Semiconducting polymer nanoprodrugs enable tumor-specific therapy via sono-activatable ferroptosis.

Ferroptosis, a recently identified form of cell death, holds promise for cancer therapy, but concerns persist regarding its uncontrolled actions and potential side effects. Here, we present a semiconducting polymer nanoprodrug (SPNpro) featuring an innovative ferroptosis prodrug (DHU-CBA7) to induce sono-activatable ferroptosis for tumor-specific therapy. DHU-CBA7 prodrug incorporate methylene blue, ferrocene and urea bond, which can selectively and specifically respond to singlet oxygen (1O2) to turn on ferroptosis action via rapidly cleaving the urea bonds. DHU-CBA7 prodrug and a semiconducting polymer are self-assembled with an amphiphilic polymer to construct SPNpro. Ultrasound irradiation of SPNpro leads to the production of 1O2 via sonodynamic therapy (SDT) of the semiconducting polymer, and the generated 1O2 activated DHU-CBA7 prodrug to achieve sono-activatable ferroptosis. Consequently, SPNpro combine SDT with the controlled ferroptosis to effectively cure 4T1 tumors covered by 2-cm tissue with a tumor inhibition efficacy as high as 100 %, and also completely restrain tumor metastases. This study introduces a novel sono-activatable prodrug strategy for regulating ferroptosis, allowing for precise cancer therapy.

Novel Directed Enzyme Prodrug Therapy for Cancer Treatment Based on 2'-Deoxyribosyltransferase-Conjugated Magnetic Nanoparticles.

Directed enzyme prodrug therapy (DEPT) strategies show promise in mitigating chemotherapy side effects during cancer treatment. Among these, the use of immobilized enzymes on solid matrices as prodrug activating agents (IDEPT) presents a compelling delivery strategy, offering enhanced tumor targeting and reduced toxicity. Herein, we report a novel IDEPT strategy by employing a His-tagged Leishmania mexicana type I 2'-deoxyribosyltransferase (His-LmPDT) covalently attached to glutaraldehyde-activated magnetic iron oxide nanoparticles (MIONPs). Among the resulting derivatives, PDT-MIONP3 displayed the most favorable catalyst load/retained activity ratio, prompting its selection for further investigation. Substrate specificity studies demonstrated that PDT-MIONP3 effectively hydrolyzed a diverse array of 6-oxo and/or 6-amino purine 2'-deoxynucleosides, including 2-fluoro-2'-deoxyadenosine (dFAdo) and 6-methylpurine-2'-deoxyribose (d6MetPRib), both well-known prodrugs commonly used in DEPT. The biophysical characterization of both MIONPs and PDT-MIONPs was conducted by TEM, DLS, and single particle ICPMS techniques, showing an ideal nanosized range and a zeta potential value of -47.9 mV and -78.2 mV for MIONPs and PDT-MIONPs, respectively. The intracellular uptake of MIONPs and PDT-MIONPs was also determined by TEM and single particle ICPMS on HeLa cancer cell lines and NIH3T3 normal cell lines, showing a higher intracellular uptake in tumor cells. Finally, the selectivity of the PDT-MIONP/dFAdo IDEPT system was tested on HeLa cells (24 h, 10 µM dFAdo), resulting in a significant reduction in tumoral cell survival (11% of viability). Based on the experimental results, PDT-MIONP/dFAdo presents a novel and alternative IDEPT strategy, providing a promising avenue for cancer treatment.

Carbon-Spaced Tandem-Disulfide Bond Bridge Design Addresses Limitations of Homodimer Prodrug Nanoassemblies: Enhancing Both Stability and Activatability.

