A nanoplatform reshaping intracellular osmolarity and redox homeostasis against colorectal cancer.

Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemoresistance remaining a major obstacle in CRC treatment. Sodium persulfate (Na2S2O8) is a novel agent capable of producing •SO4- and Na+ for chemodynamic therapy (CDT). This can induce pyroptosis and ferroptosis instead of conventional apoptosis in tumor cells. Meanwhile, IR780-iodide (IR780), as an excellent phototherapy agent, can generate hyperthermia and generate a large amount of reactive oxygen species (ROS) to synergize with the CDT of Na2S2O8, with potential to overcome chemoresistance in CRC. However, the low stability of Na2S2O8 and the poor solubility of IR780 limit their applications in the medical field. Accordingly, for the first time, D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), Na2S2O8 and IR780 were rationally designed in a cascade-amplifying nanoplatform (Na2S2O8-IR780 NPs) via a co-assembly strategy. Combining Na2S2O8 and IR780 in a nanoplatform improves the stability of Na2S2O8 and the solubility of IR780. As a result, the Na2S2O8-IR780 NPs exhibited excellent antitumor efficacy in CRC cell lines and five chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models. This photo-chemodynamic nanoplatform provides a brand-new paradigm by manipulating osmolarity and redox homeostasis to overcome chemo-resistance and holds great potential for the treatment of CRC.

Functional 2D Iron-Based Nanosheets for Synergistic Immunotherapy, Phototherapy, and Chemotherapy of Tumor.

Immunotherapy efficacy has been limited by tumor-associated macrophages (TAMs), which are the most abundant immune regulatory cells infiltrating around tumor tissues. The repolarization of pro-tumor M2 TAMs to anti-tumor M1 TAMs is a very promising immunotherapeutic strategy for cancer therapy. In this manuscript, multifunctional 2D iron-based nanosheets (FeNSs) are synthesized via a simple hydrothermal method for the first time, which not only possess photothermal and photodynamic properties, but also can repolarize TAMs from M2 to M1. After modifying with polyethylene glycol and loading with bioreductive prodrug banoxantrone (AQ4N), abbreviated as AP FeNSs, it can effectively repolarize TAMs from M2 to M1 and deliver AQ4N to tumor microenvironment (TME). Moreover, the repolarized M1 TAMs overexpress inducible nitric oxide synthase, which can convert nontoxic AQ4N to cytotoxic AQ4 under hypoxic TME, enabling immunomodulation-activated chemotherapy. A series of in vitro and in vivo results corroborate that AP FeNSs effectively exert photothermal and photodynamic effects and repolarize M2 TAMs to M1 TAMs, releasing inflammatory factors and activating the chemotherapeutic effect, thereby realizing synergistic tumor therapy.

A targeted nanomodulator capable of manipulating tumor microenvironment against metastasis.

Recently, lactate has been considered as an alternative direct energy substance to glucose for tumor proliferation and metastasis. Meanwhile, mitochondria, as important energy-supplying organelles, are also closely related to tumor progression. Consequently, a new research direction for lactate comprises lactate deprivation coupled with mitochondria-targeted phototherapy to achieve a safer and more effective strategy against tumor metastasis. Herein, linoleic acid-conjugated hyaluronic acid (HL), disulfide bond-rich nanovehicle (mesoporous silica, MOS), mitochondria-targeted IR780 (M780) and lactate oxidase (LOD) are rationally designed as a specific-targeting metabolism nanomodulator (HL/MOS@M780&LOD NPs), fulfilling the task of simultaneous depriving cells of lactate and damaging mitochondria to prevent tumor metastasis. Interestingly, M780-mediated photodynamic therapy (PDT) and LOD-mediated starvation therapy can effectively exacerbate the hypoxia state of tumor cells, thereby increasing the free iron levels to activate ferroptosis. On one hand, pyruvic acid and H2O2 generated by LOD-mediated lactate metabolism can provide powerful conditions for iron-catalyzed ferroptosis. On the other, the depleted GSH and increased reactive oxygen species (ROS) can oxidize linoleic acid into lipid peroxides (LPO) to further augment ferroptosis. The designed nanomodulator therefore shows great promise for fighting tumor metastasis by manipulating energy metabolism and the hypoxia microenvironment.

