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The anticancer efficacy of doxorubicin, an anthracycline‐based and FDA‐approved chemotherapeutic drug, is significantly hindered by acquired chemoresistance and severe side effects despite its potent anticancer properties. To overcome these challenges, we developed an innovative therapeutic formulation that integrates targeted chemotherapy and phototherapy within a single platform using gold nanoparticles (AuNPs). This novel nanoconjugate, designated as Dox‐Fe@FA‐AuNPs, is co‐functionalized with folic acid, doxorubicin, and an iron(III)‐phenolate/carboxylate complex, enabling cancer‐specific drug activation. Here, we report the synthesis, characterization, and comprehensive physico‐chemical and biological evaluations of Dox‐Fe@FA‐AuNPs. The nanoconjugate exhibited excellent solubility, stability, and enhanced cellular uptake in folate receptor‐positive cancer cells. The nanoconjugate was potently cytotoxic against HeLa and MDA‐MB‐231 cancer cells (HeLa: 105.5±16.52 μg mL−1; MDA‐MB‐231: 112.0±12.31 μg mL−1; MDA‐MB‐231 (3D): 156.31±19.35 μg mL−1) while less cytotoxic to the folate(−) cancer cells (MCF‐7, A549 and HepG2). The cytotoxicity was attributed to the pH‐dependent release of doxorubicin, which preferentially occurs in the acidic tumor microenvironment. Additionally, under red light irradiation, the nanoconjugate generated ROS, inducing caspase‐3/7‐dependent apoptosis with a photo‐index (PI) >50, and inhibited cancer cell migration. Our findings underscore the potential of Dox‐Fe@FA‐AuNPs as a highly effective and sustainable platform for targeted chemo‐phototherapy. [ABSTRACT FROM AUTHOR]

Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here, we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5′-triphosphate AT-9010, with an obligate order of reactions. AT-9010 selectively inhibits essential viral enzymes, accounting for antiviral potency. Functional and structural data at atomic resolution decipher N6-purine deamination compatible with its metabolic activation. Crystal structures of human histidine triad nucleotide binding protein 1, adenosine deaminase-like protein 1, guanylate kinase 1, and nucleoside diphosphate kinase at 2.09, 2.44, 1.76, and 1.9 Å resolution, respectively, with cognate precursors of AT-9010 illuminate the activation pathway from the orally available bemnifosbuvir to AT-9010, pointing to key drug–protein contacts along the activation pathway. Our work provides a framework to integrate the design of antiviral nucleotide analogues, confronting requirements and constraints associated with activation enzymes along the 5′-triphosphate assembly line. Bemnifosbuvir (AT-527) and AT-752 are broad-spectrum antiviral guanosine analogues currently in clinical trials. This study reconstitutes their intracellular 5-step enzymatic activation pathway, characterizing each enzymatic complex at atomic resolution, which provides insight into substrate binding and drug activation. [ABSTRACT FROM AUTHOR]

Approved anticancer drugs typically face challenges due to their narrow therapeutic window, primarily because of high systemic toxicity and limited selectivity for tumors. Prodrugs are initially inactive drug molecules designed to undergo specific chemical modifications. These modifications render the drugs inactive until they encounter specific conditions or biomarkers in vivo, at which point they are converted into active drug molecules. This thoughtful design significantly improves the efficacy of anticancer drug delivery by enhancing tumor specificity and minimizing off-target effects. Recent advancements in prodrug design have focused on integrating these strategies with delivery systems like liposomes, micelles, and polymerosomes to further improve targeting and reduce side effects. This review outlines strategies for designing stimuli-responsive small molecule prodrugs focused on cancer treatment, emphasizing their chemical structures and the mechanisms controlling drug release. By providing a comprehensive overview, we aim to highlight the potential of these innovative approaches to revolutionize cancer therapy. [ABSTRACT FROM AUTHOR]

This article provides an overview of the field of bioorthogonal chemistry and its advancements at Radboud University. Bioorthogonal chemistry involves conducting chemical reactions within a biological environment with high selectivity and compatibility. Radboud University has made significant contributions to this field, including the development of strained alkynes and the synthesis of bioorthogonal tools such as BCN and TCO. These tools have been applied in various areas such as chemical biology and materials science. The article also highlights the interdisciplinary nature of research at Radboud University and the importance of synthetic availability in bioorthogonal reagents. The text specifically discusses the use of VBAs in bioorthogonal chemistry, particularly in the IEDDA reaction with tetrazines. The authors found that introducing boronic acid substituents on linear alkenes improved their reactivity in the IEDDA reaction. They also observed that the reactivity of VBAs varied depending on the coordinating substituent on the tetrazine. The authors explored the potential of VBAs in click-to-release chemistry, protein modification, and drug delivery applications. The article emphasizes the collaborative efforts and interdisciplinary approach necessary for advancing bioorthogonal chemistry. [Extracted from the article]

Controlled drug delivery systems that can respond to mechanical force offer a unique solution for on-demand activation and release under physiological conditions. Compression, tension, and shear forces encompass the most commonly utilized mechanical stimuli for controlled drug activation and release. While compression and tension forces have been extensively explored for designing mechanoresponsive drug release systems through object deformation, ultrasound (US) holds advantages in achieving spatiotemporally controlled drug release from micro−/nanocarriers such as microbubbles, liposomes, and micelles. Unlike light-based methods, the US bypasses drawbacks such as phototoxicity and limited tissue penetration. Conventional US-triggered drug release primarily relies on heat-induced phase transitions or chemical transformations in the nano−/micro-scale range. In contrast, the cutting-edge approach of "Sonopharmacology" leverages polymer mechanochemistry, where US-induced shear force activates latent sites containing active pharmaceutical ingredients incorporated into polymer chains more readily than other bonds within the polymeric structure. This article provides a brief overview of controlled drug release systems based on compression and tension, followed by recent significant studies on drug activation using the synergistic effects of US and polymer mechanochemistry. The remaining challenges and potential future directions in this subfield are also discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Enzyme esterase is an enzyme important for detoxification and activation of drugs found in various body tissues. Here, we introduce and establish A high-performance liquid chromatographic procedure was established to determine esterase activity, relying on the organic probe EBOAc. Experiments show high sensitivity and wide linear range from 0 to 28 U/ml. [ABSTRACT FROM AUTHOR]

