
Review
Water solubility has been identified as a critical parameter and the main responsible by affecting poor performance of oral drug delivery. Poorly soluble drugs can originate unsatisfactory ADME properties leading to low oral bioavailability, insufficient chemical stability, low half-life, fast pre-systemic metabolism and difficulties in formulation. In this context, the prodrug design is an alternative in order to improve physicochemical, biopharmaceutical and pharmacokinetic properties such as permeability, solubility, bioavailability, chemical stability and metabolism of molecules presenting poor drug-like properties. In this article we highlight the importance of the prodrug design in the early stages of drug discovery and development process, in an attempt to diminish the attrition rate and end up falling into the valley of death. Selected examples of this strategy are provided in this review and they are classified by some basic functional groups that are amenable to the prodrug approach with the aim of increasing aqueous solubility of poorly water-soluble compounds. Over the past decade, the number of approved prodrugs is considerable among all drugs launched in the market, emphasizing the importance of this tool on drug design. It is reported that 10% of all marketed drug worldwide can be classified as prodrugs. Furthermore, prodrugs designed to be more water soluble launched in the past decade are summarized in a table to have a closer look and finally state that the prodrug design is an amenable approach to increase water solubility.
Topics: Animals; Drug Design; Humans; Prodrugs; Solubility; Water
PubMed: 31301465
DOI: 10.1016/j.ijpharm.2019.118498 -
Advanced Healthcare Materials Nov 2023It is challenging to manage inflammatory diseases using traditional anti-inflammatory drugs due to their limited efficacy and systemic side effects, which are a result...
It is challenging to manage inflammatory diseases using traditional anti-inflammatory drugs due to their limited efficacy and systemic side effects, which are a result of their lack of selectivity, poor stability, and low solubility. Herein, it reports the development of a novel nanoparticle system, called ROS-CA-NPs, which is formed using polymer-cinnamaldehyde (CA) conjugates and is responsive to reactive oxygen species (ROS). ROS-CA-NPs exhibit excellent drug stability, tissue selectivity, and controlled drug release upon oxidative stress activation. Using mouse models of chronic rheumatoid arthritis and acute ulcerative colitis, this study demonstrates that the systemic administration of ROS-CA-NPs results in their accumulation at inflamed lesions and leads to greater therapeutic efficacy compared to traditional drugs. Furthermore, ROS-CA-NPs present excellent biocompatibility. The findings suggest that ROS-CA-NPs have the potential to be developed as safe and effective nanotherapeutic agents for a broad range of inflammatory diseases.
Topics: Animals; Mice; Prodrugs; Reactive Oxygen Species; Polymers; Anti-Inflammatory Agents; Nanoparticles
PubMed: 37540810
DOI: 10.1002/adhm.202301394 -
Journal of Controlled Release :... Sep 2023Owing to the unique DNA damaging cytotoxicity, platinum (Pt)-based chemotherapy has long been the first-line choice for clinical oncology. Unfortunately, Pt drugs are... (Review)
Review
Owing to the unique DNA damaging cytotoxicity, platinum (Pt)-based chemotherapy has long been the first-line choice for clinical oncology. Unfortunately, Pt drugs are restricted by the severe dose-dependent toxicity and drug resistance. Correspondingly, Pt(IV) prodrugs are developed with the aim to improve the antitumor performance of Pt drugs. However, as "free" molecules, Pt(IV) prodrugs are still subject to unsatisfactory in vivo destiny and antitumor efficacy. Recently, Pt(IV) prodrug nanotherapeutics, inheriting both the merits of Pt(IV) prodrugs and nanotherapeutics, have emerged and demonstrated the promise to address the underexploited dilemma of Pt-based cancer therapy. Herein, we summarize the latest fronts of emerging Pt(IV) prodrug nanotherapeutics. First, the basic outlines of Pt(IV) prodrug nanotherapeutics are overviewed. Afterwards, how versatile Pt(IV) prodrug nanotherapeutics overcome the multiple biological barriers of antitumor drug delivery is introduced in detail. Moreover, advanced combination therapies based on multimodal Pt(IV) prodrug nanotherapeutics are discussed with special emphasis on the synergistic mechanisms. Finally, prospects and challenges of Pt(IV) prodrug nanotherapeutics for future clinical translation are spotlighted.
Topics: Humans; Prodrugs; Neoplasms; Combined Modality Therapy; Drug Delivery Systems; Medical Oncology; Platinum
PubMed: 37597809
DOI: 10.1016/j.jconrel.2023.08.035 -
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 -
Journal of Materials Chemistry. B Feb 2022Chemotherapy is the major strategy for cancer therapy, but its limited therapeutic efficiency and serious toxicity to normal tissues greatly restrict its clinical...