Phyto-fabrication, purification, characterisation, optimisation, and biological competence of nano-silver.

Published studies indicate that virtually any kind of botanical material can be exploited to make biocompatible, safe, and cost-effective silver nanoparticles. This hypothesis is supported by the fact that plants possess active bio-ingredients that function as powerful reducing and coating agents for Ag+. In this respect, a phytomediation method provides favourable monodisperse, crystalline, and spherical particles that can be easily purified by ultra-centrifugation. However, the characteristics of the particles depend on the reaction conditions. Optimal reaction conditions observed in different experiments were 70-95 °C and pH 5.5-8.0. Green silver nanoparticles (AgNPs) have remarkable physical, chemical, optical, and biological properties. Research findings revealed the versatility of silver particles, ranging from exploitation in topical antimicrobial ointments to in vivo prosthetic/organ implants. Advances in research on biogenic silver nanoparticles have led to the development of sophisticated optical and electronic materials with improved efficiency in a compact configuration. So far, eco-toxicity of these nanoparticles is a big challenge, and no reliable method to improve the toxicity has been reported. Therefore, there is a need for reliable models to evaluate the effect of these nanoparticles on living organisms.

Neutrophil mediated postoperative photoimmunotherapy against melanoma skin cancer.

Surgery is the primary treatment option for most melanoma; however, high tumor recurrence rate after surgical resection becomes the main cause of death in cancer patients. The development of efficient drug delivery nanosystems to inhibit postoperative tumor recurrence becomes very necessary. In the present study, IR780 molecules and TRP-2 peptide were encapsulated in the hydrophobic shell and hydrophilic interior of TAT peptide functionalized liposomes to form TLipIT NPs, which were further internalized into neutrophils (NEs) to achieve TLipIT/NEs. After being intravenously injected into postoperative B16F10-bearing mice, TLipIT/NEs could actively migrate toward the inflamed residual tumor and release TLipIT through neutrophil extracellular traps (NETs). Under NIR laser irradiation, the TLipIT exhibited both photothermal and photodynamic effects to induce immunogenic cell death for maturation of DCs, and simultaneously, to release TRP-2 peptide as a melanoma associated antigen to further strengthen the maturation of DCs, both of which prompts the activation of T cells and induces potent immune responses. TLipIT/NEs hold great potential for the inhibition of postoperative tumor recurrence.

Density functional theory, molecular docking and in vivo muscle relaxant, sedative, and analgesic studies of indanone derivatives isolated from Heterophragma adenophyllum.

Heterophragma adenophyllum (HA) is an important medicinal plant which is used in traditional medicine for the treatment of muscular tension and pain. Herein, we report the isolation of methyl,1,2-dihydroxy-2-(3-methylbut-2-en-1-yl)-3-oxo-2,3-dihydro-1H-indene-1-carboxylate (1), from the roots of H. adenophyllum. The isolated compound 1 was evaluated for in vivo muscle relaxant, sedative, and analgesic potential in Swiss albino mice. Results revealed that the isolated compound 1 exhibited a dose- and time-dependent muscle coordination (51%) and a significant (p < 01) sedative effect. It also showed a considerable (p < 0.5) analgesia after 30 min of post treatment and was maintained for up-to 120 min of experimental duration. In acute toxicity studies, no mortality was observed which indicates a preliminary safety of compound 1. Furthermore, the experimental results were compared with the theoretical studies by using density functional theory (DFT). The stability of the compound as well as the flow of electrons was determined by the calculated Frontier orbital analysis. The calculated stretching frequencies, 1H-NMR/13C-NMR chemical shift values and UV-visible spectra were found to be in agreement with experimental values. The results obtained from molecular docking studies were used to explore the mechanism of analgesic and muscle relaxant activity.Communicated by Ramaswamy H. Sarma.

Time-staggered delivery of erlotinib and doxorubicin by gold nanocages with two smart polymers for reprogrammable release and synergistic with photothermal therapy.