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 in vivo 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. [ABSTRACT FROM AUTHOR]

[Display omitted] Excessive production of epidural fibrosis in the nerve root can be a pain source after laminectomy. Pharmacotherapy is a minimally invasive treatment option to attenuate epidural fibrosis by suppressing proliferation and activation of fibroblasts, inflammation, and angiogenesis, and inducing apoptosis. We reviewed and tabulated pharmaceuticals with their respective signaling axes implicated in reducing epidural fibrosis. Additionally, we summarized current literature for the feasibility of novel biologics and microRNA to lessen epidural fibrosis. Systematic Review. According to the PRISMA guidelines, we systematically reviewed the literature in October 2022. The exclusion criteria included duplicates, nonrelevant articles, and insufficient detail of drug mechanism. We obtained a total of 2,499 articles from PubMed and Embase databases. After screening the articles, 74 articles were finally selected for the systematic review and classified based on the functions of drugs and microRNAs which included inhibition of fibroblast proliferation and activation, pro-apoptosis, anti-inflammation, and antiangiogenesis. In addition, we summarized various pathways to prevent epidural fibrosis. This study allows a comprehensive review of pharmacotherapies to prevent epidural fibrosis during laminectomy. We expect that our review would enable researchers and clinicians to better understand the mechanism of anti-fibrosis drugs for the clinical application of epidural fibrosis therapies. [ABSTRACT FROM AUTHOR]

Atherosclerosis can form intimal plaques in the arteries and undergo plaque rupture with followed stroke or myocardial infarction under certain pathological conditions. However, suboptimal intraplaque accumulation, along with severe off‐target effects, remain formidable obstacles for efficient pharmacotherapy of atherosclerosis. A characteristic feature of the progression of atherosclerosis is the continuous recruitment of inflammatory monocytes that differentiate into foamy macrophages with the generation of legumain in the plaques. In this study, a bio‐activatable nano‐shuttle based on human serum albumin is conceived that contained curcumin to allow the precise inhibition of atherosclerosis progression. Following intravenous injection, the nano‐shuttles are almost exclusively engulfed by inflammatory monocytes in an efferocytosis‐mimetic manner and selectively co‐migrated with the monocytes towards the plaques. The nano‐shuttles are readily activated to release the initially arrested curcumin in response to the generation of legumain upon the differentiation of monocytes into foamy macrophages within the plaques. Treatment assessments on atheroprone apolipoprotein‐E‐deficient mice indicated that the nano‐shuttles substantially inhibit the progression of atherosclerosis by attenuating the plaque inflammation burden without any obvious adverse effects. The integration of highly selective accumulation and specific drug activation of the nano‐shuttles in plaques can arouse an advanced therapeutic strategy to prevent atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Conventional pharmacology lacks spatial and temporal selectivity in terms of drug action. This leads to unwanted side effects, such as damage to healthy cells, as well as other less obvious effects, such as environmental toxicity and the acquisition of resistance to drugs, especially antibiotics, by pathogenic microorganisms. Photopharmacology, based on the selective activation of drugs by light, can contribute to alleviating this serious problem. However, many of these photodrugs are activated by light in the UV–visible spectral range, which does not propagate through biological tissues. In this article, to overcome this problem, we propose a dual-spectral conversion technique, which simultaneously makes use of up-conversion (using rare earth elements) and down-shifting (using organic materials) techniques in order to modify the spectrum of light. Near-infrared light (980 nm), which penetrates tissue fairly well, can provide a "remote control" for drug activation. Once near-IR light is inside the body, it is up-converted to the UV–visible spectral range. Subsequently, this radiation is down-shifted in order to accurately adjust to the excitation wavelengths of light which can selectively activate hypothetical and specific photodrugs. In summary, this article presents, for the first time, a "dual tunable light source" which can penetrate into the human body and deliver light of specific wavelengths; thus, it can overcome one of the main limitations of photopharmacology. It opens up promising possibilities for the moving of photodrugs from the laboratory to the clinic. [ABSTRACT FROM AUTHOR]

The aim of the work was to examine the possibility of using modified halloysite nanotubes as a gentamicin carrier and to determine the usefulness of the modification in terms of the effect on the amount of the drug attached, its release time, but also on the biocidal properties of the carriers. In order to fully examine the halloysite in terms of the possibility of gentamicin incorporating, a number of modifications of the native halloysite were carried out prior to gentamicin intercalation with the use of sodium alkali, sulfuric and phosphoric acids, curcumin and the process of delamination of nanotubes (expanded halloysite) with ammonium persulfate in sulfuric acid. Gentamicin was added to unmodified and modified halloysite in an amount corresponding to the cation exchange capacity of pure halloysite from the Polish Dunino deposit, which was the reference sample for all modified carriers. The obtained materials were tested to determine the effect of surface modification and their interaction with the introduced antibiotic on the biological activity of the carrier, kinetics of drug release, as well as on the antibacterial activity against Escherichia coli Gram-negative bacteria (reference strain). For all materials, structural changes were examined using infrared spectroscopy (FTIR) and X-ray diffraction (XRD); thermal differential scanning calorimetry with thermogravimetric analysis (DSC/TG) was performed as well. The samples were also observed for morphological changes after modification and drug activation by transmission electron microscopy (TEM). The conducted tests clearly show that all samples of halloysite intercalated with gentamicin showed high antibacterial activity, with the highest antibacterial activity for the sample modified with sodium hydroxide and intercalated with the drug. It was found that the type of halloysite surface modification has a significant effect on the amount of gentamicin intercalated and then released into the surrounding environment but does not significantly affect its ability to further influence drug release over time. The highest amount of drug released among all intercalated samples was recorded for halloysite modified with ammonium persulfate (real loading efficiency above 11%), for which high antibacterial activity was found after surface modification, before drug intercalation. It is also worth noting that intrinsic antibacterial activity was found for non-drug-intercalated materials after surface functionalization with phosphoric acid (V) and ammonium persulfate in the presence of sulfuric acid (V). [ABSTRACT FROM AUTHOR]