Redox-responsive homodimer prodrug nanoassemblies (RHPNs) have emerged as a significant technology for overcoming chemotherapeutical limitations due to their high drug-loading capacity, low excipient-associated toxicity, and straightforward preparation method. Previous studies indicated that α-position disulfide bond bridged RHPNs exhibited rapid drug release rates but unsatisfactory assembly stability. In contrast, γ-disulfide bond bridged RHPNs showed better assembly stability but low drug release rates. Therefore, designing chemical linkages that ensure both stable assembly and rapid drug release remains challenging. To address this paradox of stable assembly and rapid drug release in RHPNs, we developed carbon-spaced double-disulfide bond (CSDD)-bridged RHPNs (CSDD-RHPNs) with two carbon-spaces. Pilot studies showed that CSDD-RHPNs with two carbon-spaces exhibited enhanced assembly stability, reduction-responsive drug release, and improved selective toxicity compared to α-/γ-position single disulfide bond bridged RHPNs. Based on these findings, CSDD-RHPNs with four and six carbon-spaces were designed to further investigate the properties of CSDD-RHPNs. These CSDD-RHPNs exhibited excellent assembly ability, safety, and prolonged circulation. Particularly, CSDD-RHPNs with two carbon-spaces displayed the best antitumor efficacy on 4T1 and B16-F10 tumor-bearing mice. CSDD chemical linkages offer novel perspectives on the rational design of RHPNs, potentially overcoming the design limitations regarding contradictory assembly ability and drug release rate.

Alkaline phosphatase-activated prodrug system based on a bifunctional CuO NP tandem nanoenzyme for on-demand bacterial inactivation and wound disinfection.

Nanozymes are promising antimicrobials, as they produce reactive oxygen species (ROS). However, the intrinsic lack of selectivity of ROS in distinguishing normal flora from pathogenic bacteria deprives nanozymes of the necessary selectivities of ideal antimicrobials. Herein, we exploit the physiological conditions of bacteria (high alkaline phosphatase (ALP) expression) using a novel CuO nanoparticle (NP) nanoenzyme system to initiate an ALP-activated ROS prodrug system for use in the on-demand precision killing of bacteria. The prodrug strategy involves using 2-phospho-L-ascorbic acid trisodium salt (AAP) that catalyzes the ALP in pathogenic bacteria to generate ascorbic acid (AA), which is converted by the CuO NPs, with intrinsic ascorbate oxidase- and peroxidase-like activities, to produce ROS. Notably, the prodrug system selectively kills Escherichia coli (pathogenic bacteria), with minimal influence on Staphylococcus hominis (non-pathogenic bacteria) due to their different levels of ALP expression. Compared to the CuO NPs/AA system, which generally depletes ROS during storage, CuO NPs/AAP exhibits a significantly higher stability without affecting its antibacterial activity. Furthermore, a rat model is used to indicate the applicability of the CuO NPs/AAP fibrin gel in wound disinfection in vivo with negligible side effects. This study reveals the therapeutic precision of this bifunctional tandem nanozyme platform against pathogenic bacteria in ALP-activated conditions.

Bio-inspired biorthogonal compartmental microparticles for tumor chemotherapy and photothermal therapy.

Microcarrier is a promising drug delivery system demonstrating significant value in treating cancers. One of the main goals is to devise microcarriers with ingenious structures and functions to achieve better therapeutic efficacy in tumors. Here, inspired by the nucleus-cytoplasm structure of cells and the material exchange reaction between them, we develop a type of biorthogonal compartmental microparticles (BCMs) from microfluidics that can separately load and sequentially release cyclooctene-modified doxorubicin prodrug (TCO-DOX) and tetrazine-modified indocyanine green (Tz-ICG) for tumor therapy. The Tz-ICG works not only as an activator for TCO-DOX but also as a photothermal agent, allowing for the combination of bioorthogonal chemotherapy and photothermal therapy (PTT). Besides, the modification of DOX with cyclooctene significantly decreases the systemic toxicity of DOX. As a result, the developed BCMs demonstrate efficient in vitro tumor cell eradication and exhibit notable tumor growth inhibition with favorable safety. These findings illustrate that the formulated BCMs establish a platform for bioorthogonal prodrug activation and localized delivery, holding significant potential for cancer therapy and related applications.

