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Molecular Pharmaceutics Sep 2023The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer...
The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer therapy. Here, we show that the combination of two targeted therapies, including bevacizumab (), and a β-glucuronidase-responsive albumin-binding prodrug of monomethyl auristatin E (), is efficient for the treatment of colorectal cancer implanted in mice. This combined therapy produces a therapeutic activity superior to that of the association of and currently used to treat patients with this pathology. The increased anticancer efficacy is due to either a synergistic or an additive effect between and selectively released from the glucuronide prodrug in the tumor microenvironment. Since numerous drug delivery systems such as antibody-drug conjugates employ as a cytotoxic payload, this finding may be of great interest for improving their therapeutic index by combining them with , particularly for the therapy of colorectal cancer.
Topics: Animals; Mice; Prodrugs; Antineoplastic Agents; Immunoconjugates; Molecular Targeted Therapy; Colorectal Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37579031
DOI: 10.1021/acs.molpharmaceut.3c00224 -
Small (Weinheim An Der Bergstrasse,... Oct 2023Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give...
Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide-mediated self-assembly nano-prodrug that can achieve the co-delivery of ferroptosis drug, differentiation-inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano-prodrug, the disulfide bond not only induces self-assembly behavior of different small molecular drug but also serves as a glutathione (GSH)-responsive trigger in controlled drug release. More importantly, the differentiation-inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis-induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano-prodrug significantly improves anti-tumor efficacy and effectively inhibits the tumor metastasis. This all-in-one strategy enables controlled drug release and reduces stemness-related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment.
Topics: Humans; Animals; Mice; Antineoplastic Agents; Prodrugs; Triple Negative Breast Neoplasms; Cell Line, Tumor; Neoplastic Stem Cells; Disulfides
PubMed: 37328445
DOI: 10.1002/smll.202301600 -
Journal of Labelled Compounds &... May 2024Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has...
Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ-331 (MMV-167), an alkoxy carbonate prodrug of 4(1H)-quinolone ELQ-300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ-331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)-quinolone ELQ-300, its alkoxycarbonate prodrug ELQ-331, and their respective N-oxides using deuterated acetic acid.
Topics: Quinolones; Deuterium; Chemistry Techniques, Synthetic; Prodrugs; Antimalarials
PubMed: 38661253
DOI: 10.1002/jlcr.4092 -
Journal of Enzyme Inhibition and... Dec 2023Boronic acids/esters have recently emerged in the field of medicinal and pharmaceutical research due to their exceptional oxophilicity, low toxicity, and unique... (Review)
Review
Boronic acids/esters have recently emerged in the field of medicinal and pharmaceutical research due to their exceptional oxophilicity, low toxicity, and unique structure. They are known as potent enzyme inhibitors, cancer therapy capture agents, and can mimic certain types of antibodies to fight infections. They have been designed and developed into drugs, and this approach has emerged in the last 20 years. Five boronic acid drugs have been approved by the FDA and Health Canada, two of which are used to treat cancer, specifically multiple myeloma. The purpose of this review is to investigate boronic acid/ester derivatives as potential pharmaceutical agents as well as the mechanism of action. It will concentrate on six types of cancer: multiple myeloma, prostate cancer, breast cancer, lung cancer, cervical cancer, and colon cancer. Some newly developed boron-containing compounds have already demonstrated highly promising activities, but further investigation is required before final conclusions can be drawn.
Topics: Humans; Prodrugs; Esters; Multiple Myeloma; Boronic Acids; Boron Compounds
PubMed: 37318308
DOI: 10.1080/14756366.2023.2220084 -
Advanced Materials (Deerfield Beach,... Feb 2024Advanced chemotherapeutic strategies including prodrug and nanocatalytic medicine have significantly advanced tumor-selective theranostics, but delicate prodrug...
