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Comprehensive Summary: Stimuli‐controlled disassembly process has shown promise to direct delivery of probes and/or spatial‐temporally control imaging signals for molecular imaging in vivo. Via the disassembly process, well defined nanoprobes with a stimulus‐responsive moiety can be controllably converted into small‐molecular imaging agents in response to a stimulus, leading to a switch in imaging signals. Moreover, the on‐site released small‐molecule probes could enhance penetration into the deep tissue for improved imaging of deep‐seated molecular targets. Therefore, such a stimuli‐controllable disassembly approach has been widely utilized to build activatable molecular imaging probes for the noninvasive detection of various molecular targets in living subjects. In this review article, we first briefly introduce the general principle of stimuli‐controlled disassembly. We then summarize the activatable probes based on different internal or external stimulus that has been utilized to control disassembly process. Activatable probes by using multiple stimuli to control cascaded in situ self‐assembly and disassembly processes are also discussed. Finally, we close with a conclusion of current challenges and perspective in this field. We wish this review paper will give readers useful information on molecular imaging via the intelligent stimuli‐controlled disassembly process. [ABSTRACT FROM AUTHOR]

Directed self-assembly of small molecules in living systems could enable a myriad of applications in biology and medicine, and already this has been used widely to synthesize supramolecules and nano/microstructures in solution and in living cells. However, controlling the self-assembly of synthetic small molecules in living animals is challenging because of the complex and dynamic in vivo physiological environment. Here we employ an optimized first-order bioorthogonal cyclization reaction to control the self-assembly of a fluorescent small molecule, and demonstrate its in vivo applicability by imaging caspase-3/7 activity in human tumour xenograft mouse models of chemotherapy. The fluorescent nanoparticles assembled in situ were imaged successfully in both apoptotic cells and tumour tissues using three-dimensional structured illumination microscopy. This strategy combines the advantages offered by small molecules with those of nanomaterials and should find widespread use for non-invasive imaging of enzyme activity in vivo. [ABSTRACT FROM AUTHOR]

Abstract: With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC50 values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t 1/2) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents. [Copyright &y& Elsevier]

Multimodal imaging, which harnesses two or more imaging modalities to produce complementary anatomical and molecular information of a living subject, has become as a powerful tool in both basic biomedical research and clinical diagnosis. The progresses in multimodal imaging are paralleled by the advances in multimodal probes, particularly activatable multimodal imaging probes that can generate concurrent switches in different imaging modality signals upon interaction with a molecular target. These probes are extremely promising for in vivo imaging. In this Minireview, we summarize the recent progress in activatable multimodal probes for in vivo imaging and cancer theranostics, focusing on their design principle, signal activation mechanism and biomedical applications. The current challenges and perspectives for future developments of activatable multimodal probes are also briefly discussed. We hope that this Minireview will provide inspiration for the design of other activatable multimodal probes for improving in vivo imaging and theranostics. [ABSTRACT FROM AUTHOR]

Multimodal imaging, which harnesses two or more imaging modalities to produce complementary anatomical and molecular information of a living subject, has become as a powerful tool in both basic biomedical research and clinical diagnosis. The progresses in multimodal imaging are paralleled by the advances in multimodal probes, particularly activatable multimodal imaging probes that can generate concurrent switches in different imaging modality signals upon interaction with a molecular target. These probes are extremely promising for in vivo imaging. In this Minireview, we summarize the recent progress in activatable multimodal probes for in vivo imaging and cancer theranostics, focusing on their design principle, signal activation mechanism and biomedical applications. The current challenges and perspectives for future developments of activatable multimodal probes are also briefly discussed. We hope that this Minireview will provide inspiration for the design of other activatable multimodal probes for improving in vivo imaging and theranostics. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel thiophene derivatives was designed, synthesized and their activities as competitive inhibitors of protein tyrosine phosphatase (PTPs) 1B (PTP1B) inhibitors were evaluated. All the compounds showed inhibitory potencies, and 10 of these exhibited moderate inhibitory activities with IC50 values less than 10μM. The activity of the most potent compound P28 (IC50 =2.1μM) was 15 times higher than that of the hit compound P01. Further, four representative compounds (P19, P22, P28, and P31) demonstrated remarkably high selectivities against other PTPs (e.g., PTPα, LAR, CD45, and TCPTP); P19 exhibited greater than sixfold selectivity over highly homologous TCPTP. More importantly, these compounds are permeable to cell membranes. The treatment of CHO-K1 cells with P28 (10μM) resulted in increased phosphorylation of AKT, which suggested extensive cellular activity of this compound. The novel chemical entities reported in this study could be used for overcoming the poor selectivity and low cellular activity of PTP1B inhibitors and might represent a starting point for development of therapeutic PTP inhibitors. [Copyright &y& Elsevier]

We described a synthesis method by first using chlorotrimethylsilane as the activator to brominate the Ni(II) complex of the β-alanine Schiff's base [β-AlaNi(II)PABA] 1 and developed it to prepare β-amino acids 5. The procedure involves a Suzuki coupling reaction between boric acids and the bromoenone 2, followed by hydrogenation and hydrolysis. This is the first report of the application of the Ni (II) complex [β-AlaNi(II)PABA], which represents an attractive route to afford a-aryl-/heteroaryl-substituted β-amino acids. [ABSTRACT FROM AUTHOR]

Abstract: The non-proteinogenic amino acid (2S)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid [(S)-1] is a key intermediate required for the synthesis of Denagliptin (2a). Denagliptin is a dipeptidyl peptidase IV (DPP IV) inhibitor that is being developed for the treatment of type-2 diabetes mellitus. A diastereoselective, cost-efficient synthetic procedure for (S)-1 was developed by alkylating a Ni(II) glycine equivalent derived from (S)-2-[(N-benzylprolyl) amino] benzophenone [(S)-BPB]. The alkylated product was then decomposed to isolate the target amino acid (S)-1 (ee >99%) and ligand (S)-BPB, which can be reused in subsequent reactions. The enantiomer (R)-1 and racemate (rac)-1 were synthesized from their corresponding Ni(II) glycine equivalents. Denagliptin diastereomers (2), derived from the key intermediates (S)-1, (R)-1, and (rac)-1 were synthesized, and their dipeptidyl peptidase IV inhibitory activities were investigated. These findings are important in the design and synthesis of DPP IV inhibitors. [Copyright &y& Elsevier]