Self-assembled hyaluronic acid nanomicelle for enhanced cascade cancer chemotherapy via self-sensitized ferroptosis.

The clinical utility of chemotherapy is often compromised by its limited efficacy and significant side effects. Addressing these concerns, we have developed a self-assembled nanomicelle, namely SANTA FE OXA, which consists of hyaluronic acid (HA) conjugated with ferrocene methanol (FC), oxaliplatin prodrug (OXA(IV)) and ethylene glycol-coupled linoleic acid (EG-LA). Targeted delivery is achieved by HA binding to the CD44 receptors that are overexpressed on tumor cells, facilitating drug uptake. Once internalized, hyaluronidase (HAase) catalyzes the digestion of the SANTA FE OXA, releasing FC and reducing OXA(IV) into an active form. The active oxaliplatin (OXA) induces DNA damage and increases intracellular hydrogen peroxide (H2O2) levels via cascade reactions. Simultaneously, FC disrupts the redox balance within tumor cells, inducing ferroptosis. Both in vivo and in vitro experiments confirmed that SANTA FE OXA inhibited tumor growth by combining cascade chemotherapy and self-sensitized ferroptosis, achieving a tumor inhibition rate of up to 76.61 %. Moreover, this SANTA FE OXA significantly mitigates the systemic toxicity commonly associated with platinum-based chemotherapeutics. Our findings represent a compelling advancement in nanomedicine for enhanced cascade cancer therapy.

Self-immolative poly(thiocarbamate) with localized H2S signal amplification for precise cancer imaging and therapy.

Hydrogen sulfide is essential in numerous physiological and pathological processes and has emerged as a promising cancer imaging and signaling molecule and a potentially versatile therapeutic agent. However, the endogenous levels of hydrogen sulfide remain insufficient to perform its biological functions, and thus, developing novel strategies that amplify hydrogen sulfide signals at lesion sites is of increasing interest. In this work, a nanoplatform (SNP) based on hydrogen sulfide-responsive self-immolative poly(thiocarbamate) with localized hydrogen sulfide signal amplification capability is developed to encapsulate a hydrogen sulfide-responsive fluorescent probe (e.g., hemicyanine dye; p-Cy) or an anticancer prodrug (e.g., doxorubicin; p-DOX) to form a nanoprobe (SNPp-Cy) or nanomedicine (SNPp-DOX) for cancer imaging and therapy, respectively. SNPp-Cy exhibits a low detection limit for hydrogen sulfide, enabling ultrasensitive detection of small (<2 mm) tumors in female mice. In addition, SNPp-DOX can effectively inhibit the growth of DOX-resistant human breast cancer xenograft, lung metastasis, and patient-derived xenograft tumors in female mice.

Design of pH/Redox Co-Triggered Degradable Diselenide-Containing Polyprodrug via a Facile One-Pot Two-Step Approach for Tumor-Specific Chemotherapy.

The diselenide bond has attracted intense interest for drug delivery systems (DDSs) for tumor chemotherapy, owing to it possessing higher redox sensitivity than the disulfide one. Various redox-responsive diselenide-containing carriers have been developed for chemotherapeutics delivery. However, the premature drug leakage from these DDSs was significant enough to cause toxic side effects on normal cells. Here, a pH/redox co-triggered degradable polyprodrug was designed as a drug self-delivery system (DSDS) by incorporating drug molecules as structural units in the polymer main chains, using a facile one-pot two-step approach. The proposed PDOX could only degrade and release drugs by breaking both the neighboring acid-labile acylhydrazone and the redox-cleavable diselenide conjugations in the drug's structural units, triggered by the higher acidity and glutathione (GSH) or reactive oxygen species (ROS) levels in the tumor cells. Therefore, a slow solubility-controlled drug release was achieved for tumor-specific chemotherapy, indicating promising potential as a safe and efficient long-acting DSDS for future tumor treatment.