A biocatalyst is an enzyme that speeds up or slows down the rate at which a chemical reaction occurs and speeds up certain processes by 108 times. It is used as an anticancer agent because it targets drug activation inside the tumor microenvironment while limiting damage to healthy cells. Biocatalysts have been used for the synthesis of different heterocyclic compounds and is also used in the nano drug delivery systems. The use of nano-biocatalysts for tumor-targeted delivery not only aids in tumor invasion, angiogenesis, and mutagenesis, but also provides information on the expression and activity of many markers related to the microenvironment. Iosmapinol, moclobemide, cinepazide, lysine dioxygenase, epothilone, 1-homophenylalanine, and many more are only some of the anticancer medicines that have been synthesised using biocatalysts. In this review, we have highlighted the application of biocatalysts in cancer therapies as well as the use of biocatalysts in the synthesis of drugs and drug-delivery systems in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Chronic inflammatory diseases such as rheumatoid arthritis represent a substantial socio-economic impact and have a high prevalence in the modern world. Nano-sized polymer therapeutics have shown suitable characteristics for becoming the next generation of anti-inflammatory nanomedicines. Here, we present biocompatible and stimuli-sensitive N -(2-hydroxypropyl)methacrylamide based polymer conjugates with the anti-inflammatory drug dexamethasone (DEX), which has been tailored for prolonged blood circulation, enhanced inflammatory site accumulation, site-specific drug release and subsequent elimination of the carrier via urine excretion. The hydrodynamic size of novel polymer-DEX nanomedicine was adjusted to prolong its blood circulation whilst maintaining the renal excretability of the polymer carrier after drug release in inflamed tissue. The therapeutic efficacy of the studied polymer nanomedicines was evaluated in a model of dissipated chronic arthritis, i.e. collagen II-induced arthritis, in mice. The pH-sensitive drug attachment enabled enhanced blood circulation with minimal systemic drug release, as well as rapid drug activation in affected joints. Importantly, unlike free DEX, the polymer nanomedicines were able to diminish joint inflammation and arthritis-induced bone damage - even at a reduced dosing regimen - as evaluated by micro computed tomography (micro-CT). [Display omitted] [ABSTRACT FROM AUTHOR]

Covalent binding of reactive metabolites formed by drug metabolic activation with biological macromolecules is considered to be an important mechanism of drug metabolic toxicity. Recent studies indicate that the endoplasmic reticulum (ER) could play an important role in drug toxicity by participating in the metabolic activation of drugs and could be a primarily attacked target by reactive metabolites. In this article, we summarize the generation and mechanism of reactive metabolites in ER stress and their associated cell death and inflammatory cascade, as well as the systematic modulation of unfolded protein response (UPR)-mediated adaptive pathways. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a major global health problem. Response to first-line therapy is variable. This is partially due to interindividual variability across those genes codifying transport, metabolising, and drug activation proteins involved in first-line pharmacological treatment. Single nucleotide polymorphisms (SNPs) of genes SLC22A1, SLC22A2 and SLC22A3 affect metformin therapeutic response in patients with T2DM patients. The present study investigated allelic and genotypic frequencies of organic cation (OCT)1, OCT2, and OCT3 polymorphisms among metformin-treated patients with type 2 diabetes mellitus (T2DM). It also reports the association between clinical and genetic variables with glycated haemoglobin (HbA1c) control in 59 patients with T2DM. Patients were genotyped through real-time PCR (TaqMan assays). Metformin plasmatic levels were determined by mass spectrometry. Neither the analysis of HbA1c control by SNPs in SLC22A1, SLC22A2 and SLC22A3, nor the dominant genotypic model analysis yielded statistical significance between genotypes in polymorphisms rs72552763 (P=0.467), rs622342 (P=0.221), rs316019 (P=0.220) and rs2076828 (P=0.215). HbA1c levels were different in rs72552763 [GAT/GAT, 6.0 (5.7-6.6), GAT/del=6.5 (6.2-9.0), del/del=6.5 (6.4-6.8); P=0.022] and rs622342 [A/A=6.0 (5.8-6.5), A/C=6.4 (6.1-7.7), C/C=6.8 (6.4-9.3); P=0.009] genotypes. The dominant genotypic model found the lowest HbA1c levels in GAT/GAT (P=0.005) and A/A (P=0.010), in rs72552763 (GAT/GAT vs. GAT/del + del/del) and rs622342 (A/A vs. A/C + CC), respectively. There was a significant correlation between HbA1c levels and metformin dosage amongst del allele carriers in rs72552763 (β1=0.14, P<0.001, r2=0.387), as opposed to GAT/GAT in rs72552763. There were no differences between HbA1c values in the test set and those predicted by machine learning models employing a simple linear regression based on metformin dosage. Therefore, rs72552763 and rs622342 polymorphisms in SLC22A1 may affect metformin response determined by HbA1c levels in patients with T2DM. The del allele of SNP rs72552763 may serve as a metformin response biomarker. [ABSTRACT FROM AUTHOR]