Abstract: A simultaneous stereoselective 2-O-deacetylation and 4-amination reaction of peracetylated Neu5Ac 1 has been established with cyclic secondary amines, such as 1-N-Boc-piperazine. Four C 2-symmetric and two asymmetric sialic acid dimers with (4→4)-piperazine derivatives linked were synthesized. They may serve as precursors of unnatural polysialic acids. [Copyright &y& Elsevier]

The treatment of α-haloketones with 1.5 equiv. of Zn and 1 equiv. of NH4Cl in ethanol for 0.5 min gave the corresponding ketones with excellent yields under microwave irradiation. Vic-dibromides and 2,2-dibromoacetophenone can be efficiently debrominated to alkenes and acetophenones, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Treatment of methyl 5-acetamido-2,4,7,8,9-penta-O-acetyl-3,5-dideoxy-β-l-glycero-d-galacto-2-nonulopyranosidonate (1) with cyclic secondary amines in pyridine at room temperature for 24h afforded unusual products (2a–g). Related experiments were carried out to explain the formation of 4-amination and 2-O-deacetylation of peracetylated sialic acid derivatives (2a–g). This reaction may provide a new strategy for the preparation of Zanamivir analogues as neuraminidase inhibitors for anti-H5N1 subtype of avian influenza virus (AIV). [Copyright &y& Elsevier]

The treatment of aryl acyloin (α-hydroxyketone) O-alkyl and O-phenyl derivatives with 2–3 equiv of Zn and 1–2 equiv of NH4Cl in ethanol, refluxing for 20–120 min, gave the corresponding ketones with excellent yields. Further, α,β-epoxy ketones can be efficiently transformed to β-hydroxy ketones, and 2,2-dialkoxy-1-phenyl ketone also can be dealkoxylated to 1-phenyl ketone. [ABSTRACT FROM AUTHOR]

Single‐atom nanozymes (SAzymes) with atomically dispersed active sites are potential substitutes for natural enzymes. A systematic study of its multiple functions can in‐depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding‐embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu‐C3 coordinated configuration. To enhance the tumor‐specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off‐target toxicity but also possesses exceptional ultrahigh catalase‐, oxidase‐, peroxidase‐like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO′s remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme‐like behavior and physiological mechanism of action of SAzymes. [ABSTRACT FROM AUTHOR]

Single‐atom nanozymes (SAzymes) with atomically dispersed active sites are potential substitutes for natural enzymes. A systematic study of its multiple functions can in‐depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding‐embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu‐C3 coordinated configuration. To enhance the tumor‐specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off‐target toxicity but also possesses exceptional ultrahigh catalase‐, oxidase‐, peroxidase‐like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO′s remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme‐like behavior and physiological mechanism of action of SAzymes. [ABSTRACT FROM AUTHOR]

Ratiometric afterglow luminescent (AGL) probes are attractive for in vivo imaging due to their high sensitivity and signal self‐calibration function. However, there are currently few ratiometric AGL probes available for imaging enzymatic activity in living organisms. Here, we present an energy diversion (ED) strategy that enables the design of an enzyme‐activated ratiometric AGL probe (RAG‐RGD) for in vivo afterglow imaging. The ED process provides RAG‐RGD with a radiative transition for an 'always on' 520‐nm AGL signal (AGL520) and a cascade three‐step energy transfer (ET) process for an 'off‐on' 710‐nm AGL signal (AGL710) in response to a specific enzyme. Using matrix metalloproteinase‐2 (MMP‐2) as an example, RAG‐RGD shows a significant ~11‐fold increase in AGL710/AGL520 toward MMP‐2. This can sensitively detect U87MG brain tumors through ratiometric afterglow imaging of MMP‐2 activity, with a high signal‐to‐background ratio and deep imaging depth. Furthermore, by utilizing the self‐calibration effect of ratiometric imaging, RAG‐RGD demonstrated a strong negative correlation between the AGL710/AGL520 value and the size of orthotopic U87MG tumor, enabling accurate monitoring of orthotopic glioma growth in vivo. This ED process may be applied for the design of other enzyme‐activated ratiometric afterglow probes for sensitive afterglow imaging. [ABSTRACT FROM AUTHOR]

Ratiometric afterglow luminescent (AGL) probes are attractive for in vivo imaging due to their high sensitivity and signal self‐calibration function. However, there are currently few ratiometric AGL probes available for imaging enzymatic activity in living organisms. Here, we present an energy diversion (ED) strategy that enables the design of an enzyme‐activated ratiometric AGL probe (RAG‐RGD) for in vivo afterglow imaging. The ED process provides RAG‐RGD with a radiative transition for an 'always on' 520‐nm AGL signal (AGL520) and a cascade three‐step energy transfer (ET) process for an 'off‐on' 710‐nm AGL signal (AGL710) in response to a specific enzyme. Using matrix metalloproteinase‐2 (MMP‐2) as an example, RAG‐RGD shows a significant ~11‐fold increase in AGL710/AGL520 toward MMP‐2. This can sensitively detect U87MG brain tumors through ratiometric afterglow imaging of MMP‐2 activity, with a high signal‐to‐background ratio and deep imaging depth. Furthermore, by utilizing the self‐calibration effect of ratiometric imaging, RAG‐RGD demonstrated a strong negative correlation between the AGL710/AGL520 value and the size of orthotopic U87MG tumor, enabling accurate monitoring of orthotopic glioma growth in vivo. This ED process may be applied for the design of other enzyme‐activated ratiometric afterglow probes for sensitive afterglow imaging. [ABSTRACT FROM AUTHOR]

