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Future Medicinal Chemistry Aug 2019Prodrug entrapment into nanocarriers for tumor delivery is a strategy to achieve a valid therapy with high efficiency. The prodrug contains anticancer agents conjugating... (Review)
Review
Prodrug entrapment into nanocarriers for tumor delivery is a strategy to achieve a valid therapy with high efficiency. The prodrug contains anticancer agents conjugating with functional moieties or ligands so that the active component is released after metabolism in the body or tumor. The advantages of nanosystems for loading prodrugs include high loading, increased prodrug stability, improved bioavailability and enhanced targeting to tumor cells. In the present article, we introduce the prodrug delivery approaches according to nanomedicine and the recent advances in prodrug-loaded nanocarriers. First, we discuss the conceptional design of combined prodrugs and nanocarriers in response to the obstruction in anticancer therapy. Then we describe the cases of prodrug-loaded nanoparticles for cancer treatment during the past 5 years.
Topics: Animals; Antineoplastic Agents; Drug Carriers; Drug Delivery Systems; Humans; Nanoconjugates; Nanomedicine; Nanoparticles; Nanotechnology; Neoplasms; Prodrugs; Treatment Outcome
PubMed: 31538520
DOI: 10.4155/fmc-2018-0388 -
Angewandte Chemie (International Ed. in... Dec 2023Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control...
Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core-shell reactor partitioning enzyme and prodrug by ZIF-8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn-prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF-8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC value (26.3±2.6 μg/mL) are measured for B16-F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core-shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.
Topics: Humans; Prodrugs; NADP; Antineoplastic Agents; Dacarbazine; Cytochrome P-450 Enzyme System; Neoplasms
PubMed: 37881154
DOI: 10.1002/anie.202314025 -
Medical Gas Research 2019Nitric oxide (NO) is an endogenous gas with several physiological activities. Owing to the NO physiological functions, such as inhibition of platelet aggregation and... (Review)
Review
Nitric oxide (NO) is an endogenous gas with several physiological activities. Owing to the NO physiological functions, such as inhibition of platelet aggregation and adhesion, vascular muscle relaxation, modulation of inflammation and immune response, antibacterial and anticancer activity, increasing attensions have been paid to the development of biomaterials with the ability to release this medical gas. Nowadays, numerous prodrugs have been developed to release NO in vivo. However, due to the low payloads and non-controlled delivery of the prodrug, the NO-releasing devices do not fulfil the expectations, which restricts their widespread application. Recently, several methods have been proposed to address the issue above, including physical and chemical methods and specific designs. This review aims to briefly introduce the latest achievements with recent 3 years involving coatings which mimic the vascular endothelium to treat atherosclerosis, nanocarriers which generate NO for a sustained anticancer treatment, and a framework which modifies the prodrug as a stable cardiovascular stent or as an anticancer targeted drug.
Topics: Animals; Arginine; Bacteria; Biocompatible Materials; Ferrosoferric Oxide; Humans; Neoplasms; Nitric Oxide; Nitric Oxide Donors; Prodrugs
PubMed: 31898603
DOI: 10.4103/2045-9912.273956 -
ACS Applied Materials & Interfaces Dec 2021Responsive drug delivery systems possess great potential in disease diagnosis and treatment. Herein, we develop an activatable prodrug and fluorescence imaging material...
Responsive drug delivery systems possess great potential in disease diagnosis and treatment. Herein, we develop an activatable prodrug and fluorescence imaging material by engineering the endogenous NAD(P)H:quinone oxidoreductase-1 (NQO1) responsive linker. The as-prepared nanomaterials possess the NQO1-switched drug release and fluorescence enablement, which realizes the tumor-specific chemotherapy and imaging in living mice. The enzyme-sensitive prodrug nanoparticles exhibit selectively potent anticancer performance to NQO1-positive cancer and ignorable off-target toxicity. This work provides an alternative strategy for constructing smart prodrug nanoplatforms with precision, selectivity, and practicability for advanced cancer imaging and therapy.
Topics: Animals; Antineoplastic Agents; Biocompatible Materials; Cell Line; Cell Survival; Drug Delivery Systems; Drug Liberation; Drug Screening Assays, Antitumor; Humans; Materials Testing; Mice; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Nanoparticles; Neoplasms; Neoplasms, Experimental; Optical Imaging; Particle Size; Precision Medicine; Prodrugs
PubMed: 34879654
DOI: 10.1021/acsami.1c19058 -
Carbohydrate Polymers Nov 2023Natural polysaccharides, represented by dextran, chitosan, and hyaluronic acid, are widely approved for use as pharmaceutical excipients and are important carrier...