Mitochondria-Targeted Multifunctional Nanoprodrugs by Inhibiting Metabolic Reprogramming for Combating Cisplatin-Resistant Lung Cancer.

How to address the resistance of cisplatin (CDDP) has always been a clinical challenge. The resistance mechanism of platinum-based drugs is very complex, including nuclear DNA damage repair, apoptosis escape, and tumor metabolism reprogramming. Tumor cells can switch between mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis and develop resistance to chemotherapy drugs through metabolic variability. In addition, due to the lack of histone protection and a relatively weak damage repair ability, mitochondrial DNA (mtDNA) is more susceptible to damage, which in turn affects mitochondrial OXPHOS and can become a potential target for platinum-based drugs. Therefore, mitochondria, as targets of anticancer drugs, have become a hot topic in tumor resistance research. This study constructed a self-assembled nanotargeted drug delivery system LND-SS-Pt-TPP/HA-CD. ß-Cyclodextrin-grafted hydronic acid (HA-CD)-encapsulated prodrug nanoparticles can target CD44 on the tumor surface and further deliver the prodrug to intracellular mitochondria through a triphenylphosphine group (TPP+). Disulfide bonds can be selectively degraded by glutathione (GSH) in mitochondria, releasing lonidamine (LND) and the cisplatin prodrug (Pt(IV)). Under the action of GSH and ascorbic acid, Pt(IV) is further reduced to cisplatin (Pt(II)). Cisplatin can cause mtDNA damage, induce mitochondrial dysfunction and mitophagy, and then affect mitochondrial OXPHOS. Meanwhile, LND can reduce the hexokinase II (HK II) level, induce destruction of mitochondria, and block energy supply by glycolysis inhibition. Ultimately, this self-assembled nano targeted delivery system can synergistically kill cisplatin-resistant lung cancer cells, which supplies an overcome cisplatin resistance choice via the disrupt mitochondria therapy.

Acid-sensitive prodrugs; a promising approach for site-specific and targeted drug release.

Drugs administered through conventional formulations are devoid of targeting and often spread to various undesired sites, leading to sub-lethal concentrations at the site of action and the emergence of undesired effects. Hence, therapeutic agents should be delivered in a controlled manner at target sites. Currently, stimuli-based drug delivery systems have demonstrated a remarkable potential for the site-specific delivery of therapeutic moieties. pH is one of the widely exploited stimuli for drug delivery as several pathogenic conditions such as tumor cells, infectious and inflammatory sites are characterized by a low pH environment. This review article aims to demonstrate various strategies employed in the design of acid-sensitive prodrugs, providing an overview of commercially available acid-sensitive prodrugs. Furthermore, we have compiled the progress made for the development of new acid-sensitive prodrugs currently undergoing clinical trials. These prodrugs include albumin-binding prodrugs (Aldoxorubicin and DK049), polymeric micelle (NC-6300), polymer conjugates (ProLindac™), and an immunoconjugate (IMMU-110). The article encompasses a broad spectrum of studies focused on the development of acid-sensitive prodrugs for anticancer, antibacterial, and anti-inflammatory agents. Finally, the challenges associated with the acid-sensitive prodrug strategy are discussed, along with future directions.

A bioinspired supramolecular nanoprodrug for precision therapy of B-cell non-Hodgkin's lymphoma.

