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The fabrication of functional nanoparticles with unique ultra-sensitivity to endogenous tumor microenvironment (TME) is of great significance for their improved theranostic performance and easy excretion out of the body, which has not been realized among diverse nano-sized photothermal agents for photothermal therapy (PTT) of tumor. In this work, we report on the synthesis of 2D ultrathin MnO 2 nanosheets for highly efficient PTT against tumor with ultra-sensitivity to endogenous TME. These ultrathin 2D MnO 2 nanosheets show the intriguing characteristic of disintegration and releasing of Mn 2+ in response to the mild acidic condition and elevated reducing microenvironment of TME, which has successfully realized the pH- and reducing-responsive T 1 -weighted magnetic resonance imaging of tumor. Importantly, the high PTT efficiency of 2D MnO 2 nanosheets responsive to exogenous NIR irradiation has been systematically demonstrated both in vitro and in vivo for suppressing the tumor growth. This first report on the exploring of TME-sensitive photothermal agents with concurrent diagnostic and therapeutic (theranostic) functions significantly broadens the biomedical application of 2D functional biomaterials, which also promotes the further potential clinical translations of nano-sized photothermal agents. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) is one of the most widely used cancer treatments. However, the vigorous biosynthesis of cancer cells plays an important role for RT resistance. Herein, we develop a hafnium-based nanoscale metal-organic frameworks (Hf-nMOFs) loaded with 3-bromopyruvate (3-BrPA) to overcome RT resistance and achieve favorable RT efficacy. The deposition of X-rays is greatly enhanced by Hf-nMOFs to induce stronger damage to DNA in RT. Simultaneously, as an inhibitor of glycolysis, the loaded 3-BrPA can reduce the supply of energy and interfere with the biosynthesis of proteins to decrease the DNA damage repair. As a result, the 3-BrPA@Hf-nMOFs (BHT) will overcome the RT resistance and enhance the curative effect of RT. Up and down-regulated genes as well as the related pathways in cellular metabolism and biosynthesis are well investigated to reveal the radiosensitization mechanism of BHT. In addition, the Hf element endows BHT with CT imaging capability to real-timely monitor the therapeutic process. Hence, the designed strategy of biosynthesis-targeted radiosensitization could decrease the doses of ionizing radiations and provide fresh perspectives on cancer treatment. [ABSTRACT FROM AUTHOR]

The efficacy of radiotherapy has not yet achieved optimal results, partially due to insufficient priming and infiltration of effector immune cells within the tumor microenvironment (TME), which often exhibits suppressive phenotypes. In particular, the infiltration of X–C motif chemokine receptor 1 (XCR1)-expressing conventional type-1 dendritic cells (cDC1s), which are critical in priming CD8+ cytotoxic T cells, within the TME is noticeably restricted. Hence, we present a facile methodology for the efficient fabrication of a calcium phosphate hydrogel loaded with X–C motif chemokine ligand 1 (XCL1) to selectively recruit cDC1s. Manganese phosphate microparticles were also loaded into this hydrogel to reprogram the TME via cGAS-STING activation, thereby facilitating the priming of cDC1s propelled specific CD8+ T cells. They also polarize tumor-associated macrophages towards the M1 phenotype and reduce the proportion of regulatory cells, effectively reversing the immunosuppressive TME into an immune-active one. The yielded XCL1@CaMnP gel exhibits significant efficacy in enhancing the therapeutic outcomes of radiotherapy, particularly when concurrently administered with postoperative radiotherapy, resulting in an impressive 60 % complete response rate. Such XCL1@CaMnP gel, which recruits cDC1s to present tumor antigens generated in situ, holds great potential as a versatile platform for enhanced cancer treatment through modulating the immunosuppressive TME. [ABSTRACT FROM AUTHOR]

In clinics, therapeutic proteins are commonly used to treat retinal diseases through intraocular injection, the treatment which suffers from rather low patient compliance. Topical administration (e.g. eye-drops) of large molecule drugs remains a major challenge due to the presence of various barriers in the eye. In this study, zwitterion-grafted chitosan (CS-ZW) was developed and then self-assembled with protein therapeutics including adalimumab (ADA) or catalase (CAT) for the treatment of dry age-related macular degeneration (dAMD) via topical eyedrops. Since CS-ZW can cross the mucus layer and open the tight junctions between epithelial cells, their delivered therapeutic proteins can be shuttled across the ocular barriers to reach the diseased site in the fundus. CS-ZW/ADA eyedrops delivering ADA to bind TNF-α in the fundus achieved a similar therapeutic effect to intravitreal ADA injection in a mouse dAMD model. In addition, the therapeutic effect was further improved by combining eyedrop formulations of CS-ZW/ADA and CS-ZW/CAT, the latter of which can clear reactive oxygen species (ROS) in the lesion to further assist dAMD treatment. Our work provides a simple and effective delivery vehicle that can non-invasively treat fundus diseases such as dAMD, showing potential advantages in reducing side effects associated with intraocular injection and improving patient compliance. [ABSTRACT FROM AUTHOR]

Abstract: We report a new strategy of using carrier-free pure near-infrared (NIR) dye nanoparticles (NPs) to achieve highly luminescent NIR fluorescent probes for in vitro and in vivo imaging. Bis(4-(N-(2-naphthyl)phenylamino) phenyl)-fumaronitrile (NPAPF) NPs are shown to exhibit favorable biocompatibility, wide-range pH stability (pH 4–10) and much more superior photostability than conventional dyes. Importantly, the combined merits of high dye loading content and aggregation-induced emission enhancement properties, endow the NIR probes with high brightness and a high quantum yield up to 14.9%. The NPAPF NPs can be readily conjugated with folic acid for targeted in vitro cell imaging. Applications of the NPs probes in high efficiency in vivo and ex vivo imaging were successfully demonstrated. Intense fluorescent signals of NPAPF NPs can be distinctly, selectively and spatially resolved in tumor sites with ultrahigh sensitivity, even with 5 ms exposure time, due to the preferentially accumulation of NPs in tumor sites through passive enhanced permeability and retention effect. The totality of results clearly demonstrate the exciting potential of the functionalized NPAPF NPs as a NIR fluorescent probe for in vitro and in vivo imaging and diagnostics. [Copyright &y& Elsevier]

Abstract: Upconversion nanoparticles (UCNPs) with unique multi-photon excitation photoluminescence properties have recently been intensively explored as novel contrast agents for low-backgroundbiomedical imaging. In this work, we functionalize UCNPs with a polyethylene glycol (PEG) grafted amphiphilic polymer. The PEGylated UCNPs are loaded with a commonly used chemotherapy molecule, doxorubicin (DOX), by simple physical adsorption via a supramolecular chemistry approach for intracellular drug delivery. The loading and releasing of DOX from UCNPs are controlled by varying pH, with an increased drug dissociation rate in acidic environment, favorable for controlled drug release. Upconversion luminescence (UCL) imaging by a modified laser scanning confocal microscope reveals the time course of intracellular delivery of DOX by UCNPs. It is found that DOX is shuttled into cells by the UCNP nano carrier and released inside cells after endocytosis. By conjugating nanoparticles with folic acid, which targets folate receptors over expressed on various types of cancer cells, we further demonstrate targeted drug delivery and UCL cell imaging with UCNPs. Besides DOX, this non-covalent drug loading strategy can also be used for loading of photosensitizer molecules on UCNPs for potential near-infrared light induced photodynamic therapy. Our results suggest the promise of UCNPs as interesting nano carriers for multi-functional cancer therapy and imaging. [ABSTRACT FROM AUTHOR]