Natural polysaccharides, represented by dextran, chitosan, and hyaluronic acid, are widely approved for use as pharmaceutical excipients and are important carrier materials for the design of advanced drug delivery systems, particularly in the field of anticancer drug delivery. The combination of stimuli-activable prodrug based chemotherapy and photodynamic therapy (PDT) has attracted increasing attention. Recent studies have verified the effectiveness of this strategy in the treatment of multiple aggressive cancers. However, in such combination, the stimuli-responsive chemotherapy and PDT have their own problems that need to be overcome. The uneven distribution of endogenous stimuli within tumor tissues makes it difficult for prodrug to be completely activated. And the inadequate tissue penetration depth of external light results in low efficiency of PDT. Aiming at these two bottlenecks, we designed a biocompatible dextran based - multi-component nanomedicine (PCL-NPs) that integrate a chemiluminescence agent luminol, a photosensitizer chlorine e6 (Ce6), and a reactive oxygen species (ROS)-activable thioketal-based paclitaxel (PTX) prodrug. The presence of overexpressed hydrogen peroxide (HO) inside tumor oxidizes the luminol moiety to generate in-situ light for PDT through chemiluminescence resonance energy transfer (CRET). The singlet oxygen (O) produced in this process not only directly kills tumor cells but also amplifies oxidative stress to accelerate the activation of PTX prodrug. We propose that the PCL-NPs have great therapeutic potential by simultaneously enhancing chemotherapy and PDT in a combination therapy.
Topics: Micelles; Photochemotherapy; Dextrans; Prodrugs; Luminescence; Hydrogen Peroxide; Luminol; Cell Line, Tumor; Photosensitizing Agents; Paclitaxel; Nanoparticles
PubMed: 37567697
DOI: 10.1016/j.carbpol.2023.121192 -
Chemical Communications (Cambridge,... Oct 2023Bioorthogonal catalysis, a class of catalytic reactions that are mediated by abiotic metals and proceed in biological environments without interfering with native... (Review)
Review
Bioorthogonal catalysis, a class of catalytic reactions that are mediated by abiotic metals and proceed in biological environments without interfering with native biochemical reactions, has gained ever-increasing momentum in prodrug delivery over the past few decades. Albeit great progress has been attained in developing new bioorthogonal catalytic reactions and optimizing the catalytic performance of transition metal catalysts (TMCs), the use of TMCs to activate chemotherapeutics at the site of interest remains a challenging endeavor. To translate the bioorthogonal catalysis-mediated prodrug activation paradigm from flasks to animals, TMCs with targeting capability and stimulus-responsive behavior have been well-designed to perform chemical transformations in a controlled manner within highly complex biochemical systems, rendering on-demand drug activation to mitigate off-target toxicity. Here, we review the recent advances in the development of controllable bioorthogonal catalysis systems, with an emphasis on different strategies for engineering TMCs to achieve precise control over prodrug activation. Furthermore, we outline the envisaged challenges and discuss future directions of controllable bioorthogonal catalysis for disease therapy.
Topics: Animals; Prodrugs; Transition Elements; Metals; Catalysis; Activation, Metabolic
PubMed: 37791560
DOI: 10.1039/d3cc04286c -
ACS Chemical Biology Apr 2022The limited therapeutic effects of immunotherapy for most types of cancer stimulates the pursuit for efficient methods to improve its response rate. Herein we report the...
The limited therapeutic effects of immunotherapy for most types of cancer stimulates the pursuit for efficient methods to improve its response rate. Herein we report the design and synthesis of a cascade-responsive molecular prodrug for tandem chemoimmunotherapy. This molecular prodrug first releases doxorubicin (DOX) in the mildly acidic tumor microenvironment (TME) to induce immunogenic cell death (ICD) of tumor cells. Caspase 3/7 released during tumor cell apoptosis liberates NLG919 from the prodrug, which inhibits the activity of indoleamine 2,3-dioxygenase (IDO) and results in relief of TME immunosuppression. Meanwhile, tumor-associated antigens and immune stimulatory cytokines released during ICD activate the immune response against the tumor, leading to synergistic chemoimmunotherapy. The efficacy of this prodrug is validated by and experiments, demonstrating the success of this strategy for cancer treatment.