Photochemotherapy is currently an effective anticancer therapy. Recently, it has been reported that cancer cells pretreated with epidermal growth factor receptor (EGFR) inhibitor erlotinib (Erl) can significantly synergize its apoptosis against the DNA damaging agent doxorubicin (Dox). As a result, we designed two gold nanocages (Au NCs) microcontainers covered with different smart polymer shell-PAA (pH responsive) and p (NIPAM-co-AM) (temperature responsive) containing Erl and Dox respectively. The acidic tumor microenvironment and NIR light irradiation can selectively activate the release of Erl and Dox. Time staggered release of Erl and Dox and photothermal therapy enhance the apoptotic signaling pathways, resulting in improved tumor cell killing in both MCF-7 (low EGFR expression) and A431 (very high EGFR expression) tumor cells, but more efficient in the latter. The photochemotherapy strategy controls the order and duration of drug exposure precisely in spatial and temporal, and significantly improves the therapeutic efficacy against high EGFR expressed tumors.

Anisotropic Plasmonic Metal Heterostructures as Theranostic Nanosystems for Near Infrared Light-Activated Fluorescence Amplification and Phototherapy.

The development of sophisticated theranostic systems for simultaneous near infrared (NIR) fluorescence imaging and phototherapy is of particular interest. Herein, anisotropic plasmonic metal heterostructures, Pt end-deposited Au nanorods (PEA NRs), are developed to efficiently produce hot electrons under 808 nm laser irradiation, exhibiting the strong electric density. These hot electrons can release the heat through electron-phonon relaxation and form reactive oxygen species through chemical transformation, as a result of potent photothermal and photodynamic performance. Simultaneously, the confined electromagnetic field of PEA NRs can transfer energy to adjacent polyethylene glycol (PEG)-linked NIR fluorophores (CF) based on their energy overlap mechanism, leading to remarkable NIR fluorescence amplification in CF-PEA NRs. Various PEG linkers (1, 3.4, 5.0, and 10 kD) are employed to regulate the distance between CF and PEA NRs of CF-PEA NRs, and the maximum fluorescence intensity is achieved in CF5k-PEA NRs. After further attachment with i-motif DNA/Nrf2 siRNA chimera to simultaneously suppress both cellular antioxidant defense and hyperthermia resistance effects, the final biocompatible CF5k-bPEA@siRNA NRs present promising NIR fluorescence imaging ability and 808 nm laser-activated photothermal and photodynamic therapeutic effect in MCF7 cells and tumor-bearing mice, holding great potential for cancer therapy.

Intelligent Hollow Pt-CuS Janus Architecture for Synergistic Catalysis-Enhanced Sonodynamic and Photothermal Cancer Therapy.

As a noninvasive treatment modality, ultrasound (US)-triggered sonodynamic therapy (SDT) shows broad and promising applications to overcome the drawbacks of traditional photodynamic therapy (PDT) in combating cancer. However, the SDT efficacy is still not satisfactory without oxygen (O2) assistance. In addition, there is also much space to explore the SDT-based synergistic therapeutic modalities. Herein, a novel Pt-CuS Janus composed of hollow semiconductor CuS and noble metallic Pt was rationally designed and successfully synthesized. The hollow CuS shows a large inner cavity for loading sonosensitizer molecules (tetra-(4-aminophenyl) porphyrin, TAPP) to implement SDT. Moreover, the deposition of Pt not only enhances photothermal performance compared with those of CuS nanoparticles (NPs) due to the effect of the local electric field enhancement but also possesses nanozyme activity for catalyzing decomposition of endogenous overexpressed hydrogen peroxide (H2O2) to produce O2 that can overcome tumor hypoxia and augment the SDT-induced highly toxic reactive oxygen species (ROS) production for efficient cancer cell apoptosis. Importantly, the generated heat of Pt-CuS by 808 nm laser irradiation can accelerate the catalytic activity of Pt and elevate the O2 level that further facilitates SDT efficacy. Interestingly, the thermally sensitive copolymer coated around the Janus can act as a smart switch to regulate the catalytic ability of Pt and control TAPP release that has a significant effect on modulating the therapeutic effect. The synergistic catalysis-enhanced SDT efficiency and highly photothermal effect almost realized complete tumor resection without obvious reoccurrence and simultaneously displayed a highly therapeutic biosafety. Furthermore, the high optical absorbance allows the as-synthesized Pt-CuS Janus for photoacoustic (PA) imaging and NIR thermal imaging. This work develops a versatile nanoplatform for a multifunctional theranostic strategy and broadens the biological applications by rationally designing their structure.