Treatment of acute bacterial meningitis is difficult due to the impermeability of the blood-brain barrier, greatly limiting the antibiotic concentrations that can be achieved in the brain. Escherichia coli grown in presence of iron-oxide magnetic nanoparticles secrete large amounts of magnetic outer-membrane vesicles (OMVs) in order to remove excess Fe from their cytoplasm. OMVs are fully biomimetic nanocarriers, but can be inflammatory. Here, non-inflammatory magnetic OMVs were prepared from an E. coli strain in which the synthesis of inflammatory lipid A acyltransferase was inhibited using CRISPR/Cas9 mediated gene knockout. OMVs were loaded with ceftriaxone (CRO) and meso-tetra-(4-carboxyphenyl)porphine (TCPP) and magnetically driven across the blood-brain barrier for sonodynamic treatment of bacterial meningitis. ROS-generation upon ultrasound application of CRO- and TCPP-loaded OMVs yielded similar ROS-generation as by TCPP in solution. In vitro , ROS-generation by CRO- and TCPP-loaded OMVs upon ultrasound application operated synergistically with CRO to kill a hard-to-kill, CRO-tolerant E. coli strain. In a mouse model of CRO-tolerant E. coli meningitis, CRO- and TCPP-loaded OMVs improved survival rates and clinical behavioral scores of infected mice after magnetic targeting and ultrasound application. Recurrence did not occur for at least two weeks after arresting treatment. [Display omitted] • Magnetically-harvested OMVs can be magnetically driven across the blood-brain barrier • Magnetic OMVs can be loaded with an antibiotic and a sonosensitizer • Antibiotics work synergistically in bacterial killing with sonodynamically generated ROS • Magnetic OMVs loaded with CRO and TCPP effectively cures murine, bacterial meningitis • Treatment with CRO-TCPP loaded OMVs delays recurrence of murine, bacterial meningitis [ABSTRACT FROM AUTHOR]

Abstract Cancer vaccines for prevention and treatment of tumors have attracted tremendous interests as a type of cancer immunotherapy strategy. A major challenge in achieving robust T-cell responses to destruct tumor cells after vaccination is the abilities of antigen cross-presentation for antigen-presenting cells (APCs) such as dendritic cells (DCs). Herein, we demonstrate that a polyamidoamine dendrimer modified with guanidinobenzoic acid (DGBA) could serve as an effective protein carrier to enable delivery of protein antigen, thereby leading to effective antigen cross-presentation by DCs. With ovalbumin (OVA) as the model antigen and unmethylated cytosine-guanine dinucleotides (CpG) as the adjuvant, a unique type of tumor vaccine is formulated. Importantly, such DGBA-OVA-CpG nanovaccine can induce robust antigen-specific cellular immunities and further demonstrates outstanding prophylactic efficacy against B16-OVA melanoma. More significantly, the nanovaccine shows excellent therapeutic effect to treat established B16-OVA melanoma when used in combination with the programmed cell death protein 1 (PD-1) checkpoint-blockade immunotherapy. This study presents the great promises of employing rationally engineered cytosolic protein carriers for the development of tumor vaccines to achieve effective cancer immunotherapy. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract The limited tumor specific uptake of nanoparticles is one of major bottlenecks for clinical translation of nanoscale therapeutics. Herein, we propose a strategy using internal radioisotope therapy (RIT) delivered by liposomal nanoparticles to improve the tumor vasculature permeability, so as to increase the tumor specific uptake of the second-wave therapeutic nanoparticles for enhanced cancer therapies. Via a convenient method, a therapeutic radioisotope iodine-131 is labeled onto albumin-encapsulated liposomes with greatly improved radiolabeling stability compared to 131I labeled albumin. The obtained 131I-liposome with long blood half-life could accumulate in the tumor and damage tumor blood endothelial cells to improve the tumor vascular permeability. As the result, the tumor retention of the second wave of liposomal nanoparticles could be greatly increased owing to the RIT-enhanced EPR effect. In three separated experiments, we then demonstrate that such strategy could be utilized for photothermal therapy (PTT), hypoxia-activated chemotherapy (HCT) and checkpoint blockade immunotherapy, all of which could be enhanced by RIT with excellent in vivo synergistic therapeutic outcomes. Our work highlights the great promises of employing nanoparticle-mediated RIT to modulate tumor vasculature for further enhanced cancer therapy, and may have potential value for clinical translation. [ABSTRACT FROM AUTHOR]

Tumor hypoxia is known to be one of critical factors that aggravate the tumor resistance to photodynamic therapy (PDT) in which oxygen is essential for tumor destruction. Herein, catalase, an enzyme to trigger hydrogen peroxide (H 2 O 2 ) decomposition, is modified by in-situ free radical polymerization, using meso-tetra( p -hydroxyphenyl) porphine (THPP) as the cross-linker to enable condensed grafting of short polyethylene glycol (PEG) chains on the protein surface as a permeable brush-like safeguard. The formulated catalase-entrapped nanocapsules (CAT-THPP-PEG) with enhanced enzyme stability can be labeled with 99m Tc 4+ , a radioisotope ion that is chelated by the porphyrin structure of THPP, to allow in vivo single-photon emission computed tomography (SPECT) imaging. It is found that such CAT-THPP-PEG nanoparticles exhibit efficient tumor passive retention after intravenous injection, and are able to greatly relieve tumor hypoxia by triggering the decomposition of tumor endogenous H 2 O 2 into oxygen. With THPP functioning as a photosensitizer, in vivo PDT is further conducted, achieving a remarkable antitumor therapeutic effect. This work presents an enzyme modification strategy by in-situ polymerization with photosensitizer as the cross-linker to develop multifunctional nano-theranostics with strengthened enzymatic stability, efficient tumor passive homing, SPECT imaging capability, enhanced PDT efficacy as well as decreased immunogenicity, promising for clinical translation. [ABSTRACT FROM AUTHOR]

Owing to the existence of severe tumor hypoxia and limited X-ray absorption of solid tumors, the therapeutic efficacy of radiotherapy is far from satisfactory. Herein, ultrasmall iridium nanocrystals (IrNCs) with homogeneous size distribution are successfully synthesized. The obtained IrNCs show catalase-like catalytic activity towards hydrogen peroxide (H 2 O 2 ) with great temperatures/pH stability. As free IrNCs are prone to be toxified by thiol-containing biomolecules, we encapsulate as-prepared IrNCs within stealth liposomal carriers, obtaining Ir@liposome with well-protected catalytic activity in physiological conditions. By utilizing its efficient photothermal conversion ability, such Ir@liposome shows effective near-infrared-(NIR)-responsive catalytic activity towards H 2 O 2 decomposition. As revealed by in vivo photoacoustic imaging, our Ir@liposome exhibits efficient passive tumor accumulation upon intravenous injection, and could efficiently decompose the tumor endogenous H 2 O 2 into O 2 , particularly upon exposure to the NIR laser. As the results of relieved tumor hypoxia after such treatment and the radiosensitization capability of Ir as a high-Z element, greatly enhanced radio-therapeutic efficacy with Ir@liposome is then achieved. This work thus presents a unique type of NIR light controllable theranostic nanozyme based on noble metal nanocrystals as a nanoscale radiosensitizer with great performance in enhancing cancer radiotherapy. [ABSTRACT FROM AUTHOR]

