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The integration of magnetic resonance imaging (MRI), cGAS-STING, and anti-CTLA-4 (aCTLA-4) based immunotherapy offers new opportunities for tumor precision therapy. However, the precise delivery of aCTLA-4 and manganese (Mn), an activator of cGAS, to tumors remains a major challenge for enhanced MRI and active immunotherapy. Herein, a theragnostic nanosphere Mn-CREKA-aCTLA-4-SS (MCCS) is prepared by covalently assembling Mn 2+ , silk sericin (SS), pentapeptide CREKA, and aCTLA-4. MCCS are stable with an average size of 160 nm and is almost negatively charged or neutral at pH 5.5/7.4. T1-weighted images showed MCCS actively targeted tumors to improve the relaxation rate r1 and contrast time of MRI. This studies demonstrated MCCS raises reactive oxygen species levels, activates the cGAS-STING pathway, stimulates effectors CD8 + and CD80 + T cells, reduces regulatory T cell numbers, and increases IFN-γ and granzyme secretion, thereby inducing tumor cells autophagy and apoptosis in vitro and in vivo. Also, MCCS are biocompatible and biosafe. These studies show the great potential of Mn-/SS-based integrative material MCCS for precision and personalized tumor nanotheragnostics., (© 2023 Wiley‐VCH GmbH.)

The rational design of cancer theranostics with natural diagnostic information and therapeutic behavior has been considered to be a big challenge, since common theranostics from photothermal and photodynamic therapy need to be activated with external stimuli of photoirradiation to enable the chemotherapeutic effects. In this contribution, we have designed and synthesized a series of simple theranostic agents, TPA-N- n ( n = 4, 8, 12), which could accumulate at the tumor site over 48 h and indicate superior antiproliferative performance in vivo . TPA-N- n was constructed with electron donor triphenylamine-acceptor benzothiadiazole-mitochondria-targeting moiety pyridinium. Complex TPA-N-8 indicated the best cytotoxicity to cancerous HeLa cells, with an IC 50 value of 4.3 μM, and could self-assemble to a nanosphere with a size of 161.2 nm in the DMSO/PBS solution. It is worth noting that TPA-N-8 could accumulate in the mitochondria and produce major ROS species O 2 • - and OH• as well as small amounts of 1 O 2 without photoirradiation. Oxidative DNA damage is initiated due to the imbalance of intracellular redox homeostasis from the significant ROS storm. Multimodal synergistic therapy for HeLa cells was activated, as the PINK1-mediated mitophagy from the damaged mitochondria and DNA damage responsive (DDR) induced necroptosis and autophagy. This work not only provided a successful D-A type theranostic agent with superior anticancer performance from multimodal synergistic therapy but also further demonstrated the high efficacy of a mitochondria-targeting strategy for cancer treatment.

Residual ridge resorption combined with dimensional loss resulting from tooth extraction has a prolonged correlation with early excessive inflammation. Nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotides (ODNs) are double-stranded DNA sequences capable of downregulating the expression of downstream genes of the NF-κB pathway, which is recognized for regulating prototypical proinflammatory signals, physiological bone metabolism, pathologic bone destruction, and bone regeneration. The aim of this study was to investigate the therapeutic effect of NF-κB decoy ODNs on the extraction sockets of Wistar/ST rats when delivered by poly(lactic-co-glycolic acid) (PLGA) nanospheres. Microcomputed tomography and trabecular bone analysis following treatment with NF-κB decoy ODN-loaded PLGA nanospheres (PLGA-NfDs) demonstrated inhibition of vertical alveolar bone loss with increased bone volume, smoother trabecular bone surface, thicker trabecular bone, larger trabecular number and separation, and fewer bone porosities. Histomorphometric and reverse transcription-quantitative polymerase chain reaction analysis revealed reduced tartrate-resistant acid phosphatase-expressing osteoclasts, interleukin-1β, tumor necrosis factor-α, receptor activator of NF-κB ligand, turnover rate, and increased transforming growth factor-β1 immunopositive reactions and relative gene expression. These data demonstrate that local NF-κB decoy ODN transfection via PLGA-NfD can be used to effectively suppress inflammation in a tooth-extraction socket during the healing process, with the potential to accelerate new bone formation.