Bismuth Sulfide Nanorods with Retractable Zinc Protoporphyrin Molecules for Suppressing Innate Antioxidant Defense System and Strengthening Phototherapeutic Effects.

Bismuth (Bi)-based nanomaterials (NMs) are widely used for computed tomography (CT) imaging guided photothermal therapy, however, the photodynamic property is hardly exhibited by these NMs due to the fast electron-hole recombination within their narrow bandgap. Herein, a sophisticated nanosystem is designed to endow bismuth sulfide (Bi2 S3 ) nanorods (NRs) with potent photodynamic property. Zinc protoporphyrin IX (ZP) is linked to Bi2 S3 NRs through a thermoresponsive polymer to form BPZP nanosystems. The stretching ZP could prebind to the active site of heme oxygenase-1 overexpressed in cancer cells, suppressing the cellular antioxidant defense capability. Upon NIR laser irradiation, the heat released from Bi2 S3 NRs could retract the polymer and drive ZP to the proximity of Bi2 S3 NRs, facilitating an efficient electron-hole separation in ZP and Bi2 S3 NRs, and leading to reactive oxygen species generation. In vitro and in vivo studies demonstrate the promising photodynamic property of BPZP, together with their photothermal and CT imaging performance.

Differential photothermal and photodynamic performance behaviors of gold nanorods, nanoshells and nanocages under identical energy conditions.

Various gold (Au) nanostructures have shown promising near infrared (NIR) light-activated phototherapeutic effects; however, their reported photothermal or photodynamic performance behavior is usually inconsistent or even conflicted, dramatically limiting the improvement of phototherapeutic Au nanostructures. The potential reason for this uncertainty is mainly because the photoactivities of Au nanostructures are not evaluated under identical energy conditions. Herein, three Au nanostructures, Au nanorods (NRs), nanoshells (NSs), and nanocages (NCs), were prepared to provide the same localized surface plasmon resonance (LSPR) peaks at 808 nm. All these Au nanostructures (at the same optical density) could fully exert their photoactivities under the identical and optimal energy conditions of 808 nm laser irradiation. It was found that these Au nanostructures could induce similar levels of temperature elevation but different levels of reactive oxygen species (ROS) production, where Au NCs exhibited the highest ROS production, followed by Au NSs and NRs. In vitro and in vivo phototherapeutic assessments further supported that Au NCs could cause the most severe cell death and tumor growth regression. This means that the identical incident energy has different contributions to the photothermal and photodynamic performance of Au nanostructures, and the corner angle structures of Au NCs compared with NSs and NCs could more efficiently convert the photon energy into photodynamic properties. Altogether, Au NCs hold great potential for phototherapy due to their efficient energy utilization capability.

Multifunctional Supramolecular Materials Constructed from Polypyrrole@UiO-66 Nanohybrids and Pillararene Nanovalves for Targeted Chemophotothermal Therapy.

Multifunctional supramolecular nanomaterials capable of targeted and multimodal therapy hold great potential to improve the efficiency of cancer therapeutics. Herein, we report a proof-of-concept nanoplatform for effective chemophotothermal therapy via the integration of folic acid-based active targeting and supramolecular nanovalves-based passive targeting. Inspired by facile surface engineering and designable layer-by-layer assembly concept, we design and synthesize PPy@UiO-66@WP6@PEI-Fa nanoparticles (PUWPFa NPs) to achieve efficient synergistic chemophotothermal therapy, taking advantage of the desirable photothermal conversion capability of polypyrrole nanoparticles (PPy NPs) and high drug-loading capacity of hybrid scaffolds. Significantly, pillararene-based pseudorotaxanes as pH/temperature dual-responsive nanovalves allow targeted drug delivery in pathological environment with sustained release over 4 days, which is complementary to photothermal therapy, and folic acid-conjugated polyethyleneimine (PEI-Fa) at the outmost layer through electrostatic interactions is able to enhance tumor-targeting and therapeutic efficiency. Such PUWPFa NPs showed efficient synergistic chemophotothermal therapy of cervical cancer both in vitro and in vivo. The present strategy offers not only the distinctly targeted drug delivery and release, but also excellent tumor inhibition efficacy of simultaneous chemophotothermal therapy, opening a new avenue for effective cancer treatment.

