Search Results (177)

Ovarian cancer is the most lethal gynaecological cancer, largely because it is often diagnosed late and shows strong tumour heterogeneity, therapy resistance, and rapid metastatic spread. A key driver of this aggressive behaviour is the tumour’s ability to reshape its surrounding microenvironment to support invasion, angiogenesis, and escape from treatment. Cathepsin L (CTSL), a lysosomal cysteine protease, has emerged as an important mediator of these processes and is gaining attention as both a prognostic marker and a potential therapeutic target. This review examines the diverse roles of CTSL in ovarian cancer progression, focusing on how its expression, localisation, and extracellular release are altered within the hypoxic and acidic conditions typical of the tumour microenvironment. It also outlines emerging therapeutic strategies aimed at targeting CTSL, including selective inhibitors, multi-cathepsin approaches, CTSL-activated prodrugs and antibody-drug conjugate linkers, and nanomedicine systems designed for tumour-specific delivery. Overall, the evidence highlights CTSL as a central regulator of invasion, angiogenesis, and relapse in ovarian cancer, underscoring its potential as a target for new therapies in aggressive disease. Full article

Protein turnover and extracellular proteolysis continuously generate diverse peptide fragments within biological systems, yet the metabolic and pharmacological implications of these peptides remain incompletely understood. Among these transporters, members of the solute carrier family 15 (SLC15), including peptide transporter 1 (PEPT1/SLC15A1) and peptide transporter 2 (PEPT2/SLC15A2), mediate the proton-coupled uptake of dipeptides, tripeptides, and structurally related compounds across cellular membranes. While these transporters have been extensively studied in the context of intestinal peptide absorption and drug delivery, their potential roles in cancer biology remain incompletely understood. Tumor microenvironments are characterized by extensive proteolysis and dynamic metabolic remodeling, processes that can generate diverse peptide fragments derived from extracellular matrix proteins and intracellular protein turnover. These peptides may accumulate locally and potentially serve as substrates for cellular peptide transport systems. Once internalized through peptide transporters, dipeptides are typically hydrolyzed into free amino acids that can support biosynthetic pathways, energy metabolism, and cellular growth. In addition to their potential metabolic roles, certain endogenous dipeptides have also been reported to influence cellular signaling pathways and redox homeostasis. The broad substrate specificity of peptide transporters has also attracted significant interest in pharmacology because numerous clinically used drugs exploit these transport systems for efficient cellular uptake. This property raises the possibility that peptide transporters may be utilized for transporter-mediated drug delivery strategies, including the development of peptide-modified prodrugs or dipeptide–drug conjugates. In this review, we summarize the molecular characteristics and physiological functions of dipeptide transport systems with a particular focus on the SLC15 transporter family. We then discuss emerging evidence linking peptide transporters to tumor metabolism and the tumor microenvironment. Finally, we highlight current progress and future perspectives in exploiting peptide transport systems for transporter-mediated drug delivery and therapeutic targeting in cancer. Full article

Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood–brain barrier (BBB) transport and metabolic fate remain unclear. We investigated the pharmacokinetics of PG in postnatal day 12 rats of both sexes subjected to endothelin-1 (ET-1)-induced focal hippocampal ischemia. Animals received PG (1 mg/kg intraperitoneal (i.p.)) or vehicle; serum and hippocampal steroidomes were profiled 60 min post-administration using gas chromatography-tandem mass spectrometry (GC-MS/MS) (hippocampus: n = 16 PG+, n = 27 PG−; multi-tissue subset: n = 6 PG+, n = 21 PG−). Our data revealed a “dual-fate” mechanism: PG undergoes systemic hydrolysis as a prodrug, as suggested by the tissue distribution pattern at 60 min post-administration, but also crosses the BBB intact, with significant parent conjugate accumulation in the hippocampus (42.3 pmol/g). The brain functioned as a “metabolic sink”, passively accumulating metabolites generated in peripheral organs—such as 17-hydroxypregnanolone—despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced “metabolic segregation” within the central nervous system (CNS): the pharmacological 5β-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5α-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3β-isomers suggests autonomous regulatory buffering via oxidative 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile—combining metabolic segregation with active central buffering—defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites—several with previously established GABAergic and neuroprotective activity—without disrupting endogenous neurosteroidogenesis, positioning it as a promising neurotherapeutic candidate minimizing physiological steroid homeostasis disruption. Importantly, the present study characterizes the pharmacokinetic and metabolic fate of PG; the neuroprotective efficacy of PG was demonstrated in our prior functional studies using the same model. Full article