Fludarabine (FA) is still considered as a first-line chemotherapy drug for hematological tumors related to B lymphocytes. However, it is worth noting that the non-specific distribution and non-different cytotoxicity of FA may lead to irreversible consequences such as central nervous system damage such as blindness, coma, and even death. Therefore, it is very important to develop a system to targeting delivery FA. In preliminary studies, it was found that B lymphoma cells would specific highly expressing the sialic acid-binding immunoglobulin-like lectin 2 (known as CD22). Inspired by the specific recognition of sialic acid residues and CD22, we have developed a supramolecular prodrug based on polysialic acid, an endogenous biomacromolecule, achieving targeted-therapy of B-cell non-Hodgkin's lymphoma (B-NHL). Specifically, the prepared hydrophobic reactive oxygen species-responsive FA dimeric prodrug (F2A) interacts with the TPSA, which polysialic acid were modified by the thymidine derivatives, through non-covalent intermolecular interactions similar to "Watson-Crick" base pairing, resulting in the formation of nanoscale supramolecular prodrug (F@TPSA). Cell experiments have confirmed that F@TPSA can be endocytosed by CD22+ B lymphoma cells including Raji and Ramos cells, and there is a significant difference of endocytosis in other leukocytes. Furthermore, in B-NHL mouse model, compared with FA, F@TPSA is determined to have a stronger tumor targeting and inhibitory effect. More importantly, the distribution of F@TPSA in vivo tends to be enriched in lymphoma tissue rather than nonspecific, thus reducing the leukopenia of FA. The targeted delivery system based on PSA provides a new prodrug modification strategy for targeted treatment of B-NHL.

ROS-Responsive Nanoprobes for Bimodal Imaging-Guided Cancer Targeted Combinatorial Therapy.

Purpose: Chemotherapy mediated by Reactive oxygen species (ROS)-responsive drug delivery systems can potentially mitigate the toxic side effects of chemotherapeutic drugs and significantly enhance their therapeutic efficacy. However, achieving precise targeted drug delivery and real-time control of ROS-responsive drug release at tumor sites remains a formidable challenge. Therefore, this study aimed to describe a ROS-responsive drug delivery system with specific tumor targeting capabilities for mitigating chemotherapy-induced toxicity while enhancing therapeutic efficacy under guidance of Fluorescence (FL) and Magnetic resonance (MR) bimodal imaging. Methods: Indocyanine green (ICG), Doxorubicin (DOX) prodrug pB-DOX and Superparamagnetic iron oxide (SPIO, Fe3O4) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) by double emulsification method to prepare ICG/ pB-DOX/ Fe3O4/ PLGA nanoparticles (IBFP NPs). The surface of IBFP NPs was functionalized with mammaglobin antibodies (mAbs) by carbodiimide method to construct the breast cancer-targeting mAbs/ IBFP NPs (MIBFP NPs). Thereafter, FL and MR bimodal imaging ability of MIBFP NPs was evaluated in vitro and in vivo. Finally, the combined photodynamic therapy (PDT) and chemotherapy efficacy evaluation based on MIBFP NPs was studied. Results: The multifunctional MIBFP NPs exhibited significant targeting efficacy for breast cancer. FL and MR bimodal imaging clearly displayed the distribution of the targeting MIBFP NPs in vivo. Upon near-infrared laser irradiation, the MIBFP NPs loaded with ICG effectively generated ROS for PDT, enabling precise tumor ablation. Simultaneously, it triggered activation of the pB-DOX by cleaving its sensitive moiety, thereby restoring DOX activity and achieving ROS-responsive targeted chemotherapy. Furthermore, the MIBFP NPs combined PDT and chemotherapy to enhance the efficiency of tumor ablation under guidance of bimodal imaging. Conclusion: MIBFP NPs constitute a novel dual-modality imaging-guided drug delivery system for targeted breast cancer therapy and offer precise and controlled combined treatment options.

A nanoplatform based on allylthiopurine bio-MOF and glycosylated AIE PARP inhibitor for cancer synthetic lethal therapy.

A biological nanoplatform (Gal-ANI@ZnAP NPs) was constructed based on a prodrug-skeletal metal-organic framework (MOF) using purine nucleobase analogue prodrug 6-allylthiopurine as a bioactive ligand, and functionalized with AIE fluorescent PARP inhibitor glycoconjugate for visualization therapy and synthetic lethal cancer therapy. This nanoplatform could actively target cancer cells, selectively release drugs in response to esterase/pH, and visualize drug uptake. In vitro studies revealed that Gal-ANI@ZnAP NPs increased the synthetic lethality in cancer cells by inducing DNA repair failure with the simultaneous targeting of PARP and nucleotide metabolism, thereby exhibiting a significant cancer-killing effect. The study presents a novel strategy to construct an AIE nanoplatform using pharmaceutical molecules for drug uptake visualization and boosting synthetic lethality in cancer.