An efficient approach to the dehydrative sialylation of various substrates with C-4-aminated sialyl-hemiketal donors by using the reagent combination of diphenyl sulfoxide and triflic anhydride is reported. By using a C-4-hindered non-nucleophilic amine auxiliary, excellent yields and high a-stereoselectivities were obtained for coupling with a wide range of primary and secondary acceptors. [ABSTRACT FROM AUTHOR]

We report here a tumor‐pretargted theranostic approach for multimodality imaging‐guided synergistic cancer PDT by cascade alkaline phosphatase (ALP)‐mediated in situ self‐assembly and bioorthogonal inverse electron demand Diels–Alder (IEDDA) reaction. Using the enzymatic catalysis of ALP that continuously catalyses the dephosphorylation and self‐assembly of trans‐cyclooctene (TCO)‐bearing P‐FFGd‐TCO, a high density of fluorescent and magnetic TCO‐containing nanoparticles (FMNPs‐TCO) can be synthesized and retained on the membrane of tumor cells. They can act as 'artificial antigens' amenable to concurrently capture lately administrated tetrazine (Tz)‐decorated PS (775NP‐Tz) and carbonic anhydrase (CA) inhibitor (SA‐Tz) via the fast IEDDA reaction. This two‐step pretargeting process can further induce FMNPs‐TCO regrowth into microparticles (FMNPs‐775/SA) directly on tumor cell membranes, which is analyzed by bio‐SEM and fluorescence imaging. Thus, efficient enrichment of both SA‐Tz and 775NP‐Tz in tumors can be achieved, allowing to alleviate hypoxia by continuously inhibiting CA activity and improving PDT of tumors. Findings show that subcutaneous HeLa tumors could be completely eradicated and no tumor recurred after irradiation with an 808 nm laser (0.33 W cm−2, 10 min). This pretargeted approach may be applied to enrich other therapeutic agents in tumors to improve targeted therapy. [ABSTRACT FROM AUTHOR]

We report here a tumor‐pretargted theranostic approach for multimodality imaging‐guided synergistic cancer PDT by cascade alkaline phosphatase (ALP)‐mediated in situ self‐assembly and bioorthogonal inverse electron demand Diels–Alder (IEDDA) reaction. Using the enzymatic catalysis of ALP that continuously catalyses the dephosphorylation and self‐assembly of trans‐cyclooctene (TCO)‐bearing P‐FFGd‐TCO, a high density of fluorescent and magnetic TCO‐containing nanoparticles (FMNPs‐TCO) can be synthesized and retained on the membrane of tumor cells. They can act as 'artificial antigens' amenable to concurrently capture lately administrated tetrazine (Tz)‐decorated PS (775NP‐Tz) and carbonic anhydrase (CA) inhibitor (SA‐Tz) via the fast IEDDA reaction. This two‐step pretargeting process can further induce FMNPs‐TCO regrowth into microparticles (FMNPs‐775/SA) directly on tumor cell membranes, which is analyzed by bio‐SEM and fluorescence imaging. Thus, efficient enrichment of both SA‐Tz and 775NP‐Tz in tumors can be achieved, allowing to alleviate hypoxia by continuously inhibiting CA activity and improving PDT of tumors. Findings show that subcutaneous HeLa tumors could be completely eradicated and no tumor recurred after irradiation with an 808 nm laser (0.33 W cm−2, 10 min). This pretargeted approach may be applied to enrich other therapeutic agents in tumors to improve targeted therapy. [ABSTRACT FROM AUTHOR]

Tumor‐targeted and stimuli‐activatable nanosensitizers are highly desirable for cancer theranostics. However, designing smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor‐targeted and redox‐activatable nanosensitizers (1‐NPs) for sono‐photodynamic immunotherapy of tumors by molecular co‐assembly and redox‐controlled disassembly. 1‐NPs show a high longitudinal relaxivity (r1=18.7±0.3 mM−1 s−1), but "off" dual fluorescence (FL) emission (at 547 and 672 nm), "off" sono‐photodynamic therapy and indoleamine 2,3‐dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1‐NPs rapidly disassemble and remotely release small molecules 2‐Gd, Zn‐PPA‐SH and NLG919, concurrently switching on (1) dual FL emission, (2) sono‐photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1‐NPs are effective for bimodal FL and magnetic resonance (MR) imaging‐guided sono‐photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671‐nm laser irradiation. [ABSTRACT FROM AUTHOR]

Tumor‐targeted and stimuli‐activatable nanosensitizers are highly desirable for cancer theranostics. However, designing smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor‐targeted and redox‐activatable nanosensitizers (1‐NPs) for sono‐photodynamic immunotherapy of tumors by molecular co‐assembly and redox‐controlled disassembly. 1‐NPs show a high longitudinal relaxivity (r1=18.7±0.3 mM−1 s−1), but "off" dual fluorescence (FL) emission (at 547 and 672 nm), "off" sono‐photodynamic therapy and indoleamine 2,3‐dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1‐NPs rapidly disassemble and remotely release small molecules 2‐Gd, Zn‐PPA‐SH and NLG919, concurrently switching on (1) dual FL emission, (2) sono‐photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1‐NPs are effective for bimodal FL and magnetic resonance (MR) imaging‐guided sono‐photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671‐nm laser irradiation. [ABSTRACT FROM AUTHOR]

Review: 96 refs. [ABSTRACT FROM AUTHOR]