Conventional chemotherapy for colorectal cancer (CRC) gives only a small increase in patient survival, since it is often diagnosed at late stages, when the tumor has disseminated to other organs. Moreover, it is common to observe that malignant cells may acquire resistance to conventional chemotherapies through different mechanisms, including reducing drug activation or accumulation (by enhancing efflux), inducing alterations in molecular targets, and inhibiting the DNA damage response, among other strategies. Considering these facts, the discovery of new molecules with therapeutic potential has become an invaluable tool in chemoprevention. In this context, we previously evaluated two hybrids (SAC-CAFA-MET and SAC-CAFA-PENT) that exhibited selective cytotoxicity against SW480 cells, with better results than the conventional chemotherapeutic agent (5-fluorouracil; 5-FU). Here, we investigated the possible mechanisms of these molecules in greater depth, to identify whether they could be valuable therapeutic scaffolds in the search for new molecules with chemopreventive potential for the treatment of CRC. Both compounds reduced ROS formation, which could be related to antioxidant effects. Further evaluations showed that SAC-CAFA-MET induces cell death independent of caspases and the tumor-suppressor protein p53, but probably mediated by the negative regulation of the pro-apoptotic Bcl-2. In addition, the lack of activation of caspase-8 and the positive regulation of caspase-3 induced by SAC-CAFA-PENT suggest that this compound acts through an apoptotic mechanism, probably initiated by intrinsic pathways. Furthermore, the downregulation of IL-6 by SAC-CAFA-PENT suggests that it also induces a significant anti-inflammatory process. In addition, docking studies would suggest caspase-3 modulation as the primary mechanism by which SAC-CAFA-PENT elicits apoptosis in SW480human colorectal adenocarcinoma cells. Meanwhile, density functional theory (DFT) calculations suggest that both hybrids would produce effects in the modulation of ROS in SW480 cells via the hydrogen atom transfer (HAT) pathway. The present work notes that SAC-CAFA-MET and SAC-CAFA-PENT could be potential candidates for further investigations in the search for potential chemopreventive agents. [ABSTRACT FROM AUTHOR]

The therapeutic effects of platinum anticancer drugs are commonly whittled away by drug resistance, which is associated with drug efflux and the nucleotide excision repair (NER) pathway. Activation of drugs in a spatiotemporally controllable manner in the mitochondria of cancer cells is a very promising strategy to alleviate these problems. In this work, PtIV-PS2, a cisplatin-based PtIV prodrug, was designed to release cisplatin inside the mitochondria on red light exposure. This PtIV complex could be effectively reduced to PtII species under irradiation. PtIV-PS2 very effectively accumulates in the mitochondria of cancer cells through active transport. After photoactivation, PtIV-PS2 showed higher cytotoxicity than cisplatin in the cisplatin-resistant carcinoma cells and the amount of Pt in genomic DNA was elevated. Moreover, PtIV-PS2 decreased the cellular mitochondrial membrane potential (MMP) and the cellular content of ATP. This work developed a promising window for the design of controllably activated and mitochondrion-targeting PtIV prodrugs to overcome drug resistance of chemotherapy. [ABSTRACT FROM AUTHOR]

Photolabile Protecting Groups (PPGs) are molecular tools used, for example, in photopharmacology for the activation of drugs with light, enabling spatiotemporal control over their potency. Yet, red‐shifting of PPG activation wavelengths into the NIR range, which penetrates the deepest in tissue, has often yielded inefficient or insoluble molecules, hindering the use of PPGs in the clinic. To solve this problem, we report herein a novel concept in PPG design, by transforming clinically‐applied NIR‐dyes with suitable molecular orbital configurations into new NIR‐PPGs using computational approaches. Using this method, we demonstrate how Cy7, a class of NIR dyes possessing ideal properties (NIR‐absorption, high molecular absorptivity, excellent aqueous solubility) can be successfully converted into Cy7‐PPG. We report a facile synthesis towards Cy7‐PPG from accessible precursors and confirm its excellent properties as the most redshifted oxygen‐independent NIR‐PPG to date (λmax=746 nm). [ABSTRACT FROM AUTHOR]

Currently, clinical intravesical instillation chemotherapy has been greatly compromised by the toxicological and physiological factors. New formulations that can specifically and efficiently kill bladder cancer cells are in urgent need to overcome the low residence efficiency and dose limiting toxicity of current ones. The combination of mucoadhesive nanocarriers and cancer cell selective prodrugs can to great extent address these limitations. However, the insignificant endogenous stimulus difference between cancer cells and normal cells in most cases and the high local drug concentration make it essential to develop new drugs with broader selectivity-window. Herein, based on the statistically different NQO1 expression between cancerous and normal bladder tissues, the reactive oxygen species (ROS) activatable epirubicin prodrug and highly potent NQO1 substrate, KP372–1, was co-delivered using a GSH-responsive mucoadhesive nanocarrier. After endocytosis, epirubicin could be promptly activated by the NQO1-dependent ROS production caused by KP372–1, thus specifically inhibiting the proliferation of bladder cancer cells. Since KP372–1 is much more potent than some commonly used NQO1 substrates, for example, β-lapachone, the cascade drug activation could occur under much lower drug concentration, thus greatly lowering the toxicity in normal cells and broadening the selectivity-window during intravesical bladder cancer chemotherapy. [Display omitted] • Mucoadhesive nanoparticles enhanced the adhesion and penetration of drugs in bladder; • KP372–1 activated epirubicin prodrug in cancer cells through NQO1-dependent way; • Dual-drug loaded nanoparticles selectively killed cancer cells and exempted normal cells; • Prodrug nanoparticles caused significant tumor inhibition and negligible side effect. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy emerges as a promising therapeutic modality, while its clinical application remains constrained by low tumor immunogenicity and immunosuppressive microenvironments. Herein, we report a unique superdimeric nanoassembly pattern by elaborately integrating cyclodextrin inclusion with dimeric prodrug, enabling spatio-temporally self-adaptive drug delivery and multimodal photo-immunotherapy. Specifically, it is precisely engineered through host-guest inclusion between a GSH-sensitive cyclodextrin-photosensitizer conjugate and an oxidation-responsive homodimer prodrug of NLG919. Notably, on-demand photosensitizer activation and aggregation-caused quenching relief significantly facilitates photodynamic induction of ICD. Meanwhile, photodynamic ROS together with the endogenous ROS collaboratively facilitate on-demand NLG919 activation and release, efficiently reversing the immunosuppressive microenvironments. As such, the superdimeric nanoassembly allows spatio-temporally cascade-potentiated photo-immunotherapy, starting from photosensitizer activation to ICD induction, NLG919 release and IDO inhibition. Finally, it exerts intense antitumor efficacy, abscopal effect and synergy with PD-L1 antibody in two mouse models. This study presents new insights into the design of nanomedicines for multimodal photo-immunotherapy. [Display omitted] • A novel dimer-mediated supramolecular nanoassembly is constructed, and its unique assembly mechanism is analyzed. • The superdimeric nanoassembly demonstrates excellent stability and spatio-temporally adaptable drug activation. • The superdimeric nanoassembly provides a new nanotherapeutic paradigm enabling self-synergistic photo-immunotherapy. [ABSTRACT FROM AUTHOR]

Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry‐based strategies provide new avenues to overcome the related problems by improving drug selectivity. It is recently shown that sonomechanical bond scission enables the remote‐controlled drug release from their inactive parent macromolecules using ultrasound (US). To further expand the scope of the US‐controlled drug activation strategy, herein a mechano‐responsive nanoswitch for the selective activation of doxorubicin (DOX) to inhibit cancer cell proliferation is constructed. As a proof‐of‐concept, the synthesis, characterization, and US‐responsive drug activation evaluation of the mechano‐nanoswitch, which provides a blueprint for tailoring nanosystems for force‐induced pharmacotherapy is presented. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) are therapeutic techniques based on a photosensitizer (PS) and light. These techniques allow the spatial and temporal control of the activation of drugs with light. Transition metal complexes are attractive compounds as photoactivatable prodrugs since their excited states can be appropriately designed by subtle modifications of the ligands, the metal centre, or the oxidation state. However, most metal-based PSs contain heavy metals such as Ru, Os, Ir, Pt or Au, which are expensive and non-earth-abundant, contrary to first-row transition metals. In this context, the exploration of the photochemical properties of complexes based on first-row transition metals appears to be extremely promising. This did encourage several groups to develop promising PSs based on these metals. This review presents up-to-date state-of-the-art information on first-row-transition metal complexes, from titanium to zinc in regard to their application as PSs for phototherapeutic applications. [ABSTRACT FROM AUTHOR]

Abstract Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry‐based strategies provide new avenues to overcome the related problems by improving drug selectivity. It is recently shown that sonomechanical bond scission enables the remote‐controlled drug release from their inactive parent macromolecules using ultrasound (US). To further expand the scope of the US‐controlled drug activation strategy, herein a mechano‐responsive nanoswitch for the selective activation of doxorubicin (DOX) to inhibit cancer cell proliferation is constructed. As a proof‐of‐concept, the synthesis, characterization, and US‐responsive drug activation evaluation of the mechano‐nanoswitch, which provides a blueprint for tailoring nanosystems for force‐induced pharmacotherapy is presented.

Abstract Traditional chemotherapy suffers from severe toxicity and side effects that limit its maximum application in cancer therapy. To overcome this challenge, an ideal treatment strategy would be to selectively control the release or regulate the activity of drugs to minimize the undesirable toxicity. Recently, ultrasound (US)‐responsive drug delivery systems (DDSs) have attracted significant attention due to the non‐invasiveness, high tissue penetration depth, and spatiotemporal controllability of US. Moreover, the US‐induced mechanical force has been proven to be a robust method to site‐selectively rearrange or cleave bonds in mechanochemistry. This review describes the US‐activated DDSs from the fundamental basics and aims to present a comprehensive summary of the current understanding of US‐responsive DDSs for controlled drug release and drug activation. First, we summarize the typical mechanisms for US‐responsive drug release and drug activation. Second, the main factors affecting the ultrasonic responsiveness of drug carriers are outlined. Furthermore, representative examples of US‐controlled drug release and drug activation are discussed, emphasizing their novelty and design principles. Finally, the challenges and an outlook on this promising therapeutic strategy are discussed.

Approved anticancer drugs typically face challenges due to their narrow therapeutic window, primarily because of high systemic toxicity and limited selectivity for tumors. Prodrugs are initially inactive drug molecules designed to undergo specific chemical modifications. These modifications render the drugs inactive until they encounter specific conditions or biomarkers in vivo , at which point they are converted into active drug molecules. This thoughtful design significantly improves the efficacy of anticancer drug delivery by enhancing tumor specificity and minimizing off-target effects. Recent advancements in prodrug design have focused on integrating these strategies with delivery systems like liposomes, micelles, and polymerosomes to further improve targeting and reduce side effects. This review outlines strategies for designing stimuli-responsive small molecule prodrugs focused on cancer treatment, emphasizing their chemical structures and the mechanisms controlling drug release. By providing a comprehensive overview, we aim to highlight the potential of these innovative approaches to revolutionize cancer therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tu, Gong, Mou, Jiang, Zhao and Gao.)

Background: Through an arsenal of microbial enzymes, the gut microbiota considerably contributes to human metabolic processes, affecting nutrients, drugs, and environmental poisons. Azoreductases are a predominant group of microbiota-derived enzymes involved in xenobiotic metabolism and drug activation, but little is known about how compositional changes in the gut microbiota correlate with its azo-reducing activity. Results: To this end, we used high-throughput 16S rRNA amplicon sequencing, with Illumina MiSeq, to determine the microbial community composition of stool samples from 16 adults with different azo-reducing activity. High azo-reducing activity positively correlated with the relative abundance of phylum Firmicutes (especially genera Streptococcus and Coprococcus) but negatively with phylum Bacteroidetes (especially genus Bacteroides). Typical variations in the Firmicutes-to-Bacteroidetes and Prevotella-to-Bacteroides ratios were observed among samples. Multivariate analysis of the relative abundance of key microbial taxa and other diversity parameters confirmed the Firmicutes proportion as a major variable differentiating high and non-azo-reducers, while Bacteroidetes relative abundance was correlated with azo-reduction, sex, and BMI. Conclusions: This pilot study showed that stool samples with higher azo-reducing activity were enriched in Firmicutes but with relatively fewer Bacteroidetes. More samples and studies from different geographical areas are needed to bolster this conclusion. Better characterization of different azoreductase-producing gut microbes will increase our knowledge about the fate and differential human responses to azodye-containing drugs or orally consumed chemicals, thus contributing to efforts towards implementing microbiome testing in precision medicine and toxicology. [ABSTRACT FROM AUTHOR]