Neoadjuvant Hyperthermia Combined with Hybrid Nanoarchitectures Enhances Chemoradiotherapy Efficacy in Head and Neck Carcinoma.

Head and neck squamous cell carcinomas are characterized by a high incidence of recurrence, especially in patients with locally advanced disease. Standard treatment strategies can be associated with severe side effects to healthy tissues that can negatively impact the patient's quality of life. Hyperthermia (HT) is a noninvasive treatment modality that has improved the effectiveness of chemotherapy (CT) and/or radiotherapy (RT) for the management of some solid neoplasms. In this context, the association of this approach with rationally designed nanomaterials may further enhance the treatment outcome. In this study, we demonstrate the enhanced effect of neoadjuvant HT in combination with hybrid nanoarchitectures enclosing a cisplatin prodrug (NAs-CisPt) and RT. All the treatments and their combinations have been fully evaluated by employing standardized chorioallantoic membrane tumor models of HPV-negative head and neck carcinoma. An improved tumor-shrinking effect was observed by the administration of the trimodal treatment (HT/NAs-CisPt/RT), which also highlighted a significant increase in apoptosis. Our findings demonstrate that the combination of HT with nanotechnology-based CT and RT in a certain order enhances the in vivo treatment outcome. On a broader basis, this study paves the way for the next exploration of noninvasive treatment approaches for the clinical management of oral cancer based on innovative strategies.

Engineering hypoxia-responsive 6-aminonicotinamide prodrugs for on-demand NADPH depletion and redox manipulation.

Glucose-6-phosphate dehydrogenase (G6PD) is a promising target in cancer therapy. However, poor cellular uptake and off-target toxicity have impeded the clinical translation of a canonical G6PD inhibitor (6-aminonicotinamide/6AN). Here, we report a prodrug strategy to address this issue. The tailored 6AN prodrug contains an azo-bearing protection moiety. The hydrophobic prodrug showed increased cellular uptake than 6AN and was vulnerable to hypoxia, resulting in NAD(P)H quinone dehydrogenase 1 (NQO1)-triggered cleavage of azo bonds. Intriguingly, the prodrug showed configuration-dependent anti-cancer potency. Despite the lower thermodynamic stability, the cis isomer showed enhanced cellular uptake compared to the trans counterpart due to the increased aqueous solubility. Moreover, the boosted potency of the cis isomer compared to the trans isomer arose from the enhancement of NOQ1-catalyzed 6AN release under hypoxia, a hallmark of solid tumors. The discovery of hypoxia-responsive 6AN prodrugs in the current work opens up new avenues for G6PD-targeting cancer medicines.

Oral Saccharomyces cerevisiae-Guided Enzyme Prodrug Therapy Combined with Immunotherapy for the Treatment of Orthotopic Colorectal Cancer.