Two-photon excitation (TPE) nanoparticle-based photosensitizers (PSs) that combine the advantages of TPE and nanotechnology have emerged as attractive therapeutic agents for near-infrared red (NIR) light excited photodynamic therapy (PDT) for cancer treatment. TPE PDT is characterized by nonlinear absorption of two relatively low-energy photons of NIR light with the resulting emission of high-energy visible light. This high-energy light can sensitize oxygen to produce cytotoxic reactive oxygen species (ROS) and singlet oxygen (1O2) which can kill cancer cells. The long-wavelength light used to excite TPE NPs allows for deeper tissue penetration to achieve efficient PDT of deep-seated tumors. Moreover, TPE nanoparticles normally have large two-photon absorption (TPA) cross-sections, which hold great potential as efficient two-photon donors in PDT. In this review, we will summarize the recent advances made in the development of TPE nanoparticles for cancer PDT. Five different TPE nanoparticles, including quantum dots (QDs), carbon nanomaterials, silica nanoparticles, gold nanomaterials, and polymer nanoparticles, are summarized in detail, and the existing challenges as well as the future perspectives are also discussed. [ABSTRACT FROM AUTHOR]

10,11‐Bis[bis(4‐dimethylaminophenyl)methylene]dibenzo[bf]thiepin (1) and ‐oxepin (2) were prepared as stable yellow crystalline compounds, which are the cyclic analogues of electron‐donating hexaarylbutadienes. Upon two‐electron oxidation, they are reversibly transformed into the title dications (12+ and 22+) exhibiting near‐infrared (NIR) absorptions, which were also isolated as stable salts. These redox pairs can serve as new entries into less well‐explored organic NIR‐electrochromic systems, and the separation of redox peaks (electrochemical bistability) was attained for 1/12+ and 2/22+, thanks to drastic geometrical changes between neutral and dicationic states, as revealed by a series of X‐ray analyses. Thiepin‐S,S‐dioxide analogue (3/32+) exhibits quite similar dynamic redox behavior due to nonaromatic nature of the dibenzothiepin and ‐oxepin unit in 12+ and 22+, whereas the thiepin‐S‐oxide derivative (4/42+) does not exhibit bistability due to the smaller change in geometry upon electron transfer, showing that a subtle change of a bridging atom in the central seven‐membered ring can modify the redox properties. [ABSTRACT FROM AUTHOR]

Reversible imaging probes that allow for the dynamic visualization of the redox cycle between hydroxyl radical (⋅OH) and hydrogen sulfide (H2S) are vital to probe the redox imbalance‐involved pathological process in vivo. Herein, we report a reversible ratiometric photoacoustic (PA) imaging nanoprobe (1‐PAIN) for the real‐time imaging of ⋅OH/H2S redox cycle in vivo. 1‐PAIN displays a low PA ratio between 690 and 825 nm (PA690/PA825), which significantly increases by ≈5‐fold upon oxidation by ⋅OH, and is switched back to the initially low PA690/PA825 value upon reduction by H2S. 1‐PAIN could dynamically report on the hepatic ⋅OH production in mice during the lipopolysaccharide (LPS)‐induced liver inflammation process, and visualize hepatic H2S generation during the N‐acetyl cysteine (NAC)‐induced anti‐inflammation process. 1‐PAIN can act as a useful tool to probe the redox state in living biology, beneficial for the study of redox imbalance‐related diseases. [ABSTRACT FROM AUTHOR]

Reversible imaging probes that allow for the dynamic visualization of the redox cycle between hydroxyl radical (⋅OH) and hydrogen sulfide (H2S) are vital to probe the redox imbalance‐involved pathological process in vivo. Herein, we report a reversible ratiometric photoacoustic (PA) imaging nanoprobe (1‐PAIN) for the real‐time imaging of ⋅OH/H2S redox cycle in vivo. 1‐PAIN displays a low PA ratio between 690 and 825 nm (PA690/PA825), which significantly increases by ≈5‐fold upon oxidation by ⋅OH, and is switched back to the initially low PA690/PA825 value upon reduction by H2S. 1‐PAIN could dynamically report on the hepatic ⋅OH production in mice during the lipopolysaccharide (LPS)‐induced liver inflammation process, and visualize hepatic H2S generation during the N‐acetyl cysteine (NAC)‐induced anti‐inflammation process. 1‐PAIN can act as a useful tool to probe the redox state in living biology, beneficial for the study of redox imbalance‐related diseases. [ABSTRACT FROM AUTHOR]

Over the past decades, the pretargeted strategy has emerged as a promising approach to improve delivery of nucleotides into tumor tissues for nuclear imaging and/or therapy. Unlike conventional nuclear imaging and therapy, in which a radiolabeled tumor targeting vector (e. g. antibody) is directly administered and allowed to circulate and accumulate in the tumor tissues, the pretargeted strategy decouples the radiolabeled reporters with the targeting vectors; these two components could specifically couple through either covalent or noncovalent interactions in vivo. Such a two‐step pretargeted approach holds a flexibility to optimize the pharmacokinetics of targeting vectors and radioactive reporters independently, facilitating to improved imaging contrast. Moreover, the short‐lived radioisotopes (e. g. 18F, 68Ga) can be used with an antibody of a nanoparticle that generally holds a long blood circulation time, which could be helpful to reduce the radiation burden for patients. In this Review, we summarize the recent advances in pretargeted strategies for tumor imaging, with a focus on the discussion of engineering different targeting vectors for tumor pretargeting. Different in vivo coupling approaches for pretargeted imaging of tumors are also discussed. Finally, we discuss the outlook for the potential clinical translation and the current challenges in the pretargeted imaging approach. [ABSTRACT FROM AUTHOR]

Enzyme‐triggered macrocyclization and in situ self‐assembly of small molecules into nanoparticles has shown promise to design activatable probes for molecular imaging. However, controlling macrocyclization and self‐assembly to concurrently augment positron emission tomography (PET) and photoacoustic (PA) signals for bimodality imaging is challenging. Herein, we report the engineering of a triazole‐IR780 fluorophore as a versatile macrocyclization scaffold for controlling in situ self‐assembly and design a caspase‐3‐activatable PA/PET bimodal probe ([18F]‐IR780‐1) for in vivo imaging of tumor apoptosis. By leveraging the high‐sensitivity whole‐body imaging signals offered by PET with the high‐resolution imaging signals offered by PA, [18F]‐IR780‐1 can provide a promising tool for the early evaluation of antitumor efficacy, helpful for optimizing the therapeutic protocol for patients. This scaffold may be adopted to design other activatable bimodal probes for in vivo imaging. [ABSTRACT FROM AUTHOR]