Chemotherapy is the major strategy for cancer therapy, but its limited therapeutic efficiency and serious toxicity to normal tissues greatly restrict its clinical performance. Herein, we develop carrier-free self-activated prodrug nanoparticles combining chemotherapy and photodynamic therapy to enhance the antitumor efficiency. Reactive oxygen species (ROS)-responsive paclitaxel and porphyrin prodrugs are synthesized and co-assembled into nanoparticles without the addition of any adjuvants, which improves the drug content and reduces carrier-associated toxicity. After entering cancer cells, the obtained co-assembled nanoparticles can generate sufficient ROS upon light irradiation not only for photodynamic therapy, but also triggering on-demand drug release for chemotherapy, thus realizing self-enhanced prodrug activation and synergistic chemo-photodynamic therapy. This simple and effective carrier-free prodrug nanoplatform unifies the distinct traits of on-demand drug release and combination therapy, thus possessing great potential in advancing cancer treatment.
Topics: Cell Line, Tumor; Drug Liberation; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Polymers; Prodrugs; Reactive Oxygen Species
PubMed: 35043826
DOI: 10.1039/d1tb02638k -
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 -
Journal of Medicinal Chemistry Nov 2021Off-target drug release and insufficient drug delivery are the main obstacles for effective anticancer chemotherapy. Prodrug-based self-assembled nanoparticles...
Off-target drug release and insufficient drug delivery are the main obstacles for effective anticancer chemotherapy. Prodrug-based self-assembled nanoparticles bioactivated under tumor-specific conditions are one of the effective strategies to achieve on-demand drug release and effective tumor accumulation. Herein, stimuli-activable prodrugs are designed yielding smart tumor delivery by combination of the triglyceride-mimic (TG-mimetic) prodrug structure and disulfide bond. Surprisingly, these prodrugs can self-assemble into uniform nanoparticles (NPs) with a high drug loading (over 40%) and accumulate in tumor sites specifically. The super hydrophobic TG structure can act as a gate that senses lipase to selectively control over NP dissociation and affect the glutathione-triggered prodrug activation. In addition, the impacts of the double bonds in the prodrug NPs on parent drug release and the following cytotoxicity, pharmacokinetics, and antitumor efficiency are further demonstrated. Our findings highlight the promising potential of TG-mimetic structure-gated prodrug nanoparticles for tumor-specific drug delivery.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Carriers; Drug Liberation; Drug Synergism; Humans; Hydrophobic and Hydrophilic Interactions; Mice; Mice, Inbred C57BL; Molecular Mimicry; Molecular Structure; Nanoparticles; Neoplasms; Prodrugs; Rats; Rats, Sprague-Dawley; Triglycerides; Xenograft Model Antitumor Assays
PubMed: 34723524
DOI: 10.1021/acs.jmedchem.1c01328 -
Chemical Communications (Cambridge,... Sep 2021Central nervous system (CNS) disease is one of the most notorious arch-criminals of human health across the world. Although considerable efforts have been devoted to... (Review)
Review
Central nervous system (CNS) disease is one of the most notorious arch-criminals of human health across the world. Although considerable efforts have been devoted to promote the development of CNS drugs, ideal therapeutical effects are yet far from enough. The blood-brain barrier remains a major player that impedes the full potential of CNS therapeutical agents as it blocks the entry of CNS drugs into the brain. The past few decades have witnessed the upspring of prodrug strategies as a promising method to accelerate CNS drug development. The prodrug strategy with the ability to overcome the formidable blood-brain barrier enhances the delivery to the brain and hence improves the effects of the CNS therapeutics. In this Feature Article, we summarize the reported barriers and strategies for CNS therapeutics and spotlight prodrug design strategies to improve the efficiency of crossing the blood-brain barrier.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain; Central Nervous System Agents; Central Nervous System Diseases; Humans; Prodrugs
PubMed: 34486590
DOI: 10.1039/d1cc02940a -
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 -
Chemical Society Reviews Nov 2022In this review glycosidase activated prodrugs that target cancer cells are discussed. Glycosylated prodrugs undergo enzymatic bioconversion, cleaving the prodrug to... (Review)
Review
In this review glycosidase activated prodrugs that target cancer cells are discussed. Glycosylated prodrugs undergo enzymatic bioconversion, cleaving the prodrug to release the anticancer drug at the desired site of action, hence minimising the toxic side effects associated with many current anticancer drugs. In addition, the presence of the carbohydrate moiety increases the aqueous solubility of the drugs, allowing for a more effective treatment. In the past decade, significant advancements have been made in this field that have led to the development of many novel carbohydrate-based prodrugs - ranging from simple glycoconjugates to complex self-assemblies and materials, which are discussed in detail herein.
Topics: Humans; Prodrugs; Glycoside Hydrolases; Neoplasms; Solubility; Antineoplastic Agents; Carbohydrates
PubMed: 36349720
DOI: 10.1039/d2cs00379a