Novel Bismuth-Based Nanomaterials Used for Cancer Diagnosis and Therapy.

Theranostic nanomaterials (NMs) have gained increasing attention for their simultaneous performance of diagnosis and therapy. Bi-based NMs hold great potential as theranostic platforms based on their X-ray sensitive capability, near-infrared driven semiconductor properties, and distinctive structures, which facilitate the computed tomography (CT) imaging, photoacoustic (PA) imaging, radiation therapy, and phototherapy. The sophisticated design in composition, structure, and surface fabrication of Bi-based NMs can endow these NMs with more modalities in cancer diagnosis and therapy. In this Minireview, we focus on the recent advances in Bi-based theranostic NMs. A series of unique structures and functions as well as the underlying property-activity relationship of Bi-based NMs are showcased to highlight their promising imaging and therapeutic performance. At the end, we propose some challenges for the design and preparation of Bi-based NMs to improve their cancer diagnostic and therapeutic performance.

Resonance Energy Transfer-Promoted Photothermal and Photodynamic Performance of Gold-Copper Sulfide Yolk-Shell Nanoparticles for Chemophototherapy of Cancer.

Gold (Au) core@void@copper sulfide (CuS) shell (Au-CuS) yolk-shell nanoparticles (YSNPs) were prepared in the present study for potential chemo-, photothermal, and photodynamic combination therapy, so-called "chemophototherapy". The resonance energy transfer (RET) process was utilized in Au-CuS YSNPs to achieve both enhanced photothermal and photodynamic performance compared with those of CuS hollow nanoparticles (HNPs). A series of Au nanomaterials as cores that had different localized surface plasmon resonance (LSPR) absorption peaks at 520, 700, 808, 860, and 980 nm were embedded in CuS HNPs to screen the most effective Au-CuS YSNPs according to the RET process. Thermoresponsive polymer was fabricated on these YSNPs' surface to allow for controlled drug release. Au808-CuS and Au980-CuS YSNPs were found capable of inducing the largest temperature elevation and producing the most significant hydroxyl radicals under 808 and 980 nm laser irradiation, respectively, which could accordingly cause the most severe 4T1 cell injury through oxidative stress mechanism. Moreover, doxorubicin-loaded (Dox-loaded) P(NIPAM-co-AM)-coated Au980-CuS (p-Au980-CuS@Dox) YSNPs could more efficiently kill cells than unloaded particles upon 980 nm laser irradiation. After intravenous administration to 4T1 tumor-bearing mice, p-Au980-CuS YSNPs could significantly accumulate in the tumor and effectively inhibit the tumor growth after 980 nm laser irradiation, and p-Au980-CuS@Dox YSNPs could further potentiate the inhibition efficiency and exhibit excellent in vivo biocompatibility. Taken together, this study sheds light on the rational design of Au-CuS YSNPs to offer a promising candidate for chemophototherapy.

Deep-Level Defect Enhanced Photothermal Performance of Bismuth Sulfide-Gold Heterojunction Nanorods for Photothermal Therapy of Cancer Guided by Computed Tomography Imaging.

Bismuth sulfide (Bi2 S3 ) nanomaterials are emerging as a promising theranostic platform for computed tomography imaging and photothermal therapy of cancer. Herein, the photothermal properties of Bi2 S3 nanorods (NRs) were unveiled to intensely correlate to their intrinsic deep-level defects (DLDs) that potentially could work as electron-hole nonradiative recombination centers to promote phonon production, ultimately leading to photothermal performance. Bi2 S3 -Au heterojunction NRs were designed to hold more significant DLD properties, exhibiting more potent photothermal performance than Bi2 S3 NRs. Under 808 nm laser irradiation, Bi2 S3 -Au NRs could trigger higher cellular heat shock protein 70 expression and more apoptotic cells than Bi2 S3 NRs, and caused severe cell death and tumor growth inhibition, showing great potential for photothermal therapy of cancer guided by computed tomography imaging.