Enzyme‐triggered macrocyclization and in situ self‐assembly of small molecules into nanoparticles has shown promise to design activatable probes for molecular imaging. However, controlling macrocyclization and self‐assembly to concurrently augment positron emission tomography (PET) and photoacoustic (PA) signals for bimodality imaging is challenging. Herein, we report the engineering of a triazole‐IR780 fluorophore as a versatile macrocyclization scaffold for controlling in situ self‐assembly and design a caspase‐3‐activatable PA/PET bimodal probe ([18F]‐IR780‐1) for in vivo imaging of tumor apoptosis. By leveraging the high‐sensitivity whole‐body imaging signals offered by PET with the high‐resolution imaging signals offered by PA, [18F]‐IR780‐1 can provide a promising tool for the early evaluation of antitumor efficacy, helpful for optimizing the therapeutic protocol for patients. This scaffold may be adopted to design other activatable bimodal probes for in vivo imaging. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) is an important endogenous gasotransmitter, but the targeted delivery and real‐time feedback of exogenous H2S are still challenging. With the aid of density functional theory (DFT) calculations, we designed a new 1,3‐dithiolium‐4‐olate (DTO) compound, which can react with a strained alkyne via the 1,3‐dipolar cycloaddition and the retro‐Diels–Alder reaction to generate carbonyl sulfide (COS) as the precursor of H2S, and a thiophene derivative with turn‐on fluorescence. Moreover, the diphenylamino substituent in DTO greatly increases the mitochondrial targeting of this H2S delivery system. Such a bioorthogonal click‐and‐release reaction has integrated three functions in one system for the first time: (1) in situ controllable H2S release, (2) concomitant fluorescence response, and (3) mitochondria‐targeted delivery. In addition, we investigated the mitochondrial membrane potential loss alleviation by using this system in H9c2 cells under oxidative stress. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) is an important endogenous gasotransmitter, but the targeted delivery and real‐time feedback of exogenous H2S are still challenging. With the aid of density functional theory (DFT) calculations, we designed a new 1,3‐dithiolium‐4‐olate (DTO) compound, which can react with a strained alkyne via the 1,3‐dipolar cycloaddition and the retro‐Diels–Alder reaction to generate carbonyl sulfide (COS) as the precursor of H2S, and a thiophene derivative with turn‐on fluorescence. Moreover, the diphenylamino substituent in DTO greatly increases the mitochondrial targeting of this H2S delivery system. Such a bioorthogonal click‐and‐release reaction has integrated three functions in one system for the first time: (1) in situ controllable H2S release, (2) concomitant fluorescence response, and (3) mitochondria‐targeted delivery. In addition, we investigated the mitochondrial membrane potential loss alleviation by using this system in H9c2 cells under oxidative stress. [ABSTRACT FROM AUTHOR]

Optically active organic nanoparticles capable of emitting strong near-infrared II (NIR-II) fluorescence and eliciting tumor hyperthermia are promising for tumor imaging and photothermal therapy (PTT). However, their applications for the treatment of pancreatic tumors via mere PTT are challenging as both the nanoparticles and light are hard to enter the deeply located pancreatic tumors. Here, we report a NIR-II light excitable, carbonic anhydrase (CA)-targeting cisplatin prodrug-decorated nanoparticle (IRNPs-SBA/PtIV) for NIR-II fluorescence imaging (FLI)-guided combination PTT and chemotherapy of pancreatic tumors. IRNPs-SBA/PtIV is designed to hold a high photothermal conversion efficiency (PCE ≈ 65.17 %) under 1064 nm laser excitation, a strong affinity toward CA (K d = 14.40 ± 5.49 nM), and a prominent cisplatin release profile in response to glutathione (GSH) and 1064 nm laser irradiation. We show that IRNPs-SBA/PtIV can be actively delivered into pancreatic tumors where the CA is upregulated, and emits NIR-II fluorescence to visualize tumors with a high sensitivity and penetration depth under 980 nm laser excitation. Moreover, the tumor-resided IRNPs-SBA/PtIV can efficiently inhibit the CA activity and consequently, relieve the acidic and hypoxic tumor microenvironment, benefiting to intensify chemotherapy. Guided by the NIR-II FLI, IRNPs-SBA/PtIV is capable of efficiently inhibiting pancreatic tumor growth via combinational PTT and chemotherapy with 1064 nm laser excitation under a low-power density (0.5 W cm−2, 10 min). This study demonstrates promise to fabricate NIR-II excitable nanoparticles for FLI-guided precise theranostics of pancreatic tumors. A carbonic anhydrase-targeted NIR-II fluorescent cisplatin theranostic nanoparticle is reported, allowing to target hypoxic pancreatic tumor cells and release cisplatin for NIR-II fluorescence imaging-guided PTT and chemotherapy (Rx) of pancreatic tumors under low power 1064 nm laser irradiation. [Display omitted] [ABSTRACT FROM AUTHOR]

Accurate detection of hepatic hydrogen sulfide (H2S) to monitor H2S‐related enzymes' activity is critical for acute hepatitis diagnosis, but remains a challenge due to the dynamic and transient nature of H2S. Here, we report a H2S‐activatable near‐infrared afterglow/MRI bimodal probe F1‐GdNP, which shows an "always‐on" MRI signal and "off‐on" afterglow signal toward H2S. F1‐GdNP shows fast response, high sensitivity and specificity toward H2S, permitting afterglow imaging of H2S and evaluation of cystathionine γ‐lyase (CSE)'s activity in living mice. We further employ the high spatial‐resolution MRI signal of F1‐GdNP to track its delivery and accumulation in liver. Importantly, F1‐GdNP offers a high signal‐to‐background ratio (SBR=86.2±12.0) to sensitively report on the increased hepatic H2S level in the acute hepatitis mice via afterglow imaging, which correlated well with the upregulated CSE activity in the liver, showcasing the good potential of F1‐GdNP for monitoring of acute hepatitis process in vivo. [ABSTRACT FROM AUTHOR]