Background: To battle the side effects of anticancer Pt(II) drug cisplatin, the development of photoactivatable and/or intracellular reduction-activatable Pt(IV) prodrugs has become a promising strategy. Methods: Herein, two novel Pt(IV) prodrugs, namely, cis,cis,trans-[Pt^IV(NH₃)₂(Cl)₂(OH)(probenecid)]) (SPP) and cis,cis,trans-[Pt^IV(NH₃)₂(Cl)₂(probenecid)₂] (DPP) bearing mono- and di-probenecid at the axial positions of oxoplatin have been synthesized via covalently linking of carboxylate group in probenecid, which is a well-established clinic drug by inhibiting organic anion transporter 1 (OAT1) to reduce cisplatin-induced nephrotoxicity, with the axial hydroxyl group(s) in oxoplatin. The promising cytotoxicity of SPP and DPP against MCF-7, T47D breast cancer cells and the MDA-MB-231 triple-negative breast cancer cells was evaluated, and the mechanism of action of the two Pt(IV) prodrugs was investigated by apoptosis assay and Western blot assay. Results: SPP exhibits a comparable cytotoxicity to cisplatin against MCF-7 and T47D breast cancer cells, while it shows 2.1-fold higher cytotoxicity than cisplatin against MDA-MB-231 cells. DPP was shown to be more cytotoxic than SPP, and exhibits 8.7-, 7.5-, and 2.3-fold higher cytotoxicity than cisplatin against MCF-7, T47D, and MDA-MB-231 cells, respectively. Apoptosis assays revealed a similar early-apoptotic cell death mechanism to cisplatin for both SPP and DPP. The enhanced cellular and nuclear uptake of DPP compared to cisplatin contributes to its promising anticancer efficacy. DPP can bind to OAT1 in cancer cells, which may synergistically enhance the cytotoxicity of the Pt(IV) anticancer prodrugs. Conclusions: The direct conjugation of probenecid to the axial positions of oxoplatin confers the resulting Pt(IV) prodrugs a multitargeting property, significantly promoting the cytotoxicity of the resulting Pt(IV) complexes. This finding provides a practical strategy for drug design and cancer treatment based on platinum complexes. Full article

Platinum(II)-based drugs, such as cisplatin, are commonly used to treat various types of cancer. However, their clinical use is limited due to a number of side effects and the development of resistance. To overcome these limitations, researchers have explored the development of platinum(IV) complexes as potential prodrugs that can be selectively activated under physiological conditions. In this study, we have incorporated synthetic analogs of vitamin E into the structure of platinum(IV) complexes to further improve their safety profile. The antioxidant properties of the compounds were evaluated using DPPH and CUPRAC assays, as well as lipid peroxidation inhibition models, revealing that incorporation of phenolic ligands confers pronounced antioxidant activity. Cytotoxicity was assessed towards cancer cell lines using the MTT assay, where the novel complexes showed significantly increased cytotoxic activity compared to cisplatin, while also demonstrating less toxicity toward normal fibroblast cells under the same in vitro conditions. These results suggest that the conjugation of antioxidant ligands to platinum(IV) scaffolds can modulate both redox processes and the biological activity of the resulting complexes. This proposed design strategy has the potential to create more effective platinum-based cancer treatments with enhanced biological characteristics. Full article