Diterpenoid alkaloids from the roots of Aconitum brachypodum Diels.

A new diterpenoid alkaloid, named bullatine H (1), along with 10 known diterpenoid alkaloids were isolated from the roots of Aconitum brachypodum Diels (Ranunculaceae). The structure of 1 was elucidated by analysis of its spectroscopic data. It should be noted that compound 1 is the first example with 11, 13-dioxygenated denudatine-type diterpenoid alkaloid isolated from Aconitum brachypodum.

Cytotoxic indole alkaloids from the fruits of Melodinus cochinchinensis.

Eight indole alkaloids, melosines A-H, together with 13 known alkaloids, were isolated from the fruits of Melodinus cochinchinensis. The structure elucidation of isolated secondary metabolites was based on comprehensive spectroscopic data analysis. Melosine B showed moderate cytotoxic activity against five human cancer cell lines, HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values ranging from 1.6 to 8.1µM.

Antimicrobial Constituents of the Mature Carpels of Manglietiastrum sinicum.

Seven new compounds, including a eupodienone-type lignan (1), a dibenzocyclooctadiene-type lignan (2), three tetrahydrofuran-type lignans (3-5), and two 1-phenylbutyl benzoates (6, 7), together with six known compounds, were isolated from the mature carpels of Manglietiastrum sinicum. The structures of new compounds 1-7 were defined by spectroscopic techniques, and the absolute configuration of manglisin A (1) was determined by X-ray crystallography. Compounds 1-4 exhibited moderate antimicrobial activities (MIC values: 0.016-0.14 µM) against Staphylococcus aureus, MRSA 82(#), MRSA 92(#), MRSA 98(#), and MRSA 331(#). Compounds 2 and 3 showed weak cytotoxic activity against five human tumor cell lines.

Limonoids from the fruits of Cipadessa cinerascens.

A new limonoid, 3-de(2-methylbutanoyl)-3-propanoylcipadesin (1), along with 10 known limonoids and 1 known triterpenoid, was isolated from the fruits of Cipadessa cinerascens. Their structures were elucidated on the basis of spectroscopic analysis. All compounds were evaluated for their antimicrobial activities, and compounds 6 and 12 showed weak antimicrobial activities against MRSA 82(#) and MRSA 92(#).

Use of a high-throughput screening approach coupled with in vivo zebrafish embryo screening to develop hazard ranking for engineered nanomaterials.

Because of concerns about the safety of a growing number of engineered nanomaterials (ENM), it is necessary to develop high-throughput screening and in silico data transformation tools that can speed up in vitro hazard ranking. Here, we report the use of a multiparametric, automated screening assay that incorporates sublethal and lethal cellular injury responses to perform high-throughput analysis of a batch of commercial metal/metal oxide nanoparticles (NP) with the inclusion of a quantum dot (QD1). The responses chosen for tracking cellular injury through automated epifluorescence microscopy included ROS production, intracellular calcium flux, mitochondrial depolarization, and plasma membrane permeability. The z-score transformed high volume data set was used to construct heat maps for in vitro hazard ranking as well as showing the similarity patterns of NPs and response parameters through the use of self-organizing maps (SOM). Among the materials analyzed, QD1 and nano-ZnO showed the most prominent lethality, while Pt, Ag, SiO2, Al2O3, and Au triggered sublethal effects but without cytotoxicity. In order to compare the in vitro with the in vivo response outcomes in zebrafish embryos, NPs were used to assess their impact on mortality rate, hatching rate, cardiac rate, and morphological defects. While QDs, ZnO, and Ag induced morphological abnormalities or interfered in embryo hatching, Pt and Ag exerted inhibitory effects on cardiac rate. Ag toxicity in zebrafish differed from the in vitro results, which is congruent with this material's designation as extremely dangerous in the environment. Interestingly, while toxicity in the initially selected QD formulation was due to a solvent (toluene), supplementary testing of additional QDs selections yielded in vitro hazard profiling that reflect the release of chalcogenides. In conclusion, the use of a high-throughput screening, in silico data handling and zebrafish testing may constitute a paradigm for rapid and integrated ENM toxicological screening.