Accurate detection of hepatic hydrogen sulfide (H2S) to monitor H2S‐related enzymes' activity is critical for acute hepatitis diagnosis, but remains a challenge due to the dynamic and transient nature of H2S. Here, we report a H2S‐activatable near‐infrared afterglow/MRI bimodal probe F1‐GdNP, which shows an "always‐on" MRI signal and "off‐on" afterglow signal toward H2S. F1‐GdNP shows fast response, high sensitivity and specificity toward H2S, permitting afterglow imaging of H2S and evaluation of cystathionine γ‐lyase (CSE)'s activity in living mice. We further employ the high spatial‐resolution MRI signal of F1‐GdNP to track its delivery and accumulation in liver. Importantly, F1‐GdNP offers a high signal‐to‐background ratio (SBR=86.2±12.0) to sensitively report on the increased hepatic H2S level in the acute hepatitis mice via afterglow imaging, which correlated well with the upregulated CSE activity in the liver, showcasing the good potential of F1‐GdNP for monitoring of acute hepatitis process in vivo. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC50 =74μM). Selected compounds for concentration–response studies showed prominent inhibitory activities with IC50 values ranging from 0.74μM to 3.17μM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC50 values less than 1μM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases. [Copyright &y& Elsevier]

Pretargeted imaging has emerged as a promising approach to advance nuclear imaging of malignant tumors. Herein, we combine the enzyme‐mediated fluorogenic reaction and in situ self‐assembly with the inverse electron demand Diels–Alder (IEDDA) reaction to develop an activatable pretargeted strategy for multimodality imaging. The trans‐cyclooctene (TCO) bearing small‐molecule probe, P‐FFGd‐TCO, can be activated by alkaline phosphatase and in situ self‐assembles into nanoaggregates (FMNPs‐TCO) retained on the membranes, permitting to (1) amplify near‐infrared (NIR) fluorescence (FL) and magnetic resonance imaging (MRI) signals, and (2) enrich TCOs to promote IEDDA ligation. The Gallium‐68 (68Ga) labeled tetrazine can readily conjugate the tumor‐retained FMNPs‐TCO to enhance radioactivity uptake in tumors. Strong NIR FL, MRI, and positron emission tomography (PET) signals are concomitantly achieved, allowing for pretargeted multimodality imaging of ALP activity in HeLa tumor‐bearing mice. [ABSTRACT FROM AUTHOR]

Pretargeted imaging has emerged as a promising approach to advance nuclear imaging of malignant tumors. Herein, we combine the enzyme‐mediated fluorogenic reaction and in situ self‐assembly with the inverse electron demand Diels–Alder (IEDDA) reaction to develop an activatable pretargeted strategy for multimodality imaging. The trans‐cyclooctene (TCO) bearing small‐molecule probe, P‐FFGd‐TCO, can be activated by alkaline phosphatase and in situ self‐assembles into nanoaggregates (FMNPs‐TCO) retained on the membranes, permitting to (1) amplify near‐infrared (NIR) fluorescence (FL) and magnetic resonance imaging (MRI) signals, and (2) enrich TCOs to promote IEDDA ligation. The Gallium‐68 (68Ga) labeled tetrazine can readily conjugate the tumor‐retained FMNPs‐TCO to enhance radioactivity uptake in tumors. Strong NIR FL, MRI, and positron emission tomography (PET) signals are concomitantly achieved, allowing for pretargeted multimodality imaging of ALP activity in HeLa tumor‐bearing mice. [ABSTRACT FROM AUTHOR]

γ-Glutamyltranspeptidase (GGT) is an important aminopeptidase overexpressed in many malignant tumors, and accurate detection of its activity is useful for the diagnosis and treatment of tumors. Herein, we report a GGT-activatable ratiometric fluorescent probe (1) constructed by covalently linking an 'always-on' BODIPY fluorophore with a GGT-activatable near-infrared (NIR) fluorescent substrate. Upon interaction with GGT, the NIR fluorescence at 735 nm in probe 1 is significantly enhanced, while the fluorescence of BODIPY at 517 nm remains unchanged. Using BODIPY fluorescence as an internal standard, significantly enhanced ratiometric fluorescence between 735 nm and 517 nm could be achieved, allowing accurate detection of the activity of GGT in living subjects independent of probe concentration. We demonstrate that probe 1 is feasible for the evaluation of GGT levels in different tumor cells and differentiation of GGT-positive tumor cells from GGT-negative normal tissue cells. Moreover, probe 1 is further applied for the visualization of tumor via noninvasive ratiometric fluorescence imaging of GGT activity, which could facilitate the detection of GGT-positive tumor tissues and study of GGT-related pathological processes. [ABSTRACT FROM AUTHOR]

Stimuli‐responsive smart photosensitizer (PS) nanoassemblies that allow enhanced delivery and controlled release of PSs are promising for imaging‐guided photodynamic therapy (PDT) of tumors. However, the lack of high‐sensitivity and spatial‐resolution signals and fast washout of released PSs from tumor tissues have impeded PDT efficacy in vivo. Herein, we report tumor targeting, redox‐responsive magnetic and fluorogenic PS nanoassemblies (NP‐RGD) synthesized via self‐assembly of a cRGD‐ and disulfide‐containing fluorogenic and paramagnetic small molecule (1‐RGD) for fluorescence/magnetic resonance bimodal imaging‐guided tumor PDT. NP‐RGD show high r1 relaxivity but quenched fluorescence and PDT activity; disulfide reduction by glutathione (GSH) promotes efficient disassembly into a small‐molecule probe (2‐RGD) and an organic PS (PPa‐SH), which could further bind with intracellular albumin, allowing prolonged retention and cascade activation of fluorescence and PDT to ablate tumors. [ABSTRACT FROM AUTHOR]

