Self-immolative poly(thiocarbamate) with localized HS 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.

Self-assembled metal-phenolic network nanoparticles for delivery of a cisplatin prodrug for synergistic chemo-immunotherapy.

Despite cisplatin's pivotal role in clinically proven anticancer drugs, its application has been hampered by severe side effects and a grim prognosis. Herein, we devised a glutathione (GSH)-responsive nanoparticle (PFS-NP) that integrates a disulfide bond-based amphiphilic polyphenol (PP-SS-DA), a dopamine-modified cisplatin prodrug (Pt-OH) and iron ions (Fe) through coordination reactions between Fe and phenols. After entering cells, the responsively released Pt-OH and disulfide bonds eliminate the intracellular GSH, in turn disrupting the redox homeostasis.

A Synergistic Chemoimmunotherapy System Leveraging PD-L1 Blocking and Bioorthogonal Prodrug Activation.

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain challenging in overcoming the current limitations of chemoimmunotherapy. An antitumor chemoimmunotherapy system comprising bioorthogonal reaction-ready group tetrazine (TZ) modified with an anti-PD-L1 antibody (αPD-L1) and TZ-activatable prodrug vinyl ether-doxorubicin (DOX-VE) for self-reinforced anti-tumor chemoimmunotherapy is proposed. The αPD-L1 effectively disrupts the PD-L1/PD-1 interaction and activates the DOX prodrug in situ through the bioorthogonal click reaction of TZ and VE.

Dual stimulus-triggered bioorthogonal nanosystem for spatiotemporally controlled prodrug activation and near-infrared fluorescence imaging.

In this study, we combined low pH and cathepsin B dual-stimulus-triggered delivery carriers with a bioorthogonal reaction-activated prodrug to achieve regulated activation of the prodrug. A workable method for precise tumor therapy and imaging is provided by the bioorthogonal reaction, which activates the prodrug and fluorescent probe.

A dual-amplified ROS-responsive nanosystem with self-accelerating drug release for synergistic chemotherapy.

In this work, we have developed a tumor-specific self-accelerating prodrug activation nanosystem consisting of self-amplifying degradable polyprodrug PEG-TA-CA-DOX and encapsulated fluorescent prodrug BCyNH, equipped with a reactive oxygen species dual-cycle amplification effect. Furthermore, activated CyNH is a therapeutic agent with potential to synergistically improve chemotherapy.

Self-amplified chain-shattering cinnamaldehyde-based poly(thioacetal) boosts cancer chemo-immunotherapy.

The selective activation of stimuli-responsive polymers in the tumor microenvironment is a great concern to achieve intelligent cancer therapy, but most of them show inadequate response due to insufficient endogenous triggering agents. Herein, we rationally designed a reactive oxygen species (ROS)-responsive cinnamaldehyde (CA)-based poly(thioacetal), consisting of ROS-responsive thioacetal (TA) and ROS-generating agent CA, with self-amplified chain-shattering polymer degradation. The mechanism of self-amplified chain-shattering is that endogenous ROS as a triggering agent facilitates chain cleavage of TA with the release of CA, which in turn produces more ROS through mitochondrial dysfunction, resulting in an exponential polymer degradation cascade.

Self-immolative polyprodrug-based tumor-specific cascade amplificated drug release nanosystem for orchestrated synergistic cancer therapy.

Reactive oxygen species (ROS)-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the inability to release sufficient drugs at tumor sites due to the paucity of ROS, which is required for prodrug activation usually limits the antitumor potency. Herein, a delivery nanosystem with self-amplifiable drug release pattern is constructed by encapsulating a tumor specificity ROS inducer NAD(P)H: quinone oxidoreductase-1 (NQO1)-responsive hemicyanine fluorescent dye (NCyNH) in a ROS-responsive self-immolative polyprodrug nanoparticle for orchestrated oxidation-chemotherapy.

Cinnamaldehyde-based poly(thioacetal): A ROS-awakened self-amplifying degradable polymer for enhanced cancer immunotherapy.

Although stimuli-responsive polymers have emerged as promising strategies for intelligent cancer therapy, limited polymer degradation and insufficient drug release remain a challenge. Here, we report a novel reactive oxygen species (ROS)-awakened self-amplifying degradable cinnamaldehyde (CA)-based poly(thioacetal) polymer. The polymer consists of ROS responsive thioacetal (TA) group and CA as the ROS generation agent.

Spatial specific delivery of combinational chemotherapeutics to combat intratumoral heterogeneity.

Hypoxia-induced intratumoral heterogeneity poses a major challenge in tumor therapy due to the varying susceptibility to chemotherapy. Moreover, the spatial distribution patterns of hypoxic and normoxic tissues makes conventional combination therapy less effective. In this study, a tumor-acidity and bioorthogonal chemistry mediated in situ size transformable nanocarrier (NP@DOX plus iCPPA) was developed to spatially deliver two combinational chemotherapeutic drugs (doxorubicin (DOX) and PR104A) to combat hypoxia-induced intratumoral heterogeneity.

Self-boosting stimulus activation of a polyprodrug with cascade amplification for enhanced antitumor efficacy.

The use of polyprodrugs, which bind drugs to polymer chains through responsive linkers, is a potential technique for cancer therapy; however, a lack of endogenous triggering factors limits drug activation in tumor tissue. Herein, we rationally created a reactive oxygen species (ROS)-sensitive polyprodrug (TS) with cascade amplification of triggering agents and drug activation by incorporating both an ROS signal amplifier (TA) and a drug activation amplifier (SIP) into a delivery system. Endogenous ROS as a triggering mechanism kicked off the initial circulation phase to increase intracellular ROS signals.