Colorectal cancer (CRC) is a major global health concern, and the development of effective treatment strategies is crucial. Enzyme prodrug therapy (EPT) shows promise in combating tumors but faces challenges in achieving sustained expression of therapeutic enzymes and optimal biological distribution. To address these issues, a fungi-triggered in situ chemotherapeutics generator (named as SC@CS@5-FC) was constructed via oral delivery of a prodrug (5-fluorocytosine, 5-FC) for the treatment of orthotopic colorectal tumor. When SC@CS@5-FC targets the tumor through tropism by Saccharomyces cerevisiae (SC), the chemotherapeutic generator could be degraded under abundant hyaluronidase (HAase) in the tumor microenvironment by an enzyme-responsive gate to release prodrug (5-FC). And nontoxic 5-FC was catalyzed to toxic chemotherapy drug 5-fluorouracil (5-FU) by cytosine deaminase (CD) of SC. Meanwhile, SC and zinc-coordinated chitosan nanoparticles could be used as immune adjuvants to activate antigen-presenting cells and further enhance the therapeutic effect. Our results demonstrated that SC@CS@5-FC could effectively inhibit tumor growth and prolong mouse survival in an orthotopic colorectal cancer model. This work utilizes living SC as a dynamotor and positioning system for the chemotherapeutic generator SC@CS@5-FC, providing a strategy for oral enzyme prodrug therapy for the treatment of orthotopic colorectal.

Gold(III)-Induced Amide Bond Cleavage In Vivo: A Dual Release Strategy via π-Acid Mediated Allyl Substitution.

Selective cleavage of amide bonds holds prominent significance by facilitating precise manipulation of biomolecules, with implications spanning from basic research to therapeutic interventions. However, achieving selective cleavage of amide bonds via mild synthetic chemistry routes poses a critical challenge. Here, we report a novel amide bond-cleavage reaction triggered by Na[AuCl4] in mild aqueous conditions, where a crucial cyclization step leads to the formation of a 5-membered ring intermediate that rapidly hydrolyses to release the free amine in high yields. Notably, the reaction exhibits remarkable site-specificity to cleave peptide bonds at the C-terminus of allyl-glycine. The strategic introduction of a leaving group at the allyl position facilitated a dual-release approach through π-acid catalyzed substitution. This reaction was employed for the targeted release of the cytotoxic drug monomethyl auristatin E in combination with an antibody-drug conjugate in cancer cells. Finally, Au-mediated prodrug activation was shown in a colorectal zebrafish xenograft model, leading to a significant increase in apoptosis and tumor shrinkage. Our findings reveal a novel metal-based cleavable reaction expanding the utility of Au complexes beyond catalysis to encompass bond-cleavage reactions for cancer therapy.

RAPTA-coordinated polydiacetylene self-assembly: A chameleon-like prodrug with a dual-lock strategy for real-time release monitoring of metallodrug.

Herein, we report the first-ever design strategy of modifying RAPTA-C into a self-reporting prodrug candidate based on Ru-coordinated polydiacetylene self-assembly. This nanosystem exhibits a dual lock strategy that responds to visible light and pH-stimuli sequentially one by one with a concomitant color change for controlled RAPTA-C release and real-time release monitoring in human gastric cancer cells.

Sustained release of 5-aminosalicylic acid from azoreductase-responsive polymeric prodrugs for prolonged colon-targeted colitis therapy.

Ulcerative colitis (UC) is a challenging inflammatory gastrointestinal disorder, whose therapies encounter limitations in overcoming insufficient colonic retention and rapid systemic clearance. In this study, we report an innovative polymeric prodrug nanoformulation for targeted UC treatment through sustained 5-aminosalicylic acid (5-ASA) delivery. Amphiphilic polymer-based 13.5 nm micelles were engineered to incorporate azo-linked 5-ASA prodrug motifs, enabling cleavage via colonic azoreductases. In vitro, micelles exhibited excellent stability under gastric/intestinal conditions while demonstrating controlled 5-ASA release over 24 h in colonic fluids. Orally administered micelles revealed prolonged 24-h retention and a high accumulation within inflamed murine colonic tissue. At an approximately 60% dose reduction from those most advanced recent studies, the platform halted DSS colitis progression and outperformed standard 5-ASA therapy through a 77-97% suppression of inflammatory markers. Histological analysis confirmed intact colon morphology and restored barrier protein expression. This integrated prodrug nanoformulation addresses limitations in colon-targeted UC therapy through localized bioactivation and tailored pharmacokinetics, suggesting the potential of nanotechnology-guided precision delivery to transform disease management.

A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy.

The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models.