Peptide-based biomaterials have emerged as versatile tools for pharmaceutical drug delivery due to their biocompatibility and tunable sequences, yet a comprehensive overview of their categories, mechanisms, and optimization strategies remains lacking to guide clinical translation. This review systematically collates advances in peptide-based biomaterials, covering peptide excipients (cell penetrating peptides, tight junction modulating peptides, and peptide surfactants/stabilizers), self-assembling peptides (peptide-based nanospheres, cyclic peptide nanotubes, nanovesicles and micelles, peptide-based hydrogels and depots), and peptide linkers (for antibody drug-conjugates, peptide drug-conjugates, and prodrugs). We also dissect sequence-based optimization strategies, including rational design and biophysical optimization (cyclization, stapling, D-amino acid incorporation), functional motif integration, and combinatorial discovery with AI assistance, with examples spanning marketed drugs and research-stage candidates. The review reveals that cell-penetrating peptides enable efficient intracellular payload delivery via direct penetration or endocytosis; self-assembling peptides form diverse nanostructures for controlled release; and peptide linkers achieve site-specific drug release by responding to tumor-associated enzymes or pH cues, while sequence optimization enhances stability and targeting. Peptide-based biomaterials offer precise, biocompatible and tunable solutions for drug delivery, future advancements relying on AI-driven design and multi-functional modification will accelerate their transition from basic research to clinical application. Full article

The lysosome is no longer viewed as a simple degradative “trash can” of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical “microreactor” that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5–5), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective “safe house,” yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome’s broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody–drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine–thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies. Full article

Sexually transmitted infections, notably herpes simplex virus, remain significant global health concerns. Localized delivery systems that provide sustained antiviral activity at mucosal surfaces offer an attractive alternative to systemic therapies. In this study, we developed electrohydrodynamically deposited coatings utilizing a covalent acyclovir–poly (lactic-co-glycolic acid) (ACV–PLGA) conjugate for potential antiviral functionalization of medical devices. The ACV–PLGA prodrug was synthesized via drug-initiated ring-opening polymerization, yielding a copolymer characterized by FTIR, NMR, GPC, and DSC, with controlled drug loading and biodegradable properties. Systematic optimization of electrospinning and electrospraying parameters enabled the fabrication of both particulate and nanofibrous coatings on silicone ring models. Morphological analysis by SEM demonstrated that polymer concentration, solvent composition, and applied voltage critically governed coating architecture, ranging from microparticle layers to uniform bead-free fibers. In vitro studies revealed morphology-dependent degradation profiles and sustained release of ACV over 56 days. This integrated approach combining covalent prodrug synthesis with tunable electrohydrodynamic deposition offers a promising strategy for long-acting local antiviral prophylaxis via functionalized medical surfaces. Full article

Developing natural lipid-based conjugates/prodrugs has emerged as a promising topic in pharmaceutical chemistry and biomedicine. In this work, a natural antioxidant lipid, α-tocopherol (vitamin E), was covalently connected with doxorubicin (Dox) to synthesize a Toco–Dox conjugate through two approaches: triphosgene activation (method A) and 4-nitrophenyl chloroformate activation (method B). The latter method is non-volatile and generates safe-to-handle byproduct 4-nitrophenol, making it much less hazardous and more eco-friendly. The molecular structure of Toco–Dox was characterized by ¹H, ¹³C NMR, FT-IR, and MALDI-TOF-MS. Toco–Dox could self-assemble into nanoparticles in the DMSO/water mixture and Toco–Dox nanoparticles were further characterized by DLS. Moreover, the molecular properties of Toco–Dox were theoretically calculated or virtually analyzed (Dox as a control). In addition, unlike (free) Dox, Toco–Dox showed moderate MCF-7 breast cancer cell inhibition (cytotoxicity) and a cytoplasm localization behavior. This work provided an efficient approach to develop a natural (fat-soluble) vitamin-based prodrug system for breast cancer chemotherapy. Full article