Stimuli‐responsive smart photosensitizer (PS) nanoassemblies that allow enhanced delivery and controlled release of PSs are promising for imaging‐guided photodynamic therapy (PDT) of tumors. However, the lack of high‐sensitivity and spatial‐resolution signals and fast washout of released PSs from tumor tissues have impeded PDT efficacy in vivo. Herein, we report tumor targeting, redox‐responsive magnetic and fluorogenic PS nanoassemblies (NP‐RGD) synthesized via self‐assembly of a cRGD‐ and disulfide‐containing fluorogenic and paramagnetic small molecule (1‐RGD) for fluorescence/magnetic resonance bimodal imaging‐guided tumor PDT. NP‐RGD show high r1 relaxivity but quenched fluorescence and PDT activity; disulfide reduction by glutathione (GSH) promotes efficient disassembly into a small‐molecule probe (2‐RGD) and an organic PS (PPa‐SH), which could further bind with intracellular albumin, allowing prolonged retention and cascade activation of fluorescence and PDT to ablate tumors. [ABSTRACT FROM AUTHOR]

When the 1,1,4,4‐tetraanilinobutadiene skeleton is attached with two halogenated aryl units at the 2,3‐positions, they undergo facile two‐electron oxidation to give stable dicationic dyes which exhibit a near‐infrared (NIR) absorption whereas the neutral dienes show only pale color. Therefore, a distinct electrochromic response with an absorption change in the NIR region is achieved, which is attracting considerable recent attention from the viewpoint of bioimaging. Herein, we demonstrate that the redox potentials of the 1,1,4,4‐tetraanilinobutadiene can be precisely controlled by the donating properties of the amino group on the aniline unit as well as the number of halogen atoms on the aryl units at 2,3‐positions on the butadiene. In contrast, the NIR absorption bands mainly depend on the number of halogen atoms irrespective to the donating properties of aniline unit. Thus, the hexaarylbutadiene skeleton is proven to be a versatile scaffold to develop less‐explored organic NIR electrochromic materials, whose redox and spectroscopic properties can be finely tuned by modifying/attaching the proper substituents. [ABSTRACT FROM AUTHOR]

Photoacoustic (PA) imaging shows promise in the sensitive detection of caspase‐3 activated in early tumor apoptosis in response to chemotherapy; smart PA probes are thus in high demand. Herein, we report the first smart PA probe (1‐RGD) responsive to caspase‐3, enabling real‐time and high‐resolution imaging of tumor apoptosis. 1‐RGD is designed to leverage the synergetic effect of active delivery and caspase‐3 activation. It is selectively recognized by active caspase‐3 to trigger peptide substrate cleavage and biocompatible macrocyclization‐mediated self‐assembly, leading to an amplified PA imaging signal and prolonged retention in apoptotic tumor cells. Strong, high‐resolution PA images are obtained in chemotherapy‐induced apoptotic tumors in living mice after intravenous administration with 1‐RGD, facilitating sensitive reporting of caspase‐3 activity and distribution within tumor tissues. Good vibrations: The caspase‐3‐mediated biocompatible macrocyclization and self‐assembly of a photoacoustic (PA) probe, 1‐RGD, into indocyanine green (ICG)‐containing nanoparticles is reported. The probe allows the enhancement of PA imaging signals for the real‐time detection of tumor apoptosis in living mice with high sensitivity and spatial resolution. [ABSTRACT FROM AUTHOR]

Abstract: Selective imaging and inducing mitochondrial dysfunction in tumor cells using mitochondria‐targeting probes has become as a promising approach for cancer diagnosis and therapy. Here, we report the design of a fluorescent berberine analog, dehydroberberine (DH‐BBR), as a new mitochondria‐targeting probe capable of self‐assembling into monodisperse organic nanoparticles (DTNPs) upon integration with a lipophilic counter anion, allowing for enhanced fluorescence imaging and treatment of tumors in living mice. X‐ray crystallography revealed that the self‐assembly process was attributed to a synergy of different molecular interactions, including π–π stacking, O⋅⋅⋅π interaction and electrostatic interaction between DH‐BBR and counter anions. We demonstrated that DTNPs could efficiently enter tumor tissue following intravenous injection and enhance mitochondrial delivery of DH‐BBR via an electrostatic interaction driven anion exchange process. Selective accumulation in the mitochondria capable of emitting strong fluorescence and causing mitochondrial dysfunction was achieved, enabling efficient inhibition of tumor growth in living mice. This study demonstrates promise for applying lipophilic anions to control molecular self‐assembly and tune antitumor activity of mitochondria‐targeting probes, which can facilitate to improve cancer treatment in vivo. [ABSTRACT FROM AUTHOR]

RNA interference (RNAi) has become an appealing therapeutic approach for cancer and other diseases. One key challenge is the effective protection of these small fragile biomolecules against complicated physiological environments as well as efficient on-demand release. Here we design a photo-tearable polymer tape close-wrapped nanocapsule for efficient NIR modulated siRNA delivery. The photo-tearable nanocapsules comprise core-shell upconversion nanoparticles (UCNPs) coated with mesoporous silica layer for loading of photosensitizer hypocrellin A (HA) and small interfering RNA (siRNA) against polo-like kinase 1 (PLK1), and covalently bound thin membranes of polyethylene glycol (PEG) via a synthesized photocleavable linker (PhL). Upon irradiation at 980 nm, the UCNPs produce UV emissions to break PhL and tear out PEG membrane for siRNA release, and blue emissions to activate HA for generating reactive oxygen species (ROS). The close PEG membrane wrapping not only guarantees the efficient intracellular photocleavage, but also extends the circulation time and protects the loaded cargos from leakage and degradation. The ROS assists endosomal escape of the loaded cargos, therefore effectively improves the gene silencing efficiency and the suppressions of cell proliferation in vitro and tumor growth in vivo. The proposed photo-tearable tape-wrapped nanocapsules have promising potential application in precision medicine. [ABSTRACT FROM AUTHOR]