Advanced chemotherapeutic strategies including prodrug and nanocatalytic medicine have significantly advanced tumor-selective theranostics, but delicate prodrug screening, tedious synthesis, low degradability/biocompatibility of inorganic components, and unsatisfied reaction activity complicate treatment efficacies. Here, the intrinsic anticancer bioactivity of liquid metal nanodroplets (LMNDs) is explored through galvanic replacement. By utilizing a mechano-degradable ligand, the resultant size of the aqueous LMND is unexpectedly controlled as small as ≈20 nm (LMND20). It is demonstrated that LMND20 presents excellent tumor penetration and biocompatibility and activates tumor-selective carrier-to-drug conversion, synchronously depleting Cu ions and producing Ga ions through galvanic replacement. Together with abundant generation of reactive oxygen species, multiple anticancer pathways lead to selective apoptosis and anti-angiogenesis of breast cancer cells. Compared to the preclinical/clinical anticancer drugs of tetrathiomolybdate and Ga(NO ) , LMND20 administration significantly improves the therapeutic efficacy and survival in a BCap-37 xenograft mouse model, yet without obvious side effects.
Topics: Humans; Animals; Mice; Nanomedicine; Neoplasms; Antineoplastic Agents; Prodrugs; Metals; Ions; Cell Line, Tumor
PubMed: 37948543
DOI: 10.1002/adma.202307817 -
Biomaterials Dec 2023In the design of delivery strategies for anticancer therapeutics, the controlled release of intact cargo at the destined tumor and metastasis locations is of particular... (Review)
Review
In the design of delivery strategies for anticancer therapeutics, the controlled release of intact cargo at the destined tumor and metastasis locations is of particular importance. To this end, stimuli-responsive chemical linkers have been extensively investigated owing to their ability to respond to tumor-specific physiological stimuli, such as lowered pH, altered redox conditions, increased radical oxygen species and pathological enzymatic activities. To prevent premature action and off-target effects, anticancer therapeutics are chemically modified to be transiently inactivated, a strategy known as prodrug development. Prodrugs are reactivated upon stimuli-dependent release at the sites of interest. As most drugs and therapeutic proteins have the optimal activity when released from carriers in their native and original forms, traceless release mechanisms are increasingly investigated. In this review, we summarize the chemical toolkit for developing innovative traceless prodrug strategies for stimuli-responsive drug delivery and discuss the applications of these chemical modifications in anticancer treatment including cancer immunotherapy.
Topics: Humans; Prodrugs; Drug Delivery Systems; Neoplasms; Drug Carriers; Nanoparticles
PubMed: 37925794
DOI: 10.1016/j.biomaterials.2023.122353 -
Journal of Medicinal Chemistry Sep 2023Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation to cysteine, it is achieved by ring hydrolysis of the...
Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation to cysteine, it is achieved by ring hydrolysis of the succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that the succinimide ring open form is in equilibrium with the ring closed succinimide. Bromoacetamide (BrAc) was identified as the optimal replacement, as it affords stable attachment of the drug-linker to the antibody while completely removing the undesired ring open-closed equilibrium. Additionally, BrAc also offers multiple benefits over maleimide, especially with respect to homogeneity of the ADC structure. In combination with a short, hydrophilic linker and phosphate prodrug on the payload, this afforded a stable ADC (ABBV-154) with the desired properties to enable long-term stability to facilitate subcutaneous self-administration.
Topics: Receptors, Glucocorticoid; Tumor Necrosis Factor Inhibitors; Antibodies; Prodrugs; Glucocorticoids; Maleimides; Immunoconjugates
PubMed: 37656698
DOI: 10.1021/acs.jmedchem.3c01174 -
European Journal of Medicinal Chemistry Oct 2023The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications... (Review)
Review
The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications which allow enhanced presentation of tumor antigen and neighboring dendritic cell activation. Furthermore, DOX also facilitate the immune-mediated clearance of tumor cells. However, disadvantages such as severe off-target toxicity, and prominent hydrophobicity have resulted in unsatisfactory clinical therapeutic outcomes. The effective delivery of DOX drug molecules is still challenging despite the rapid advances in nanotechnology and biomaterials. Huge progress has been witnessed in DOX nanoprodrugs owing to their brilliant benefits such as tumor stimuli-responsive drug release capacity, high drug loading efficiency and so on. This review summarized recent progresses of DOX prodrug-based nanomedicines to provide deep insights into future development and inspire researchers to explore DOX nanoprodrugs with real clinical applications.