A variety of bioactive materials are currently developed to expand T cells ex vivo for adoptive T cell immunotherapy, also known as called artificial antigen-presenting cells (aAPCs). However, almost all the reported designs exhibit relatively smooth surface modified with T cell activating biomolecules, and therefore cannot well mimic the dendritic morphological characteristics of dendritic cells (DCs), the most important type of natural antigen-presenting cells (APCs) with high specific surface areas. Here, we propose a hydrophilic monomer-mediated surface morphology control strategy to synthesize biocompatible dendritic poly(N-isopropylacrylamide) (PNIPAM) microspheres for constructing aAPCs with surface morphology mimicking natural APCs (e.g., DCs). Interestingly, when maintaining the same ligands density, dendritic polymeric microspheres-based aAPCs (DPM beads) can more efficiently expand CD8+ T cells than that with smooth surfaces. Moreover, adoptive transfer of antigen-specific CD8+ T cells expanded by the DPM beads show significant antitumor effect of B16-OVA tumor bearing mice. Therefore, we provide a new concept for constructing biomimetic aAPCs with enhanced T cell expansion ability. [Display omitted] [ABSTRACT FROM AUTHOR]

Starvation therapy to slow down the tumor growth by cutting off its energy supply has been proposed to be an alternative therapeutic strategy for cancer treatment. Herein, glucose oxidase (GOx) is loaded into stealth liposomes and act as the glucose and oxygen elimination agent to trigger the conversion of glucose and oxygen into gluconic acid and H 2 O 2 . Such liposome-GOx after intravenous injection with effective tumor retention is able to exhaust glucose and oxygen within the tumor, producing cytotoxic H 2 O 2 and enhancing hypoxia, as vividly visualized by non-invasive in vivo photoacoustic imaging. By further combination treatment with stealth liposomes loaded with banoxantrone dihydrochloride (AQ4N), a hypoxia-activated pro-drug, a synergistically enhanced tumor growth inhibition effect is achieved in the mouse model of 4T1 tumor. Hence, by combining starvation therapy and hypoxia-activated therapy tactfully utilizing liposomal nanocarriers to co-deliver both enzymes and prodrugs, an innovative strategy is presented in this study for effective cancer treatment. [ABSTRACT FROM AUTHOR]

Nanoscale coordination polymers (NCPs) are promising nanomedicine platforms featured with biodegradability and versatile functionalities. However, multi-step post-synthesis surface modification is usually required to functionalize as-made NCPs before their biomedical applications. Moreover, efforts are still required to design therapeutic NCPs responsive to the unique tumor microenvironment to achieve more specific and effective therapy. Herein, we uncover a simple yet general strategy to synthesize a series of polyethylene glycol (PEG) modified NCPs via a one-step method by adding poly-histidine-PEG co-polymer into the mixture of metal ions and organic ligands during NCPs formation. With NCPs consisting Ca 2+ /dicarboxylic cisplatin (IV) prodrug as the example, we show that such Ca/Pt(IV)@pHis-PEG NCPs are highly sensitive to pH changes. With slightly negative charges and compact structure under pH 7.4 during blood circulation, those NCPs exhibit efficient passive accumulation in the tumor, in which the reduced pH (c.a. 6.5) would trigger charge conversion and size expansion to enhance their tumor retention and cell internationalization. After cellular uptake, NCPs within cell endo-/lysosomes with further reduced pH would then lead to decomposition of those NCPs and thus drug release. Chemotherapy with Ca/Pt(IV)@pHis-PEG NCPs in our animal tumor model demonstrates great efficacy under low drug doses, and is found to be particularly effective towards solid tumors with reduced pH. [ABSTRACT FROM AUTHOR]

The abnormal tumor vasculature is one of key reasons that lead to the limited tumor perfusion as well as hypoxic and immunosuppressive tumor microenvironment (TME). Herein, we uncover that by normalizing the tumor vasculature with erlotinib, a specific inhibitor of epidermal growth factor receptor (EGFR), the tumor perfusion and tumor oxygenation statuses in different types of tumors including murine breast tumors, colorectal tumors, and squamous cell carcinoma tumors, could be remarkably enhanced. As the results, the tumor uptake of drug-loaded nanoparticles as well as their interstitial penetration within the tumor would be greatly increased for mice pre-treated with erlotinib at the oral feeding dose of 50 mg/kg, leading to remarkably improved chemotherapeutic efficacy of nanomedicine. On the other hand, owing to the erlotinib-induced normalization of tumor vasculatures, the relieved hypoxic state in the three different types of tumors could alter the immunosuppressive TME into immunosupportive. Such an effect together with the increased tumor retention of anti-PDL1 antibody, a clinically approved checkpoint blockade agent, finally contributes to the greatly improved tumor inhibition effect in cancer immunotherapy. Therefore, our work presents a general yet effective strategy using a clinical drug to enhance the efficacies of cancer nanomedicine and immunotherapy by normalizing tumor vasculatures and modulating TME. [ABSTRACT FROM AUTHOR]

The development of smart drug delivery systems to realize controlled drug release for highly specific cancer treatment has attracted tremendous attention. Herein, nanoscale coordination polymers (NCPs) constructed from hafnium ions and bis-(alkylthio) alkene (BATA), a singlet-oxygen responsive linker, are fabricated and applied as nanocarriers to realize light-controlled drug release under a rather low optical power density. In this system, NCPs synthesized through a solvothermal method are sequentially loaded with chlorin e6 (Ce6), a photosensitizer, and doxorubicin (DOX), a chemotherapeutic drug, and then coated with lipid bilayer to allow modification with polyethylene glycol (PEG) to acquire excellent colloidal stability. The singlet oxygen produced by such NCP-Ce6-DOX-PEG nanocomposite can be used not only for photodynamic therapy, but also to induce the break of BATA linker and thus the destruction of nanoparticle structures under light exposure, thereby triggering effective drug release. Notably, with efficient tumor accumulation after intravenous injection as revealed by CT imaging, those NCP-Ce6-DOX-PEG nanoparticles could be utilized for combined chemo-photodynamic therapy with great antitumor efficacy. Thus, this work presents a unique type of NCP-based drug delivery system with biodegradability, sensitive responses to light, as well as highly efficient tumor retention for effective cancer combinational treatment. [ABSTRACT FROM AUTHOR]

Aiming at improved therapeutic efficacies, the combination of chemotherapy and radiotherapy (chemo-radiotherapy) has been widely studied and applied in clinic. However, the hostile characteristics of tumor microenvironment such as hypoxia often limit the efficacies in both types of cancer therapies. Herein, catalase (CAT), an antioxidant enzyme, is encapsulated inside liposomes constituted by cisplatin (IV)-prodrug-conjugated phospholipid, forming CAT@Pt (IV)-liposome for enhanced chemo-radiotherapy of cancer. After being loaded inside liposomes, CAT within CAT@Pt (IV)-liposome shows retained and well-protected enzyme activity, and is able to trigger decomposition of H 2 O 2 produced by tumor cells, so as to produce additional oxygen for hypoxia relief. As the result, treatment of CAT@Pt (IV)-liposome induces the highest level of DNA damage in cancer cells after X-ray radiation compared to the control groups. In vivo tumor treatment further demonstrates a remarkably improved therapeutic outcome in chemo-radiotherapy with such CAT@Pt (IV)-liposome nanoparticles. Hence, an exquisite type of liposome-based nanoparticles is developed in this work by integrating cisplatin-based chemotherapy and catalase-induced tumor hypoxia relief together for combined chemo-radiotherapy with great synergistic efficacy, promising for clinical translation in cancer treatment. [ABSTRACT FROM AUTHOR]

Physiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Herein, we discovered that metformin, a prescribed drug for type 2 diabetes, could up-regulate the oxidative phosphorylation of CAR-T cells, increase their energy metabolism, and further promote their proliferation. Inspired by this finding, we designed a hydrogel scaffold to co-deliver metformin and CAR-T cells by adding CAR-T cells into a lyophilized alginate hydrogel containing metformin. The obtained hydrogel scaffold after being implanted into the tumor resection cavity could act as a cell reservoir to sustainably release both CAR-T cells and metformin. While the released metformin could suppress oxidative and glycolytic metabolism of cancer cells and lead to decreased tumor hypoxia, CAR-T cells would respond to metformin by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype, contributing to elevated antitumor responses. As demonstrated in several post-surgical tumor models, the proliferation and tumor-infiltration of CAR-T cells were significantly enhanced and the treatment efficacy of CAR-T cells was augmented, against both local tumors and distant abscopal tumors, while showing reduced systemic immune-related adverse effects. Our work presents a new strategy to achieve effective yet safe CAR-T therapy against solid tumors using a cell-delivery scaffold based on clinically validated drugs and biomaterials. [ABSTRACT FROM AUTHOR]

Current photodynamic therapy (PDT) is suffering from limited efficacy towards hypoxia tumors and severe post-treatment photo-toxicity such as light-induced skin damages. To make PDT more effective in cancer treatment while being patient-comfortable, herein, a hexylamine conjugated chlorin e6 ( h Ce6) as the photosensitizer together with a lipophilic near-infrared (NIR) dye 1,1'-dioctadecyl-3,3,3′,3'-tetramethylindotricarbocyanine iodide (DiR) are co-encapsulated into polyethylene glycol (PEG) shelled liposomes. In the obtained DiR- h Ce6-liposome, the photosensitizing effect of h Ce6 is quenched by DiR via fluorescence resonance energy transfer (FRET). Interestingly, upon irradiation with a 785-nm NIR laser to photobleach DiR, both fluorescence and photodynamic effect of h Ce6 in DiR- h Ce6-liposome would be activated. Meanwhile, such NIR irradiation applied on tumors of mice with intravenous injection of DiR- h Ce6-liposome could result in mild photothermal heating, which in turn would promote intra-tumor blood flow and relieve tumor hypoxia, contributing to the enhanced photodynamic tumor treatment. Importantly, compared to h Ce6-loaded liposomes, DiR- h Ce6-liposome without being activated by the 785-nm laser shows much lower skin photo-toxicity, demonstrating its great skin protection effect. This work demonstrates a promising yet simple strategy to prepare NIR-light-activatable photodynamic theranostics for synergistic cancer phototherapy, which is featured high specificity/efficacy in tumor treatment with minimal photo-toxicity towards the skin. [ABSTRACT FROM AUTHOR]

Cancer radiotherapy (RT) is a clinically used tumor treatment strategy applicable for a wide range of solid tumors. However, during RT treatment of tumors, only a small portion of applied ionizing irradiation energy is absorbed by the tumor, in which the largely hypoxic microenvironment also limits the anti-tumor efficacy of RT. In this work, we rationally fabricate polyethylene glycol (PEG) stabilized perfluorocarbon (PFC) nano-droplets decorated with TaOx nanoparticles (TaOx@PFC-PEG) as a multifunctional RT sensitizer. The obtained TaOx@PFC-PEG nanoparticles on one hand can absorb X-ray by TaOx to concentrate radiation energy within tumor cells, on the other hand after saturating PFC with oxygen will act as an oxygen reservoir to gradually release oxygen and improve tumor oxygenation. As the result, remarkably enhanced in vivo RT treatment is achieved with TaOx@PFC-PEG nanoparticles in our mouse tumor model experiments. Our work thus presents a new nanotechnology strategy to enhance RT-induced tumor treatment by simultaneously concentrating radiation energy within tumors and improving tumor oxygenation, using one multifunctional agent. [ABSTRACT FROM AUTHOR]

The exploration of stimuli-responsive nano-theranostics provides powerful tools for simultaneously enhancing the accuracy and efficiency of cancer therapies. Herein, we develop mono-dispersed CaCO 3 nanoparticles modified with polyethylene glycol (PEG) as a multifunctional nano-carrier for efficient loading of both Mn 2+ -chelated chlorin e6 (Ce6(Mn)) as a photosensitizer, and doxorubicin (DOX) as a chemotherapy drug. Our CaCO 3 @Ce6(Mn)-PEG(DOX) nanoparticles, while being stable under physiological pH at 7.4, appear to be highly sensitive to reduced pH and would be rapidly degraded under slightly acidic environment, effectively releasing loaded therapeutic agents. Interestingly, owing to released Ce6(Mn), those nanoparticles show an interesting pH-dependent T1 signal enhancement under magnetic resonance (MR) imaging, which could be utilized for real-time monitoring of drug release. As discovered by MR and fluorescence imaging, intravenously (i.v.) injected CaCO 3 @Ce6(Mn)/DOX-PEG could gradually accumulate in the tumor, contributing to a superior synergistic anti-tumor effect in the combined photodynamic & chemotherapy. In conclusion, we have developed a tumor-pH-activated nanocarrier based on biodegradable CaCO 3 nanoparticles, which may be an ideal cancer theranostic nanoplatform with substantial potential for future clinical translation. [ABSTRACT FROM AUTHOR]

Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. 64 Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of 64 Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ( 64 Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics. [ABSTRACT FROM AUTHOR]

Human amniotic fluid stem (hAFS) cells have generated a great deal of excitement in cell-based therapies and regenerative medicine. Here, we examined the effect of hAFS cells labeled with dual-polymer-coated UCNP-PEG-PEI nanoparticles in a murine model of acute lung injury (ALI). We observed hAFS cells migration to the lung using highly sensitive in vivo upconversion luminescence (UCL) imaging. We demonstrated that hAFS cells remained viable and retained their ability to differentiate even after UCNP-PEG-PEI labeling. More importantly, hAFS cells displayed remarkable positive effects on ALI-damaged lung tissue repair compared with mouse bone marrow mesenchymal stem cells (mBMSCs), which include recovery of the integrity of alveolar-capillary membrane, attenuation of transepithelial leukocyte and neutrophil migration, and down-regulation of proinflammatory cytokine and chemokine expression. Our work highlights a promising role for imaging-guided hAFS cell-based therapy in ALI. [ABSTRACT FROM AUTHOR]

As peripheral arterial disease (PAD) results in muscle ischemia and neovascularization, it has been claimed that nanoparticles can passively accumulate in ischemic tissues through the enhanced permeability and retention (EPR) effect. At this time, a quantitative evaluation of the passive targeting capabilities of nanoparticles has not been reported in PAD. Using a murine model of hindlimb ischemia, we quantitatively assessed the passive targeting capabilities of 64 Cu-labeled PEGylated reduced graphene oxide – iron oxide nanoparticles ( 64 Cu-RGO-IONP-PEG) through the EPR effect using positron emission tomography (PET) imaging. Serial laser Doppler imaging was performed to monitor changes in blood perfusion upon surgical induction of ischemia. Nanoparticle accumulation was assessed at 3, 10, and 17 days post-surgery and found to be highest at 3 days post-surgery, with the ischemic hindlimb displaying an accumulation of 14.7 ± 0.5% injected dose per gram (%ID/g). Accumulation of 64 Cu-RGO-IONP-PEG was lowest at 17 days post-surgery, with the ischemic hindlimb displaying only 5.1 ± 0.5%ID/g. Furthermore, nanoparticle accumulation was confirmed by photoacoustic imaging (PA). The combination of PET and serial Doppler imaging showed that nanoparticle accumulation in the ischemic hindlimb negatively correlated with blood perfusion. Thus, we quantitatively confirmed that 64 Cu-RGO-IONP-PEG passively accumulated in ischemic tissue via the EPR effect, which is reduced as the perfusion normalizes. As 64 Cu-RGO-IONP-PEG displayed substantial accumulation in the ischemic tissue, this nanoparticle platform may function as a future theranostic agent, providing both imaging and therapeutic applications. [ABSTRACT FROM AUTHOR]