Self-catalyzed tumor ferroptosis based on ferrocene conjugated reactive oxygen species generation and a responsive polymer.

In this work, we developed a ferroptosis self-catalyst, PTAF, exhibiting self-catalyzed ferroptosis for enhanced cancer therapy. Briefly, synergistic actions of self-catalyzed ˙OH accumulation and GPX4 indirect inactivation based on the establishment of the ROS self-catalytic loop effectively induced tumor ferroptosis, which provided a novel approach for enhanced tumor therapy.

Tumor-Acidity and Bioorthogonal Chemistry-Mediated On-Site Size Transformation Clustered Nanosystem to Overcome Hypoxic Resistance and Enhance Chemoimmunotherapy.

Hypoxia, a common feature of most solid tumors, causes severe tumor resistance to chemotherapy and immunotherapy. Herein, a tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem is designed to overcome hypoxic resistance and enhance chemoimmunotherapy. The nanosystem utilized the tumor-acidity responsive group poly(2-azepane ethyl methacrylate) with a rapid response rate and highly efficient bioorthogonal click chemistry to form large-sized aggregates in tumor tissue to enhance accumulation and retention.

Time-programmed activation of dual polyprodrugs for synergistic cascade oxidation-chemotherapy.

Combination therapy using multiple drugs with time-programmed administration is promising for enhanced cancer treatment. However, it is still challenging to achieve time-programmed drug release from a single nanocarrier. Here, dual polyprodrugs of hemicyanine dye (CyNH) and doxorubicin (DOX) are developed to achieve time-programmed prodrug activation for synergistic cascade oxidation therapy and chemotherapy.

Dual-locking nanoprobe based on hemicyanine for orthogonal stimuli-triggered precise cancer imaging and therapy.

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 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 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, resulting in strong NIR fluorescence turn-on for cancer imaging.

Theranostic Heterodimeric Prodrug with Dual-Channel Fluorescence Turn-On and Dual-Prodrug Activation for Synergistic Cancer Therapy.

Theranostic prodrugs that can precisely monitor drug activation with synergistic therapeutic effects are highly desirable for personalized medicine. In this study, a theranostic heterodimeric prodrug, CyNH-SS-DOX, with synchronous and independent dual-channel fluorescence turn-on and dual-prodrug activation for synergistic cancer therapy is developed. A hemicyanine fluorescent drug, CyNH , with good therapeutic effects found in this work, is conjugated to doxorubicin (DOX) through a disulfide linker to form CyNH-SS-DOX.

Sequential enzyme-activated macrotheranostic probe for selective tumor mitochondria targeting.

Subcellular organelle targeted imaging and therapy are of enormous interest in cancer theranostics. However, the lack of tumor-selective organelle targeting has compromised their efficacy and safety. In this work, we found that the near-infrared (NIR) fluorophore hemicyanine (CyNH) can selectively target mitochondria with strong cytotoxicity through decreasing the mitochondrial membrane potential and increasing the intracellular reactive oxygen species (ROS) levels.

Amplification of tumor oxidative stresses by Poly(disulfide acetal) for multidrug resistance reversal.

Discovering new strategies to overcome multidrug resistance (MDR) is still urgently needed. MDR is associated with the overexpression of transmembrane efflux pumps, and adenosine triphosphate (ATP) is indispensable for its function. Herein, we developed a pH- and glutathione (GSH)-responsive amphiphilic poly(disulfide acetal) (PCS) containing cinnamaldehyde (CA) and disulfide groups that amplify oxidative stress for anticancer drug delivery and simultaneously overcome drug resistance in cancer cells.

Polyprodrug with glutathione depletion and cascade drug activation for multi-drug resistance reversal.

High intracellular glutathione (GSH) levels play an important role in multidrug resistance (MDR) in cancer cells. It remains challenging to develop a drug delivery system that is simultaneously capable of GSH depletion and drug activation for multidrug resistance reversal. Herein, we designed a polyprodrug (denoted as PSSD) based on poly(disulfide) conjugated with doxorubicin (DOX) on the polymer side chains that exhibits GSH depletion and cascade DOX activation for drug resistance reversal.

Size-Switchable Nanoparticles with Self-Destructive and Tumor Penetration Characteristics for Site-Specific Phototherapy of Cancer.

The normoxic and hypoxic microenvironments in solid tumors cause cancer cells to show different sensitivities to various treatments. Therefore, it is essential to develop different therapeutic modalities based on the tumor microenvironment. In this study, we designed size-switchable nanoparticles with self-destruction and tumor penetration characteristics for site-specific phototherapy of cancer.

Co-delivery of Metformin and Paclitaxel Via Folate-Modified pH-Sensitive Micelles for Enhanced Anti-tumor Efficacy.

Single chemotherapeutic agent like paclitaxel (PTX) has shown some limitations in anti-tumor treatment, such as undesirable side effects, multidrug resistance, and high toxicity. In order to reduce the toxicity of PTX and increase the anti-tumor effect, folate-modified amphiphilic and biodegradable biomaterial was developed to co-deliver PTX and metformin (MET) for exerting the synergistic effect. PTX was physically entrapped in the hydrophobic inner core of the amphiphilic block copolymer by a solvent evaporation method, whereas MET was chemically conjugated to the hydrophilic terminals of copolymer via a pH-sensitive cis-aconityl linkage (Cis).