Currently, stimulus-responsive nanomedicines are usually activated by a single cancer-associated biomarker and utilize different image/therapeutic agents for cancer imaging/therapy, which restricts the specificity of nanomedicine and complicates their design. Herein, we report a novel dual-locking theranostic nanoprobe (DL-P) based on near-infrared (NIR) hemicyanine CyNH 2 with two orthogonal stimuli of cancer cell lysosomal pH (first "lock")- and lysosome-overexpressed cathepsin B (CTB, second "lock")-triggered NIR fluorescence turn-on and drug activation to improve the specificity of cancer imaging and therapy. The fluorescence of CyNH 2 was initially quenched due to intramolecular charge transfer (ICT) but could be selectively activated under the dual-key stimulation of lysosomal pH and CTB to liberate CyNH 2 , resulting in strong NIR fluorescence turn-on for cancer imaging. Moreover, CyNH 2 caused mitochondrial dysfunction to inhibit cancer cell proliferation in the absence of laser irradiation, which can be used in cancer therapy. Compared with previously reported probes that respond to a single stimulus, this dual-locking nanoprobe that is responsive to two orthogonal stimuli triggers with integrated imaging and therapy function in a single agent exhibits increased selectivity and specificity, which provides a prospective strategy for precise cancer imaging and therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Photochemical internalization (PCI) is a modified form of photodynamic therapy (PDT) that enhances the efficacy of therapeutic agents in a site and temporal specific manner in both in vitro and in vivo publications. The purpose of the study reported here was to evaluate the benefits of a modified PCI protocol in a 3D rat glioma spheroid model. In the modified protocol, F98 glioma cells were incubated with photosensitizer (AlPcS2a) prior to spheroid generation, as opposed to post-spheroid formation photosensitizer exposure commonly used in conventional protocols. The efficacy of both bleomycin and doxorubicin PCI was evaluated using either the conventional or modified protocols. The formed spheroids were then exposed to light treatment from a diode laser, λ= 670 nm. Spheroid growth was monitored for a period of 14 days. The results of spheroid growth assays showed that there was no statistically significant difference in PCI efficacy between the conventional and modified protocols for both of the drugs tested. The direct PDT effect was significantly reduced using the modified protocol. Therefore, due to its several advantages, the modified protocol is recommended for evaluating the efficacy of PCI in tumor spheroid models. [ABSTRACT FROM AUTHOR]

Chemotherapy has been widely used for treating the vast majority of cancer patients. Unfortunately, only a fraction of patients can respond to chemotherapies, but these patients still experience severe side effects. In this context, a wide range of nanotherapeutic platforms have been developed with the aim of improving treatment outcomes while reducing drug toxicities. Nanohydrogels are highly appealing "smart" biocompatible and biodegradable vehicles for either local or systemic delivery of bioactive compounds. Here, we developed prodrug hydrogelators that can undergo one-step distillation-precipitation polymerization to form systemically injectable nanohydrogels. The optimized nanohydrogels were capable of rapidly releasing active agents (e.g., the cytotoxic agent cabazitaxel or the PI3K molecular inhibitor PI103) in response to the reducing tumor microenvironment, while drug release was very slow in the absence of the reductive reagent glutathione. Cabazitaxel-loaded nanogels showed preferential tumor accumulation, and administration of nanogels produced durable tumor regression in a docetaxel-resistant cervical tumor xenograft-bearing mouse model. More significantly, nanogel-based therapy was proven to demonstrate a higher safety profile than solution-based free cabazitaxel. Collectively, this study provides an alternative formulation that meets the essential requirements of high stability in the blood, spontaneous drug release at diseased sites, favorable safety in vivo , and translational capacity for further investigations. Chemotherapy remains a considerable challenge and only a fraction of patients can respond to chemotherapies. Here we report an intratumoral reducing agent-activatable, tumor-targeting prodrug nanogel platform for therapeutic delivery. To this end, two anticancer agents (e.g., cytotoxic cabazitaxel or PI3K molecular inhibitor PI103) are tested. Prodrug nanogels are stable in the blood but performed reduction-triggered release of chemically unmodified drug molecules in cancerous tissues. Cabazitaxel-loaded nanogels exhibit satisfactory anticancer performance in a preclinical docetaxel-resistant tumor model. This is a practical and expedient approach that combines the prodrug strategy and nanogel scaffold to re-engineer a hydrophobic and toxic anticancer drug. The approach also is broadly applicable for the formulation of other agents to improve the therapeutic index. [Display omitted] [ABSTRACT FROM AUTHOR]

The dynamical properties of solvation water of hyperactive antifreeze protein from Choristoneura fumiferana (Cf AFP) are analyzed and discussed in context of its antifreeze activity. The protein comprises of three well-defined planes and one of them binds to the surface of ice. The dynamical properties of solvation water around each of these planes were analyzed separately; the results are compared with the dynamical properties of solvation water of ice around its two crystallographic planes: basal and prism. Three main conclusions are inferred from our investigations. The first one is that the solvation shell of CfAFP does not seem to be particularly far-ranged, at least not beyond what is usually observed for proteins that do not interact with ice. Therefore, it does not appear to us that the antifreeze activity is enhanced by a long-ranged retardation of water mobility. Also the correlation between the collective mobility of water and the collective mobility of protein atoms highly resembles the one measured for the protein that does not interact with ice. Our second conclusion is that the dynamical properties of solvation water of CfAFP are non-uniform. The dynamics of solvation water of ice-binding plane is, in some respects, different from the dynamics of solvation water of the two remaining planes. The feature that distinguishes the dynamics of solvation water of the three planes is the activation energy of diffusion process. The third conclusion is that--from the three analyzed solvation shells of Cf AFP--the dynamical properties of solvation water of the ice-binding plane resemble the most the properties of solvation water of ice; note, however, that these properties still clearly differ from the dynamic properties of solvation water of ice. [ABSTRACT FROM AUTHOR]