Real-time in vivo pH imaging in the tumor, as well as designing therapies responsive to the acidic tumor microenvironment to achieve optimized therapeutic outcomes have been of great interests in the field of nanomedicine. Herein, a pH-responsive near-infrared (NIR) croconine (Croc) dye is able to induce the self-assembly of human serum albumin (HSA) to form HSA-Croc nanoparticles useful not only for real-time ratiometric photoacoustic pH imaging of the tumor, but also for pH responsive photothermal therapy with unexpected great performance against tumors with relatively large sizes. Such HSA-Croc nanoparticles upon intravenous injection exhibit efficient tumor homing. As the decrease of pH, the absorption of Croc at 810 nm would increase while that at 680 nm would decrease, allowing real-time pH sensing in the tumor by double-wavelength ratiometric photoacoustic imaging, which reveals the largely decreased pH inside the cores of large tumors. Moreover, utilizing HSA-Croc as a pH-responsive photothermal agent, effective photothermal ablation of large tumors is realized, likely owing to the more evenly distributed intratumoral heating compared to that achieved by conventional pH-insensitive photothermal agents, which are effective mostly for tumors with small sizes. [ABSTRACT FROM AUTHOR]

Nanoscale metal organic frameworks (NMOFs) have shown great potential in biomedicine owing to their structural/chemical diversities, high molecular loading capacities, and intrinsic biodegradability. Herein, we report the rational design of a NMOF composed by hafnium (Hf 4+ ) and tetrakis (4-carboxyphenyl) porphyrin (TCPP). In such Hf-TCPP NMOFs, while TCPP is a photosensitizer to allow photodynamic therapy (PDT), Hf 4+ with strong X-ray attenuation ability could serve as a radio-sensitizer to enhance radiotherapy (RT). Those NMOFs with polyethylene glycol (PEG) coating show efficient tumor homing upon intravenous injection, and thus could be used for in vivo combined RT & PDT, achieving a remarkable anti-tumor effect. Importantly, Hf-TCPP NMOFs show efficient clearance from the mouse body, minimizing concerns regarding their possible long-term toxicity. Our work thus presents a new concept of developing multifunctional NMOFs as a biodegradable carrier-free system, in which both metal ions and organic ligands are fully utilized to exert their therapeutic functions. [ABSTRACT FROM AUTHOR]

Oxidative stress and mitochondrial damage are the main mechanisms of ischemia-reperfusion injury in ischemic stroke. Herein, cerium oxide nanoparticles with powerful free radical scavenging ability were used as carriers to load dl-3- n -butylphthalide (NBP–CeO 2 NPs) for the combined treatment of ischemic stroke. NBP-CeO 2 NPs could eliminate reactive oxygen species (ROS) in mouse brain microvascular endothelial cells and hippocampal neurons after oxygen-glucose deprivation/reoxygenation (OGD/R), and also save mitochondrial membrane potential, morphology, and function, thus alleviating the in vitro blood brain barrier (BBB) disruption and neuronal apoptosis. In the middle cerebral artery embolization/recanalization (MCAO/R) mouse model, the NBP-CeO 2 NPs also possessed superior ROS scavenging ability, protected mitochondria, and preserved BBB integrity, thereby reducing cerebral infarction and cerebral edema and inhibiting neuroinflammation and neuronal apoptosis. The long-term neurobehavioral tests indicated that the NBP-CeO 2 NPs significantly improved sensorimotor function and spatial learning ability by promoting angiogenesis after ischemic stroke. Therefore, the NBP-CeO 2 NPs provided a novel therapeutic approach for ischemic stroke by combining antioxidant and neurovascular repair abilities, highlighting its wide application in ischemia-reperfusion injury. [Display omitted] [ABSTRACT FROM AUTHOR]

Considering the huge cost and long test periods required for new drug development, repurposing drugs that have already been applied in the clinic as new cancer treatment candidates represents an attractive alternative. Disulfiram (DSF) was originally used to treat alcoholism and has proven to have anticancer effects with the coadministration of copper ions (Cu2+). However, the limited water-solubility of DSF and systemic toxicity induced by exogenous Cu2+ hinder its practical application. Herein, we constructed pH-responsive lipid-coated calcium phosphate nanoparticles (LCP NPs) co-loaded with Cu2+ and DSF. After intravenous injection, those nanoparticles with long blood half-life preferentially accumulate in tumors, followed by the degradation of nanoparticles in response to the acidic tumor microenvironment, subsequently releasing Cu2+ and DSF to generate cytotoxic metabolite DTC−Copper complex, bis(diethyldithiocarbamate)–copper (CuET) for tumor treatment. In addition to direct cytotoxicity, the active metabolite CuET could effectively induce immunogenic cell death (ICD) of cancer cells to regulate the immunosuppressive tumor microenvironment, contributing to enhanced immune checkpoint blockade (ICB) therapy in triggering systemic immune responses. This work thus demonstrates the great promises of repurposing the old drug DSF as a new ICD inducer with nano-formulation, to achieve improved synergetic tumor-responsive therapy with low side effects. [ABSTRACT FROM AUTHOR]

Vitamin C (VitC) has shown great promise to promote cancer immunotherapy, however, its high hydrophilicity makes it quickly excreted, leading to limited therapeutic efficiency even with frequent high-dose administration. Herein, we provide a pioneering report about the employment of VitC amphiphile self-assembled nanofiber hydrogels for enhanced cancer immunotherapy. Specifically, driven by hydrogen bonding and hydrophobic interactions, the synthesized VitC amphiphile, consisting of a hydrophilic VitC headgroup and a hydrophobic alkyl chain, could self-assemble into an injectable nanofiber hydrogel with self-healing properties. The formed VitC hydrogel not only serves as a reservoir for VitC but also acts as an effective delivery platform for stimulator of interferon genes (STING) agonist-4 (SA). Interestingly, the VitC hydrogel itself exhibits antitumor effects by upregulating genes related to interferon (IFN) signaling, apoptotic signaling and viral recognition and defense. Moreover, the SA-encapsulated VitC hydrogel (SA@VitC hydrogel) synergistically activated the immune system to inhibit the progression of both local and abscopal tumors. [ABSTRACT FROM AUTHOR]

Physical stimulus-responsive therapies often employing multifunctional theranostic agents responsive to external physical stimuli such as light, magnetic field, ultra-sound, radiofrequency, X-ray, etc., have been widely explored as novel cancer therapy strategies, showing encouraging results in many pre-clinical animal experiments. Unlike conventional cancer chemotherapy which often accompanies with severe toxic side effects, physical stimulus-responsive agents usually are non-toxic by themselves and would destruct cancer cells only under specific external stimuli, and thus could offer greatly reduced toxicity and enhanced treatment specificity. In addition, physical stimulus-responsive therapies can also be combined with other traditional therapeutics to achieve synergistic anti-tumor effects via a variety of mechanisms. In this review, we will summarize the latest progress in the development of physical stimulus-responsive therapies, and discuss the important roles of nanoscale theranostic agents involved in those non-conventional therapeutic strategies. [ABSTRACT FROM AUTHOR]