Abstract: Biocompatible reactions have emerged as versatile tools to build various molecular imaging probes that hold great promise for the detection of biological processes in vitro and/or in vivo. In this Minireview, we describe the recent advances in the development of a firefly luciferin‐inspired biocompatible reaction between cyanobenzothiazole (CBT) and cysteine (Cys), and highlight its versatility to label proteins and build multimodality molecular imaging probes. The review starts from the general introduction of biocompatible reactions, which is followed by briefly describing the development of the firefly luciferin‐inspired biocompatible chemistry. We then discuss its applications for the specific protein labeling and for the development of multimodality imaging probes (fluorescence, bioluminescence, MRI, PET, photoacoustic, etc.) that enable high sensitivity and spatial resolution imaging of redox environment, furin and caspase‐3/7 activity in living cells and mice. Finally, we offer the conclusions and our perspective on the various and potential applications of this reaction. We hope that this review will contribute to the research of biocompatible reactions for their versatile applications in protein labeling and molecular imaging. [ABSTRACT FROM AUTHOR]

Targeted delivery of intracellular stimuli-activatable photosensitizers (PSs) into tumor cells to achieve selective imaging and on-demand photodynamic therapy (PDT) of tumors has provided a vital opportunity for precise cancer diagnosis and therapy. In this paper, we report a tumor targeting and adenosine triphosphate (ATP)-activatable nanophotosensitizer Apt-HyNP/ BHQ2 by modifying hybrid micellar nanoparticles with both nucleolin-targeting aptamer AS1411 and quencher BHQj-labeled ATP-binding aptamer BHQ2-ATP-apt. We demonstrated that both of the fluorescence emissions at 555 and 627 nm were quenched by BHQ2 in Apt-HyNP/BHQ2, resulting in low PDT capacity. After selective entry into tumor cells through nucleolin-mediated endocytosis, the high concentration of intracellular ATP could bind to BHQj-ATP-apt and trigger Apt-HyNP/BHQ dissociation, leading to turning "on" both fluorescence and PDT. The "off-on" fluorescence emissions at both 555 and 627 nm were successfully applied for dual color fluorescence imaging of endogenous ATP levels and real-time monitoring of intracellular activation of Apt-HyNP/BHQ2 in tumor cells. Moreover, imaging-guided precise PDT of tumors in living mice was also demonstrated, allowing for selective ablation of tumors without obvious side effects. This study highlights the potential of using a combination of tumor-targeting and ATP-binding aptamers to design ATP-activatable PSs for both fluorescence imaging and imaging-guided PDT of tumors in vivo. [ABSTRACT FROM AUTHOR]

Semiconductor quantum dots (QDs) have served as superior optically active nanomaterials for molecular imaging and photodynamic therapy (PDT), but the low singlet oxygen ( 1 O 2 ) quantum yield and lack of tumor selectivity have limited their applications for tumor PDT in vivo . Here, we report the rational engineering of QDs into tumor-targeting hybrid nanoparticles through micelle-encapsulating a pre-assembled unique QD-Zn-porphyrin complex, a highly fluorescent organic photosensitizer rhodamine 6G (R6G), and a near-infrared fluorophore NIR775 with folic acid labeled phospholipid polymers. These nanoparticles have large porphyrin payloads and strong light absorption capability, thus contributing to an extremely high 1 O 2 quantum yield (∼0.91) via an efficient dual energy transfer process. In vivo studies show that they can preferably accumulate in tumors through folate receptor-mediated active delivery, permitting non-invasive fluorescence imaging and effective PDT of tumors in living mice. This study highlights the utility of hybrid semiconductor QDs for both tumor imaging and PDT in vivo . [ABSTRACT FROM AUTHOR]

γ-Glutamyl transpeptidase (GGT) is a cell-membrane-bound enzyme that is involved in various physiological and pathological processes and is regarded as a potential biomarker for many malignant tumors, precise detection of which is useful for early cancer diagnosis. Herein, a new GGT-activatable near-infrared (NIR) fluorescence imaging probe (GANP) by linking of a GGT-recognitive substrate γ-glutamate (γ-Glu) and a NIR merocyanine fluorophore (mCy-Cl) with a self-immolative linker p-aminobenzyl alcohol (PABA) is reported. GANP was stable under physiological conditions, but could be efficiently activated by GGT to generate ≈100-fold enhanced fluorescence, enabling high sensitivity (detection limit of ≈3.6 mU L−1) and specificity for the real-time imaging of GGT activity as well as rapid evaluation of the inhibition efficacy of GGT inhibitors in living tumor cells. Notably, the deep tissue penetration ability of NIR fluorescence could further allow GANP to image GGT in frozen tumor tissue slices with large penetration depth (>100 μm) and in xenograft tumors in living mice. This GGT activatable NIR fluorescence imaging probe could facilitate the study and diagnosis of other GGT-correlated diseases in vivo. [ABSTRACT FROM AUTHOR]

Dual stimuli-responsive nanoparticles capable of fine-tuning drug release to augment therapeutic efficacy have become a promising tool for anticancer drug delivery. However, the rational design of these 'smart' nanoparticles for a selective delivery and controlled release of multidrug combinations in cancer cells to achieve synergistic effects remain challenging. Here we report the pH/redox dual responsive nanoparticle FA-DOX-Ind-NP (FA=folic acid, DOX=doxorubicin, Ind=indomethacin, NP=nanoparticle) based on the novel tumor targeting and biodegradable poly(β-amino ester) polymer, and demonstrate its high ability to enter into cancer cells and release a combination of the anticancer drug doxorubicin and the non-steroidal anti-inflammatory drug indomethacin to achieve synergistic chemo-anti-inflammatory effects and overcome multidrug resistance. This study highlights the great potential of tumor targeting and dual stimuli-responsive nanoparticles for an efficient delivery of multidrug combination to improve the cancer therapeutic efficacy. [ABSTRACT FROM AUTHOR]