Traditional combinational photodynamic therapy (PDT) and photothermal therapy (PTT) were limited in clinical therapy of cancer due to exceptionally low drug payload and activation by light with separate wavelengths. We have accidentally discovered that zinc phthalocyanine (ZNPC, a typical hydrophobic photosensitizer) and indocyanine green (ICG, a clinically approved fluorescence probe) could be co-assembled into carrier-free nanodrugs (almost 100 wt%) for single NIR laser-induced efficient PDT/PTT. Interestingly, ICG could act as "transformers" for modulating the geometric shape of ZNPC/ICG co-assembling structures from needle-like/spindle-like structure via cubic structure finally to spherical structure. Unfortunately, the nanodrugs suffered from rapid immune clearance. The ZNPC-ICG nanoprobes were further embedded into the erythrocyte membrane (RBC)-camouflaged framework. The designed ZNPC-ICG@RBC could be efficiently accumulated within the tumor sites (continue for ~60 h) and rapidly internalized into cancer cells upon laser irradiation rather than macrophage RAW264.7 cells. Compared with the free ZnPC or ICG, the biomimetic ZNPC-ICG@RBC nanoprobes exhibited amplified therapeutic effects by simultaneously producing ROS and hyperthermia, thereby synergistically improving antitumor efficiency and eliminating the tumors without any regrowth under the guidance of fluorescence imaging. The co-delivery of ZnPC and ICG via a biomimetic carrier-free system might be a promising strategy for bimodal phototherapy of cancer. [Display omitted] • We developed a carrier-free nanoprobe for single NIR laser-induced efficient PDT/PTT. • ICG could act as "transformers" to modulate the geometric shape of ZnPc-ICG nanoprobe. • The small-molecule co-assembly strategy endows the nanoprobe with excellent antitumor efficacy under single NIR laser irradiation. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the ten most commonly diagnosed cancers. Doxorubicin is an antibiotic used in cancer treatment protocols that has several side effects. L-Arginine is a non-essential amino acid that is used as immune system activation and antitumor drugs. Therefore, the current study was designed to compare using doxorubicin, L-arginine, or their combination as a prophylactic agent against hepatic carcinoma induced by hepatocellular carcinoma cells (HepG2) injection in mice. The mice were divided into five groups: normal mice and mice that received HepG2, doxorubicin and HepG2, L-arginine and HepG2, and doxorubicin, L-Arginine, and HepG2, respectively. Liver function test as, aspartate transaminase (AST) and alanine transaminase (ALT), and alpha-fetoprotein (AFP), caspase 3, interleukin 6 (IL-6), tumor necrotic factor (TNF), lipid peroxidation (NDA), and some antioxidant parameters were determined. A significant increase in AST and ALT, α-fetoprotein, TNF-α, and cytokines IL6 and MDA and a significant decrease in the serum caspase and liver catalase were determined in HepG2-injected mice. Moreover, some large hyperchromatic heptocytes were observed and the percentage of the positive area/field of HepPar-1, the most specific HCC marker, was 9.56%. Interestingly, mice that received doxorubicin, L-arginine, or their combination showed an improvement in some of the previous parameters. The improvement was more prominent with L-arginine administration. [ABSTRACT FROM AUTHOR]

Diabetes is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) in which dyslipidaemia plays a crucial role. Statins are first line therapy for primary and secondary prevention of ASCVD; however, adverse events include reversible musculoskeletal and liver side effects in addition to a diabetogenic association. In this short review, we provide a succinct narrative of the future role and current trial data of a novel first-in-class molecule, bempedoic acid. The authors provide their expert insight with a focus on Phase III randomised controlled trials (RCT) of bempedoic acid. Bempedoic acid was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in February and March 2020, respectively, and is a novel molecule which inhibits cholesterol biosynthesis in the same mechanistic pathway as statins. It is a first-in-class small molecule, delivered as a prodrug and administered as an oral, once-daily dose that decreases low-density lipoprotein cholesterol (LDL-C) levels. Phase II and III RCTs have demonstrated efficacy with adequate safety data as mono- or combination therapy with statins and ezetimibe. Bempedoic acid is hepatically converted to the active drug with a lack of activation in skeletal muscle. Due to this novel mechanism, musculoskeletal-related adverse events exhibit a lower prevalence providing an alternative pharmacotherapy in statin-intolerant patients. Bempedoic acid may be used as an adjunct to diet and maximally tolerated statin therapy or in statin-intolerant patients for the treatment of dyslipidaemia. The recent National Institute of Health and Care Excellence (NICE) (UK) technology appraisal guidance [TA694] published in April 2021 recommended bempedoic acid with ezetimibe as a treatment option for primary hypercholesterolaemia or mixed dyslipidaemia if statins are not tolerated or contraindicated and if there is inadequate control of LDL-C with ezetimibe alone. Additionally, outcomes trials evaluating 'hard' endpoints in statin-intolerant patients or those with ASCVD are currently underway. [ABSTRACT FROM AUTHOR]

6‐mercaptopurine (6‐MP) is widely used in the treatment of acute lymphoblastic leukemia (ALL), and its cytotoxicity is primarily mediated by thioguanine nucleotide (TGN) metabolites. A recent genomewide association study has identified germline polymorphisms (e.g., rs72846714) in the NT5C2 gene associated with 6‐MP metabolism in patients with ALL. However, the full spectrum of genetic variation in NT5C2 is unclear and its impact on 6‐MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of NT5C2 in 588 children with ALL and identified 121 single nucleotide polymorphisms nominally associated with erythrocyte TGN during 6‐MP treatment (P < 0.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6‐MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6‐MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated NT5C2 transcription in‐cis. Our results indicated that NT5C2 germline variation significantly contributes to interpatient variability in thiopurine drug disposition. [ABSTRACT FROM AUTHOR]

Considering recent breakthroughs in the field of optogenetics, a powerful tool is established in the present study to modulate the activities of target neurons through the application of light‐based methods. Near‐infrared (NIR) light enables the penetration of deep‐tissue. As a result, it can be used to modulate the functions of proteins/cells. Herein, it is aimed to develop a NIR light‐sensitive drug delivery system to spatially and temporally control the activation of the loaded drug at the stimulation sites through its release from a nanoparticle sensitive to NIR. Owing to their excellent photothermal effect under NIR irradiation, the nanoparticles are found to penetrate the blood‐brain barrier effectively, ultimately reaching neurons. Furthermore, by loading fasudil, a selective activator of the Kv7.4 potassium channel, into the precisely designed and synthesized NIR light‐sensitive nanoparticles, the firing frequency of dopaminergic neurons in the ventral tegmental area is found to be remarkably reduced upon NIR light irradiation. Such findings shed light on a new concept that can be used for developing more selective drug therapies for the treatment of diseases, such as major depression. [ABSTRACT FROM AUTHOR]

Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy. [ABSTRACT FROM AUTHOR]

Backgrounds. Cancer cell resistance to chemotherapy drugs such as Gemcitabine, Oxaliplatin, Cisplatin, Doxorubicin, and 5-fluorouracil account for the main reason of chemotherapy failure for HCC patients, especially for those with advanced HCC or metastasis patients. This emerging resistance limits the effectiveness and clinical application of these chemotherapy drugs. Previous studies reported that drug-resistant tumor cell-derived exosomes could transfer their resistance property to tumor sensitive cells in some cancer, including lung and gastric cancer. This study sought to explore whether HepG2/DDP cell-derived exosomes transmit cisplatin (DDP) resistance to HepG2 and other HCC sensitive cells, and provide considerable guidance for HCC nursing with Cisplatin DDP clinically. Methods. The HepG2 DDP-resistant cell line (HepG2/DDP) was established, and the exosomes from both HepG2/DDP and HepG2 cells were isolated and named ES-2, ES-1, respectively. HepG2 or SMMC-7721 or Huh7 cells were treated with DDP or DDP + ES-2, and HepG2/DDP cells were treated with ES-1. Then, the activation of drug resistance via HepG2/DDP exosomes transfer to HepG2, SMMC-7721 and Huh7 cells were assessed by cell viability assay and ROS formation. Moreover, the relative expression of P-glycoprotein (P-gp) was measured by western blot analysis. Results. HepG2/DDP cell-derived exosomes were successfully isolated from cisplatin-resistant HepG2 cells, and named ES-2. Cell viability of HepG2 or SMMC-7721 or Huh7 cells treated with DDP + ES-2 was enhanced compared with that of DDP treatment group. Also, the concentration of ROS generated in cells under DDP or DDP + ES-2 treatment was strongly increased compared with that of control, although the concentration of ROS was clearly smaller in DDP + ES-2 treatment group compared with DDP treatment. At the same time, the expression of P-gp was upregulated on the ES-2 surface. Conclusion. The results mentioned above clarified that HepG2/DDP cell-derived exosomes conferred cisplatin resistance to HepG2 and other HCC cell lines, and provided a new significance for improving the effectiveness of DDP in treating HCC. [ABSTRACT FROM AUTHOR]

Immature neurons dominantly express the Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) rather than the K+-Cl- cotransporter isoform 2 (KCC2). The intracellular chloride ion concentration ([Cl-]i) is higher in immature neurons than in mature neurons; therefore, γ-aminobutyric acid type A (GABAA) receptor activation in immature neurons does not cause chloride ion influx and subsequent hyperpolarization. In our previous work, we found that midazolam, benzodiazepine receptor agonist, causes less sedation in neonatal rats compared to adult rats and that NKCC1 blockade by bumetanide enhances the midazolam-induced sedation in neonatal, but not in adult, rats. These results suggest that GABA receptor activation requires the predominance of KCC2 over NKCC1 to exert sedative effects. In this study, we focused on CLP290, a novel KCC2-selective activator, and found that midazolam administration at 20 mg/kg after oral CLP290 intake significantly prolonged the righting reflex latency even in neonatal rats at postnatal day 7. By contrast, CLP290 alone did not exert sedative effects. Immunohistochemistry showed that midazolam combined with CLP290 decreased the number of phosphorylated cAMP response element-binding protein-positive cells in the cerebral cortex, suggesting that CLP290 reverted the inhibitory effect of midazolam. Moreover, the sedative effect of combined CLP290 and midazolam treatment was inhibited by the administration of the KCC2-selective inhibitor VU0463271, suggesting indirectly that the sedation-promoting effect of CLP290 was mediated by KCC2 activation. To our knowledge, this study is the first report showing the sedation-promoting effect of CLP290 in neonates and providing behavioral and histological evidence that CLP290 reverted the sedative effect of GABAergic drugs through the activation of KCC2. Our data suggest that the clinical application of CLP290 may provide a breakthrough in terms of midazolam-resistant sedation. [ABSTRACT FROM AUTHOR]

Anti-PEG antibodies have been witnessed in patients and experimental animals, accelerating the blood clearance (termed ABC phenomenon) of PEGylated nanomedicines by activating complement after absorption on the nano-surface. The ABC phenomenon presents an obstacle to the clinical translation of PEGylated nanomedicines. Herein, an anti-PEG single-chain variable fragment (PEG-scFv) that possesses a low molecule weight (30 kDa) and high PEG binding affinity was exploited to ameliorate the ABC phenomenon of PEGylated liposomes (sLip). Pre-deposition of PEG-scFv on the surface of sLip was incompetent to activate complement due to the lack of Fc chains, exhibiting negligible influence on in vivo performance of sLip in naïve rats (without anti-PEG antibodies). However, PEG-scFv effectively competed the binding of anti-PEG IgM in rats that were pre-stimulated with low dose of sLip, thus ameliorated the ABC phenomenon of sLip. PEG- scFv was also effective to inhibit the binding of anti-PEG antibodies with sLip in human plasma and the consequent complement activation, presenting a promising tool to improve the performance of PEGylated nanomedicines and to mitigate individual difference occurred by the varying levels of anti-PEG antibodies in the clinic. The application of anti-PEG scFv paves a new avenue for the development of nanocarriers to achieve precise medication. Unlabelled Image • Pre-deposition of anti-PEG scFv mitigates the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes. • Anti-PEG scFv competes the binding of PEGylated liposomes with anti-PEG antibodies in human plasma. • Anti-PEG scFv ameliorates complement activation and drug release from PEGylated liposomes. [ABSTRACT FROM AUTHOR]