Topics: Cell Line, Tumor; Dendrimers; Doxorubicin; Humans; Immunotherapy; Nanoparticles; Neoplasms; Prodrugs; Receptors, Chimeric Antigen; Tumor Microenvironment
PubMed: 35285234
DOI: 10.1021/acschembio.1c00933 -
Acta Biomaterialia Oct 2022Selective in situ activation of prodrugs or generation of bioactive drugs is an important approach to reducing the side effects of chemotherapy. Herein, a tailored...
Selective in situ activation of prodrugs or generation of bioactive drugs is an important approach to reducing the side effects of chemotherapy. Herein, a tailored ROS-activable prodrug nanomedicine (Cu-SK@DTC-PPB) was developed as the prodrug activation nanoamplifier for highly selective antitumor therapy. Cu-SK@DTC-PPB was rationally constructed by the diethyldithiocarbamate (DTC) prodrug DTC-PPB and the nanoscale coordinated framework Cu-SK based on copper and the ROS generator shikonin (SK). Cu, SK and DTC were kept in the inactive state in the fabricated Cu-SK@DTC-PPB. In the presence of ROS within tumors, DTC-PPB can be activated to release less cytotoxic DTC, which can rapidly chelate Cu from the Cu-SK framework to synthesize highly cytotoxic Cu(DTC) and induce SK to release in a cascade. The released SK can generate ROS to increase the intracellular ROS level, further activating DTC-PPB to release more DTC. That is, Cu-SK@DTC-PPB can undergo a self-amplifying positive feedback loop to induce numerous bioactive Cu(DTC) formation and SK release triggered by a small amount of ROS within the tumor microenvironment, which endows the transformation of "less toxic-to-high toxic" and thus significantly improve its selectivity towards tumors. Therefore, this study provides a new strategy of prodrug activation for tumor therapy with high efficiency and low toxicity. STATEMENT OF SIGNIFICANCE: Owing to the striking difference in ROS level between cancer cells and normal cells, ROS-responsive prodrugs are regarded as a promising approach for tumor-specific therapy. However, the stability and responsiveness of prodrugs are hard to balance. Preferable sensitivity may cause premature activation while favorable stability may lead to incomplete prodrug activation and insufficient active drug release. This study provides a tailored ROS-responsive prodrug activation nanoamplifier with favorable stability and effective prodrug activation capacity. The nanoamplifier can undergo a self-amplifying positive feedback loop to achieve numerous bioactive drugs generation in situ under ROS triggers within the tumor microenvironment, showing the enhanced antitumor therapeutic effect. Thus, this study provides a new strategy for prodrug activation and tumor-specific therapy.
Topics: Cell Line, Tumor; Copper; Ditiocarb; Humans; Nanoparticles; Neoplasms; Prodrugs; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 36084924
DOI: 10.1016/j.actbio.2022.08.072 -
European Journal of Pharmacology Nov 2020Bufadienolides are cardioactive C24 steroids with an α-pyrone ring at position C17. In the last ten years, accumulating studies have revealed the anticancer activities... (Review)
Review
Bufadienolides are cardioactive C24 steroids with an α-pyrone ring at position C17. In the last ten years, accumulating studies have revealed the anticancer activities of bufadienolides and their underlying mechanisms, such as induction of autophagy and apoptosis, cell cycle disruption, inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and stemness, and multidrug resistance reversal. As Na/K-ATPase inhibitors, bufadienolides have inevitable cardiotoxicity. Short half-lives, poor stability, low plasma concentration and oral bioavailability in vivo are obstacles for their applications as drugs. To improve the drug potency of bufadienolides and reduce their side effects, prodrug strategies and drug delivery systems such as liposomes and nanoparticles have been applied. Therefore, systematic and recapitulated information about the antitumor activity of bufadienolides, with special emphasis on the molecular or cellular mechanisms, prodrug strategies and drug delivery systems, is of high interest. Here, we systematically review the anticancer effects of bufadienolides and the molecular or cellular mechanisms of action. Research advancements regarding bufadienolide prodrugs and their tumor-targeting delivery strategies are critically summarized. This work highlights recent scientific advances regarding bufadienolides as effective anticancer agents from 2011 to 2019, which will help researchers to understand the molecular pathways involving bufadienolides, resulting in a selective and safe new lead compound or therapeutic strategy with improved therapeutic applications of bufadienolides for cancer therapy.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Bufanolides; Cell Line, Tumor; Humans; Neoplasms; Prodrugs
PubMed: 32758567
DOI: 10.1016/j.ejphar.2020.173379 -
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