Background/Objectives: Probenecid (PBN) is a uricosuric agent that facilitates the excretion of uric acid and is used to treat gout. Here, a colon-targeted prodrug of PBN was designed to facilitate repositioning as a treatment for inflammatory bowel disease (IBD). Methods: The carboxylic group in PBN was amide-conjugated with the amine groups of acidic amino acids to yield aspartic acid-conjugated PBN (PBN-AA) and glutamic acid-conjugated PBN (PBN-GA). Conjugation with amino acids increased the hydrophilicity of PBN and decreased cell permeability across the Caco-2 cell monolayer. While remaining intact in buffers (pH 1.2, 6.8) and in the small intestinal contents of rats, the conjugates were cleaved to release PBN from the cecal contents of rats, with a significant difference in the maximal conversion percentage between PBN-AA (12%) and PBN-GA (74%). Results: Upon oral gavage, PBN-GA accumulated a much greater amount of PBN in the cecum than PBN alone, thus verifying the in vitro colon specificity of PBN-GA. Oral PBN-GA enhanced the anticolitis effectiveness in dinitrobenzene sulfonic acid-induced rat colitis and limited the systemic absorption of PBN, thus reducing the risk of systemic adverse effects ascribed to PBN. Moreover, PBN-GA therapeutically surpassed sulfasalazine, a currently used anti-IBD drug, in rat colitis. Conclusions: These results suggest that amide conjugation with GA can be used to design a colon-targeting prodrug for PBN. Colon-targeted PBN may not only enhance therapeutic effectiveness but also improve the safety of PBN repositioned for the treatment of IBD and may be a pharmacological alternative for current small-molecule anti-IBD drugs with low efficacy or serious adverse effects with long-term use. Full article

Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the rapidly evolving field of senotyping based on cellular heterogeneity in lung development and aging in health and disease. It also delves into the molecular mechanisms driving senescence and SASP production, highlighting pathways such as p53/p21, p16^INK4a/RB, mTOR, and p38 MAPK as therapeutic targets. The involvement of various novel SASP proteins, such as GDP15, cytokines/chemokines, growth factors, and DNA damage response proteins. We further highlight the effectiveness of senotherapeutics in mitigating the detrimental effects of senescent cell (SnC) accumulation within the lungs. It also outlines two main therapeutic approaches: senolytics, which selectively trigger apoptosis in SnCs, and senomorphics (also known as senostatics), which mitigate the detrimental effects of the SASP without necessarily removing the senescent cells. Various classes of senolytic and senomorphic drugs are currently in clinical trials including natural products (e.g., quercetin, fisetin, resveratrol) and repurposed drugs (e.g., dasatinib, navitoclax, metformin, rapamycin) that has demonstrated therapeutic promise in improving tissue function, alleviating LARDs, and extending health span. We discuss the future of these strategies in lung research and further elaborate upon the usability of novel approaches including HSP90 inhibitors, senolytic CAR-T cells, Antibody drug conjugate and galactose-modified prodrugs in influencing the field of personalized medicine in future. Overall, this comprehensive review highlights the progress made so far and the challenges faced in the field of cellular senescence including SnC heterogeneity, states of senescence, senotyping, immunosenescence, drug delivery, target specificity, long-term safety, and the need for robust cell-based biomarkers. Future perspectives, such as advanced delivery systems, and combination therapies, are considered critical for translating the potential of senotherapeutics into effective clinical applications for age-related pulmonary diseases/conditions. Full article