Topics: Humans; Prodrugs; Drug Delivery Systems; Nanomedicine; Doxorubicin; Neoplasms; Nanoparticles; Cell Line, Tumor
PubMed: 37441851
DOI: 10.1016/j.ejmech.2023.115612 -
Chemistry & Biodiversity Nov 2023This article emphasizes the importance of prodrugs and their diverse spectrum of effects in the field of developing novel drugs for a variety of biological applications.... (Review)
Review
This article emphasizes the importance of prodrugs and their diverse spectrum of effects in the field of developing novel drugs for a variety of biological applications. Prodrugs are chemicals that are supplied inactively, but then go through enzymatic and chemical transformation in vivo to release the active parent medication that can have the desired pharmacological effect. By adding an inactive chemical moiety, prodrugs are improved in a number of ways that contribute to their potency and durability. For the purpose of illustrating the usefulness of the prodrug approach, this review covers examples of prodrugs that have been made available or are now undergoing human trials. Additionally, it included lists of the most common functional groups, carrier linkers, and reactive chemicals that can be used to create prodrugs. The current study also provides a brief introduction, several chemical methods and modifications for creating prodrugs and mutual prodrugs, as well as an explanation of recent advancements and difficulties in the field of prodrug design. The primary chemical carriers employed in the creation of prodrugs, such as esters, amides, imides, NH-acidic carriers, amines, alcohols, carbonyl, carboxylic, and azo-linkages, are also discussed. This review also discusses glycosidic and triglyceride mutually activated prodrugs, which aim to deliver the drugs after bioconversion at the intended site of action. The article also discusses the extensive chemistry and wide variety of applications of recently approved prodrugs, such as antibacterial, anti-inflammatory, cardiovascular, antiplatelet, antihypertensive, atherosclerotic, antiviral, etc. In order to illustrate the prodrug and mutual drug concept's various applications and highlight its many triumphs in overcoming the formulation and delivery of problematic pharmaceuticals, this work represents a thorough guide that includes the synthetic moiety for the reader.
Topics: Humans; Prodrugs; Chemistry, Pharmaceutical; Drug Design; Amides; Amines
PubMed: 37833241
DOI: 10.1002/cbdv.202301169 -
Biomacromolecules Jan 2024The prodrug strategy for its potential to enhance the pharmacokinetic and/or pharmacodynamic properties of drugs, especially chemotherapeutic agents, has been widely...
The prodrug strategy for its potential to enhance the pharmacokinetic and/or pharmacodynamic properties of drugs, especially chemotherapeutic agents, has been widely recognized as an important means to improve therapeutic efficiency. Irinotecan's active metabolite, 7-ethyl-10-hydroxycamptothecin (SN38), a borate derivative, was incorporated into a G-quadruplex hydrogel () by the ingenious and simple approach. Drug release does not depend on carboxylesterase, thus bypassing the side effects caused by ineffective activation, but specifically responds to the ROS-overexpressed tumor microenvironment by oxidative hydrolysis of borate ester that reduces serious systemic toxicity from nonspecific biodistribution of SN38. Comprehensive spectroscopy was used to define the structural and physicochemical characteristics of the drug-loaded hydrogel. The hydrogel's high level of biosafety and notable tumor-suppressive properties were proven in and tests.
Topics: Prodrugs; Tissue Distribution; Borates; Cell Line, Tumor; Hydrogels; Camptothecin
PubMed: 38065622
DOI: 10.1021/acs.biomac.3c00990