Nano-graphene and its derivatives have attracted great attention in biomedicine, including their applications in cancer theranostics. In this work, we develop 131I labeled, polyethylene glycol (PEG) coated reduced nano-graphene oxide (RGO), obtaining 131I-RGO-PEG for nuclear imaging guided combined radiotherapy and photothermal therapy of cancer. Compared with free 131I, 131IRGO- PEG exhibits enhanced cellular uptake and thus improved radio-therapeutic efficacy against cancer cells. As revealed by gamma imaging, efficient tumor accumulation of 131I-RGO-PEG is observed after its intravenous injection. While RGO exhibits strong near-infrared (NIR) absorbance and could induce effective photothermal heating of tumor under NIR light irradiation, 131I is able to emit high-energy X-ray to induce cancer killing as the result of radio ionization effect. By utilizing the combined photothermal therapy and radiotherapy, both of which are delivered by a single agent 131IRGO- PEG, effective elimination of tumors is achieved in our animal tumor model experiments. Toxicology studies further indicate that 131I-RGO-PEG induces no appreciable toxicity to mice at the treatment dose. Our work demonstrates the great promise of combing nuclear medicine and photothermal therapy as a novel therapeutic strategy to realize synergistic efficacy in cancer treatment. [ABSTRACT FROM AUTHOR]

Integrating multiple imaging and therapy functionalities into one single nanoscale platform has been proposed to be a promising strategy in cancer theranostics. In this work, WS 2 nanosheets with their surface pre-adsorbed with iron oxide (IO) nanoparticles via self-assembly are coated with a mesoporous silica shell, on to which polyethylene glycol (PEG) is attached. The obtained WS 2 -IO@MS-PEG composite nanoparticles exhibit many interesting inherent physical properties, including high near-infrared (NIR) light and X-ray absorbance, as well as strong superparamagnetism. In the mean time, the mesoporous silica shell in WS 2 -IO@MS-PEG could be loaded with a chemotherapy drug, doxorubicin (DOX), whose intracellular release afterwards may be triggered by NIR-induced photothermal heating for enhanced cancer cell killing. Upon systemic administration of such drug-loaded nano-theranostics, efficient tumor homing of WS 2 -IO@MS-PEG/DOX is observed in tumor-bearing mice as revealed by three-modal fluorescence, magnetic resonance (MR), and X-ray computed tomography (CT) imaging. In vivo combined photothermal & chemotherapy is then carried out with WS 2 -IO@MS-PEG/DOX, achieving a remarkably synergistic therapeutic effect superior to the respective mono-therapies. Our study highlights the promise of developing multifunctional nanoscale theranostics based on two-dimensional transition metal dichalcogenides (TMDCs) such as WS 2 for multimodal imaging-guided combination therapy of cancer. [ABSTRACT FROM AUTHOR]

Transcatheter arterial chemoembolization (TACE) is widely used for the treatment of advanced hepatocellular carcinoma (HCC). However, the long-term hypoxic microenvironment caused by TACE seriously affects the therapeutic effect of TACE. HIF-2α plays a crucial role on the chronic hypoxia process, which might be an ideal target for TACE therapy. Herein, a multifunctional polyvinyl alcohol (PVA)/hyaluronic acid (HA)-based microsphere (PT/DOX-MS) co-loaded with doxorubicin (DOX) and PT-2385, an effective HIF-2α inhibitor, was developed for enhanced TACE treatment efficacy. In vitro and in vivo studies revealed that PT/DOX-MS had a superior ability to treat HCC by blocking the tumor cells in G2/M phase, prompting cell apoptosis, and inhibiting tumor angiogenesis. The antitumor mechanisms of PT/DOX-MS were possibly due to that the introduction of PT-2385 could effectively inhibit the expression level of HIF-2α in hypoxic HCC cells, thereby down-regulating the expression levels of Cyclin D1, VEGF and TGF-α. In addition, the combination of DOX and PT-2385 could jointly inhibit VEGF expression, which was another reason accounting for the combined anti-cancer effect of PT/DOX-MS. Overall, our study demonstrated that PT/DOX-MS is a promising embolic agent for enhanced HCC treatment via the combined effect of hypoxia microenvironment improvement, chemotherapy, and embolization. [ABSTRACT FROM AUTHOR]

The combination of chemotherapy with photothermal therapy, which may lead to improved therapeutic efficacies and reduced side effects of conventional chemotherapy, would require safe drug delivery systems (DDSs) with strong near-infrared (NIR) absorbance, efficient drug loading, and effective tumor homing ability. Herein, we fabricate nano-assemblies containing J-aggregates of a NIR dye, IR825, for drug delivery and combined photothermal & chemotherapy of cancer. It is found that IR825 could be complexed with a low-molecular-weight cationic polymer polyethylenimine (PEI), forming IR825@PEI J-aggregates with greatly enhanced NIR absorbance red-shifted to 915 nm. Those nano-assemblies of J-aggregates are further modified with polyethylene glycol (PEG), obtaining IR825@PEI-PEG nano-complex which exhibits great dispersity in physiological solutions, excellent photostability, and is able to efficiently load chemotherapeutic drug doxorubicin (DOX) via a unique strategy different from drug loading in conventional amphiphilic polymer-based DDSs. In vivo animal experiments uncover that IR825@PEI-PEG/DOX upon intravenous injection into tumor-bearing mice shows rather high tumor uptake as illustrated by photoacoustic imaging. In vivo combined photothermal & chemotherapy is then carried out, demonstrating great synergistic anti-tumor therapeutic effect remarkably superior to those achieved by the respective mono-therapies. Hence, we present a novel type of nanoscale DDSs based on nano-assemblies of small molecules without involving amphiphilic polymers, promising for imaging-guided combination cancer therapy. [ABSTRACT FROM AUTHOR]

The development of sensitive and convenient methods for detection, enrichment, and analysis of circulating tumor cells (CTCs), which serve as an importance diagnostic indicator for metastatic progression of cancer, has received tremendous attention in recent years. In this work, a new approach characteristic of simultaneous CTC capture and detection is developed by integrating a microfluidic silicon nanowire (SiNW) array with multifunctional magnetic upconversion nanoparticles (MUNPs). The MUNPs were conjugated with anti-EpCAM antibody, thus capable to specifically recognize tumor cells in the blood samples and pull them down under an external magnetic field. The capture efficiency of CTCs was further improved by the integration with a microfluidic SiNW array. Due to the autofluorescence free nature in upconversion luminescence (UCL) imaging, our approach allows for highly sensitive detection of small numbers of tumor cells, which afterward could be collected for further analysis and re-culturing. We have further demonstrated that this approach can be applied to detect CTCs in clinical blood samples from lung cancer patients, and obtained consistent results by analyzing the UCL signals and the clinical outcomes of lung cancer metastasis. Therefore our approach represents a promising platform in CTC capture and detection with potential clinical utilization in cancer diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Although graphene oxide (GO) has recently been considered as a highly attractive nanomaterial for future cancer imaging and therapy, it is still a major challenge to improve its in vivo tumor active targeting efficiency. Here in this full article, we demonstrated the successful and significantly enhanced in vivo tumor vasculature targeting efficacy of well-functionalized GO nanoconjugates by using vascular endothelial growth factor 121 (VEGF121) as the targeting ligand. As-developed GO nanoconjugate exhibits excellent in vivo stability, specific in vitro and in vivo vascular endothelial growth factor receptor (VEGFR) targeting, significantly enhanced tumor accumulation (>8 %ID/g) as well as high tumor-to-muscle contrast, showing great potential for future tumor targeted imaging and therapy. [ABSTRACT FROM AUTHOR]