Objectives: Immunotherapy utilizing immune-stimulating cytokines such as IL12 holds great promise for the treatment of cancer. However, clinical use of IL12 is hampered due to severe toxicity following systemic administration. We here present a novel treatment strategy in which IL12 is chemically silenced by conjugation to PEG masks that sterically hinder the receptor binding. Subsequently, the masks can be released on demand using a bioorthogonal click reaction, cleaving the linker connecting the masks, thereby restoring the native cytokine. This “click-to-release” approach is based on the highly selective Inverse electron-demand Diels–Alder (IEDDA) pyridazine elimination reaction between a tetrazine (Tz) and a trans-cyclooctene (TCO), optimized for fast reaction kinetics and in vivo compatibility. Selective activation in the tumor microenvironment is achieved by pretargeting one component of this reaction to the tumor, triggering local activation of the masked IL12 once it is given in a secondary i.v. injection. Methods: IL12 masking and unmasking were evaluated in vitro with PAGE and HEK-Blue reporter cells and ex vivo with ELISA. Biodistribution in mice was evaluated with I-125 radiolabeling and biotin-click histochemistry. Results: Several designs were evaluated and optimized in vitro, resulting in an IL12-TCO-PEG construct that exhibited superior masking and subsequent reactivation upon reaction with a tetrazine bound to a TAG-72-targeted diabody. In tumor-bearing mice, we demonstrated that this diabody-tetrazine could efficiently pre-localize tetrazine in the tumor. Administration of IL12-TCO-PEG 24 h later afforded efficient and selective unmasking in tumors, but not in the blood. Conclusions: These results demonstrate proof of principle of the click-cleavable IL12 prodrug approach and showcase the versatility of the click-to-release reaction. Full article

Background: Redox-responsive prodrug nanoassemblies (NAs) have been extensively utilized in precise cancer therapy. But there is no research shedding light on the impacts of the π–π stacking interactions on the self-assembly capacity of redox-responsive prodrugs and the in vivo delivery fate of NAs. Methods: Three structurally engineered doxorubicin (DOX) prodrugs (FAD, FBD, and FGD) were developed through α-, β-, and γ-positioned disulfide linkages with π-conjugated Fmoc moieties. The NAs were comprehensively characterized for their self-assembly kinetics, redox-responsive drug release profiles, and physicochemical stability. Biological evaluations included cellular uptake efficiency, in vivo pharmacokinetics, and antitumor efficacy in tumor-bearing mouse models. Results: Systematic characterization revealed that π-conjugated disulfide bond positioning dictates prodrug self-assembly and inversely regulates reductive drug release relative to carbon spacer length. The FBD NAs demonstrated optimal redox-responsive release kinetics while maintaining minimal systemic toxicity, achieving 101.7-fold greater tumor accumulation (AUC) than DiR Sol controls. In 4T1 tumor-bearing models, FBD NAs displayed potent antitumor efficacy, yielding a final mean tumor volume of 518.06 ± 54.76 mm³ that was statistically significantly smaller than all comparator groups (p < 0.001 by ANOVA at a 99% confidence interval). Conclusion: These findings demonstrate that strategic incorporation of redox-sensitive disulfide bonds with different π–π stacking interactions in the prodrug structure effectively optimizes the delivery-release balance of DOX in vivo, ensuring both potent antitumor efficacy and reduced systemic toxicity. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine–niclosamide improves upon niclosamide’s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine–niclosamide in advanced HCC and in other cancers or diseases is warranted. Full article

Cancer has remained one of the leading causes of death worldwide throughout history despite significant advancements in drug development, radiation therapy, and surgery. Traditional chemotherapeutic small molecules are often hindered by narrow therapeutic indices and limited specificity, leading to suboptimal clinical outcomes. On the other hand, more advanced approaches, such as antibody–drug conjugates (ADCs), frequently encounter obstacles, including poor tumor penetration and prohibitive production costs. The tumor-forming and metastatic capacity of cancer further challenges currently available cancer therapies by creating a biochemical milieu known as the tumor microenvironment (TME). Although solid tumor development presents significant obstacles, it also opens new avenues for innovative therapeutic approaches. It is well-documented that as tumors grow beyond 1–2 mm³ in size, they undergo profound changes in their microenvironment, including alterations in oxygen levels, pH, enzymatic activity, surface antigen expression, and the cellular composition of the stroma. These changes create unique opportunities that can be exploited to develop novel and innovative therapeutics. Currently, numerous ADCs, small-molecule–drug conjugates (SMDCs), and prodrugs are being developed to target specific aspects of these microenvironmental changes. In this review, we explore five TME parameters in detail, with a focus on their relevance to specific cancer types, phenotypic identifiers, and preferred methods of therapeutic targeting. Additionally, we examine the chemical moieties available to target these changes, providing a framework for design strategies that exploit the dynamics of the tumor microenvironment. Full article