Theranostic agents with both imaging and therapeutic functions have attracted enormous interests in cancer diagnosis and treatment in recent years. In this work, we develop a novel theranostic agent based on Prussian blue nanocubes (PB NCs), a clinically approved agent with strong near-infrared (NIR) absorbance and intrinsic paramagnetic property, for in vivo bimodal imaging-guided photothermal therapy. After being coated with polyethylene glycol (PEG), the obtained PB-PEG NCs are highly stable in various physiological solutions. In vivo T 1 -weighted magnetic resonance (MR) and photoacoustic tomography (PAT) bimodal imaging uncover that PB-PEG NCs after intravenous (i.v.) injection show high uptake in the tumor. Utilizing the strong and super stable NIR absorbance of PB, in vivo cancer treatment is then conducted upon i.v. injection of PB-PEG NCs followed by NIR laser irradiation of the tumors, achieving excellent therapeutic efficacy in a mouse tumor model. Comprehensive blood tests and careful histological examinations reveal no apparent toxicity of PB-PEG NCs to mice at our tested dose, which is two-fold of the imaging/therapy dose, within two months. Our work highlights the great promise of Prussian blue with well engineered surface coating as a multifunctional nanoprobe for imaging-guided cancer therapy. [ABSTRACT FROM AUTHOR]

A large variety of cancers are associated with a high incidence of lymph node metastasis, which leads to a high risk of cancer death. Herein, we demonstrate that multimodal imaging guided photothermal therapy can inhibit tumor metastasis after surgery by burning the sentinel lymph nodes (SLNs) with metastatic tumor cells. A near-infrared dye, IR825, is absorbed onto human serum albumin (HSA), which is covalently linked with diethylenetriamine pentaacetic acid (DTPA) molecules to chelate gadolinium. The formed HSA-Gd-IR825 nanocomplex exhibits strong fluorescence together with high near-infrared (NIR) absorbance, and in the mean time could serve as a T1 contrast agent in magnetic resonance (MR) imaging. In vivo bi-modal fluorescence and MR imaging uncovers that HSA-Gd-IR825 after being injected into the primary tumor would quickly migrate into tumor-associated SLNs through lymphatic circulation. Utilizing the strong NIR absorbance of HSA-Gd-IR825, SLNs with metastatic cancer cells can be effectively ablated under exposure to a NIR laser. Such treatment when combined with surgery to remove the primary tumor offers remarkable therapeutic outcomes in greatly inhibiting further metastatic spread of cancer cells and prolonging animal survival. Our work presents an albumin-based theranostic nano-probe with functions of multimodal imaging and photothermal therapy, together with a ‘photothermal ablation assisted surgery’ strategy, promising for future clinical cancer treatment. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) is emerging as a non-invasive strategy to eradicate tumors, but its therapeutic efficacy is still not ideal. To achieve more effective SDT, water insoluble sonosensitizer meso-5, 10, 15, 20-tetra(4-hydroxylphenyl)porphyrin (THPP) is here esterified with succinic acid conjugated oxaliplatin prodrug (Oxa(IV)SA 2) and carboxyl group terminated PEG (PEG 5k -COOH). The obtained covalent organic polymer (COP) of THPP-Oxa(IV)-PEG with good physiological stability, sonosensitization efficacy and glutathione (GSH) responsive oxalipatin responsive behaviors can induce effective immunogenic cancer cell death upon the ultrasound exposure. In addition, THPP-Oxa(IV)-PEG is shown to be a versatile carrier for both hydrophobic near infrared dye and radioisotope 99mTc, thereby enabling real-time tracking of its pharmacokinetics behavior under corresponding imaging facilities. Furthermore, treatment with THPP-Oxa(IV)-PEG injection and ultrasound exposure is shown to be most effectively in suppressing tumor growth, with 3 of 6 CT26 tumor bearing mice fully cured, ascribing to its high potency in eliciting profound antitumor immune responses. This work highlights a promising strategy in constructing multifunctional nanosonosensitizer as a potent immunogenic nanomedicine to enhance the treatment outcome of SDT. [ABSTRACT FROM AUTHOR]

Intravesical instillation of chemotherapeutics or immune-stimulating agents could reduce the recurrence rate of non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of the bladder tumors. Its efficacy, however, remains to be improved due to the bladder epithelial barrier. Although certain transmucosal delivery carriers are able to enhance the transepithelial penetration of intravesical agents, they could hardly differentiate carcinoma and adjacent normal tissues of the bladder wall. Here, we reported polyethylene glycol (PEG) & glutaraldehyde co-modified fluorinated chitosan (PGFCS) as a collagen-targeted transepithelial penetration enhancer, which could create a tumor-targeted adhesive interface by the aldehyde-selective reaction with collagen amines enriched in the tumor, thus opening the transepithelial-delivery barrier at the tumor site though the fluorinated-chitosan-mediated tight junction regulation. Interestingly, with the help of PGFCS pre-treatment, intravesical instillation of chemotherapeutics pirabucin (THP) combined with immune stimulating agent interleukin-12 could trigger potent antitumor chemoimmunotherapeutic responses in destructing orthotopic bladder tumors and inhibiting cancer recurrence. Our work presents a unique type of tumor-specific transepithelial penetration enhancer, which shows great potential for safe and effective intravesical instillation of NMIBC. [Display omitted] [ABSTRACT FROM AUTHOR]

The limited penetration depth of external excitation light would remarkably impair the therapeutic efficacy of photodynamic therapy (PDT) and its clinical utilization. Herein, we engineered bioluminescent bacteria by transforming attenuated Salmonella typhimurium strain ΔppGpp (S.T. ΔppGpp) with firefly-luciferase-expressing plasmid (Luc-S.T.ΔppGpp) as an internal light source to evenly illuminate whole tumors. Upon being fixed inside tumors with in-situ formed hydrogel, the colonized Luc-S.T.ΔppGpp together with D-luciferin could continuously generate light to excite photosensitizer chlorin e6 (Ce6), leading to effective suppression of different types of tumors including opaque melanoma and large rabbit tumors. Such bioluminescence-triggered PDT presented significant advantages over conventional PDT excited with an external 660-nm light, which at a much high light energy could only slightly retard the growth of small subcutaneous tumors. Furthermore, we uncovered that Luc-S.T.ΔppGpp boosted PDT could also elicit potent antitumor immunity post the treatment to inhibit tumor metastasis and prevent tumor challenge. Therefore, this work highlights that such bioluminescent bacteria boosted PDT is a general and highly effective therapeutic approach toward diverse cancers with varying light-absorbing capacities and tumor sizes, promising for potential clinical translation because of their acceptable safety profiles. [ABSTRACT FROM AUTHOR]

Abstract: The ‘sea urchin’-like nanostructures with particular small size (<100 nm) and abundant multi-tips have not yet been employed for the cancer photothermal therapy (PTT). Here we report sub-100 nm hollow Au–Ag alloy nanourchins (HAAA-NUs) with ultrahigh density of nanotips synthesized via a facile seed-mediated growth. The HAAA-NUs exhibit a remarkably integrated high-quality photothermal feature including well-defined but tunable surface plasmon resonance peak, strong absorption (2.2 × 1010 M−1 cm−1) as well as high photothermal conversion efficiency (80.4%) in the near-infrared region. Importantly, the HAAA-NUs demonstrate improved photothermal stability verified via continuous exposition and cyclic irradiation of laser beam. The cell assay, in vitro cell ablation and in vivo breast cancer treatment verify that the HAAA-NUs are superior photothermal agent for photothermal tumor ablation therapy owing to low toxicity and high cell destruction capability. [Copyright &y& Elsevier]

Abstract: In this work, we develop a multifunctional nano-platform by coating upconversion nanoparticles (UCNPs) with bovine serum albumin (BSA), obtaining UCNP@BSA nanoparticles with great solubility and stability in physiological environments. Two types of dye molecules, including a photosensitizer, Rose Bengal (RB), and an NIR-absorbing dye, IR825, can be simultaneously loaded into the BSA layer of the UCNP@BSA nanoparticles. In this carefully designed UCNP@BSA-RB&; IR825 system, RB absorbs green light emitted from UCNPs under 980-nm excitation to induce photodynamic cancer cell killing, while IR825 whose absorbance shows no overlap with upconversion excitation and emission wavelengths, offers nanoparticles a strong photothermal perform under 808-nm laser irradiation. Without showing noticeable dark toxicity, the obtained dual-dye loaded nanoparticles are able to kill cancer via combined photothermal and photodynamic therapies, both of which are induced by NIR light with high tissue penetration, by a synergetic manner both in vitro and in vivo. In addition, the intrinsic paramagnetic and optical properties of Gd3+-doped UCNPs can further be utilized for in vivo dual modal imaging. Our study suggests that UCNPs with well-designed surface engineering could serve as a multifunctional nano-platform promising in cancer theranostics. [Copyright &y& Elsevier]

Abstract: Magnetic targeting that utilizes a magnetic field to specifically delivery theranostic agents to targeted tumor regions can greatly improve the cancer treatment efficiency. Herein, we load chlorin e6 (Ce6), a widely used PS molecule in PDT, on polyethylene glycol (PEG) functionalized iron oxide nanoclusters (IONCs), obtaining IONC–PEG–Ce6 as a theranostic agent for dual-mode imaging guided and magnetic-targeting enhanced in vivo PDT. Interestingly, after being loaded on PEGylated IONCs, the absorbance/excitation peak of Ce6 shows an obvious red-shift from ∼650 nm to ∼700 nm, which locates in the NIR region with improved tissue penetration. Without noticeable dark toxicity, Ce6 loaded IONC–PEG (IONC–PEG–Ce6) exhibits significantly accelerated cellular uptake compared with free Ce6, and thus offers greatly improved in vitro photodynamic cancer cell killing efficiency under a low-power light exposure. After demonstrating the magnetic field (MF) enhanced PDT using IONC–PEG–Ce6, we then further test this concept in animal experiments. Owing to the strong magnetism of IONCs and the long blood-circulation time offered by the condensed PEG coating, IONC–PEG–Ce6 shows strong MF-induced tumor homing ability, as evidenced by in vivo dual modal optical and magnetic resonance (MR) imaging. In vivo PDT experiment based magnetic tumor targeting using IONC–PEG–Ce6 is finally carried out, achieving high therapeutic efficacy with dramatically delayed tumor growth after just a single injection and the MF-enhanced photodynamic treatment. Considering the biodegradability and non-toxicity of iron oxide, our IONC–PEG–Ce6 presented in this work may be a useful multifunctional agent promising in photodynamic cancer treatment under magnetic targeting. [Copyright &y& Elsevier]

Abstract: We developed carrier-free multidrug nanocrystals (MDNCs) for the combination chemotherapy with synergistic effect, improved tolerance and imaging capability for cancer treatment. Three widely used hydrophobic drugs, methotrexate (MTX), 10-hydroxycamptothecin (HCPT) and paclitaxel (PTX), were prepared into one nanorod, and then conjugated with poly(ethylene glycol) (PEG) to improve their water dispersity and bio-environmental stability. It should be noted that only trace amount of PEG was used for surface modification, which ensures a high drug loading capacity of the resulting PEGylated MDNCs. In vitro studies showed that the MDNCs revealed an obviously higher cytotoxicity than individual drugs in the same dose and suppressed drug resistance against PTX resistant MCF-7/ADR cancer cells, indicating its synergistic effect and improved tolerance. After in vivo intravenous injection, the MDNCs exhibits a synergetic in vivo therapeutic effect and possesses obviously superior antitumor effect compared to free multidrugs treatment group and individual drug treatment groups, and no statistically significant weight loss was observed. The MDNCs can also gain imaging capabilities by encapsulated with an organic dye, which render the multidrug nanorod an all-in-one processing system for cancer diagnosis and treatment. [Copyright &y& Elsevier]

Relieving tumor hypoxia has recently been found to be a promising approach to reverse tumor immunosuppression and thus enhance the treatment outcomes of diverse cancer treatments. Herein, we prepared a type of fluorinated covalent conjugate polymers (COPs) with sonosensitizer meso-5, 10, 15, 20-tetra (4-hydroxylphenyl) porphyrin (THPP) and perfluorosebacic acid (PFSEA) as cross-linkers, yielding THPP pf -COPs with efficient sonodynamic efficacy and loading capacity towards perfluoro-15-crown-5-ether (PFCE), a model perfluorocarbon molecule. Upon intratumoral injection, such PFCE@THPP pf -COPs could not only attenuate tumor hypoxia, but also exhibit the most effective suppression effect on tumor growth in the presence of ultrasound exposure by inducing immunogenic cell death of cancer cells. Furthermore, we found that the sonodynamic therapy of PFCE@THPP pf -COPs together with anti-CD47 immunotherapy would synergistically suppress tumor growth by increasing the tumor-infiltrating frequencies of phagocytic M1 macrophages and cytotoxic CD3+CD8+ T cells, while reducing the frequency of immunosuppressive regulatory T cells. Moreover, such combination treatment could also elicit potent protective memory antitumor immunity to prevent tumor challenge. Therefore, this work presents PFCE@THPP pf -COPs are a type of multifunctional nano-sonosensitizers potent in removing negative impacts of inherent tumor hypoxia and immunosuppression, and suppressing tumor growth and tumor recurrence by priming host's antitumor immunity, particularly in synergizing with anti-CD47 immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: In recent years, graphene and graphene-based nanocomposites owning to their highly enriched physical and chemical properties have been widely explored for applications in many different fields including biomedicine. In the present work, we decorate graphene oxide (GO) by both iron oxide nanoparticles (IONPs) and gold, forming a multi-functional magnetic & plasmonic GO–IONP–Au nanocomposite with strong superparamagnetism and significantly enhanced optical absorbance in the near-infrared (NIR) region. We then coat the nanocomposite with polyethylene glycol (PEG), obtaining GO–IONP–Au–PEG with high stability in physiological environments and no significant in vitro toxicity. Remarkably enhanced photothermal cancer ablation effect using GO–IONP–Au–PEG is realized in comparison to PEGylated GO used in our earlier studies, as demonstrated in both in vitro cell tests and in vivo animal experiments. Moreover, the IONP and Au compartments in the GO–IONP–Au–PEG nanocomposite could be further taken advantages for magnetic resonance (MR) and X-ray dual-modal imaging. Our work shows the promise of using graphene-based multi-functional nanocomposite as cancer theranostics. [Copyright &y& Elsevier]

Abstract: Ag2S quantum dots (QDs) have been demonstrated as a promising near-infrared II (NIR-II, 1.0–1.4 μm) emitting nanoprobe for in vivo imaging and detection. In this work, we carefully study the long-term in vivo biodistribution of Ag2S QDs functionalized with polyethylene glycol (PEG) and systematically examine the potential toxicity of Ag2S QDs over time. Our results show that PEGylated-Ag2S QDs are mainly accumulated in the reticuloendothelial system (RES) including liver and spleen after intravenous administration and can be gradually cleared, mostly by fecal excretion. PEGylated-Ag2S QDs do not cause appreciable toxicity at our tested doses (15 and 30 mg/kg) to the treated mice over a period of 2 months as evidenced by blood biochemistry, hematological analysis and histological examinations. Our work lays a solid foundation for further biomedical applications of Ag2S QDs as an important in vivo imaging agent in the NIR-II region. [Copyright &y& Elsevier]