Recent developments in the area of resonant dielectric nanostructures have created attractive opportunities for concentrating and manipulating light at the nanoscale and the establishment of the new exciting field of all-dielectric nanophotonics. Transition metal dichalcogenides (TMDCs) with nanopatterned surfaces are especially promising for these tasks. Still, the fabrication of these structures requires sophisticated lithographic processes, drastically complicating application prospects. To bridge this gap and broaden the application scope of TMDC nanomaterials, we report here femtosecond laser-ablative fabrication of water-dispersed spherical TMDC (MoS 2 and WS 2 ) nanoparticles (NPs) of variable size (5 to 250 nm). Such NPs demonstrate exciting optical and electronic properties inherited from TMDC crystals, due to preserved crystalline structure, which offers a unique combination of pronounced excitonic response and high refractive index value, making possible a strong concentration of electromagnetic field in the NPs. Furthermore, such NPs offer additional tunability due to hybridization between the Mie and excitonic resonances. Such properties bring to life a number of nontrivial effects, including enhanced photoabsorption and photothermal conversion. As an illustration, we demonstrate that the NPs exhibit a very strong photothermal response, much exceeding that of conventional dielectric nanoresonators based on Si. Being in a mobile colloidal state and exhibiting superior optical properties compared to other dielectric resonant structures, the synthesized TMDC NPs offer opportunities for the development of next-generation nanophotonic and nanotheranostic platforms, including photothermal therapy and multimodal bioimaging.

We developed hybrid nanospheres comprised of two of the most important biomolecules in nature, DNA and proteins, which have excellent biocompatibility, high drug payload capacity, in vivo imaging ability, and in vitro / in vivo cancer targeting capability. The synthesis can be done in a facile one-pot assembly system that includes three steps: step-growth polymerization of two DNA oligomers, addition of streptavidin to assemble spherical hybrid nanostructures, and functionalization of hybrid nanospheres with biotinylated aptamers. To test the feasibility of cancer targeting and drug-loading capacity of the hybrid nanospheres, MUC1-specific aptamers (MA3) were conjugated to nanosphere surfaces (apt-nanospheres), and doxorubicin (Dox) was loaded into nanospheres by DNA intercalation. The successful construction of nanospheres and apt-nanospheres was confirmed by agarose gel electrophoresis and dynamic light scattering (DLS). Their uniform spherical morphology was confirmed by transmission electron microscopy (TEM). Fluorescence spectra of nanospheres demonstrated high Dox-loading capability and slow-release characteristics. In vitro MUC1-specific binding of the apt-nanospheres was confirmed by flow cytometry and confocal microscopy. Dox-loaded apt-nanospheres significantly increased cytotoxicity of the MUC1-positive cancer cells due to aptamer-mediated selective internalization, as shown via cell viability assays. Apt-nanospheres could also be imaged in vivo through the synthesis of hybrid nanospheres using fluorescent dye-conjugated DNA strands. Finally, in vivo specific targeting ability of apt-nanospheres was confirmed in a MUC1-positive 4T1 tumor-bearing mouse model, whereas apt-nanospheres did not cause any sign of systemic toxicity in normal mice. Taken together, our self-assembled DNA-streptavidin hybrid nanospheres show promise as a biocompatible cancer targeting material for contemporary nanomedical technology.

Ulcerative colitis (UC) is one type of inflammatory bowel disease (IBD) and lactoferrin (LF) is a promising protein drug to treat UC. However, targeted LF delivery to optimize bioavailability, targeting and effectiveness remains a challenge. Here, we report an effective strategy to fabricate silk sericin nanospheres systems for the delivery of recombinant human lactoferrin (SS-NS-rhLF). The system is based on the use of optimized transgenic silkworms to generate genetically engineered silk fibers (rhLF-silks). The rhLF silks were used for fabricating SS-NS-rhLF by ethanol precipitation. The SS-NS-rhLF were stable with a spherical morphology with an average diameter of 123 nm. The negatively charged sericins in a pH ≥ 5.5 environment achieved specific targeting of the SS-NS-rhLF to positively charged colonic sites. The SS-NS-rhLF achieved efficient uptake by cells in the inflamed colon of mice when compared to free lactoferrin in solution (SOL-rhLF). Furthermore, oral administration of the SS-NS-rhLF with low dose of rhLF significantly relived symptoms of UC in mice and achieved comparable therapeutic effect to the high dose of SOL-rhLF by supporting the reformation of cell structure and length of colon tissue, reducing the release of inflammatory factors, inhibiting the activation of the NF-κB inflammatory pathway, and maintaining a stable intestinal microbial population in mice. These results showed that the SS-NS-rhLF is a promising system for colitis treatment. STATEMENT OF SIGNIFICANCE: Targeting and effective delivery of multiple biological functional protein human lactoferrin (rhLF) is a promising strategy to treat ulcerative colitis in the clinic. Here, rhLF-transgenic silk cocoons were used to fabricate a rhLF-sericin nanosphere delivery system (SS-NS-rhLF). The fabricated SS-NS-rhLF showed identical spherical morphology, stable structure, sustainable rhLF release, efficient cell uptake and negative charge in an environment of pH above 5.5, thus realized the specific targeting to the positively charged colonic sites to treat UC mice through oral administration. The therapeutic effect of SS-NS-rhLF with a low rhLF dose in the UC mice was comparable to the high dose of free rhLF treatment in solution form, suggesting that the SS-NS-rhLF is a promising system for colitis treatment., Competing Interests: Declaration of Competing Interest The authors declare no competing of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Metallic and semimetallic mesoporous frameworks are of great importance owing to their unique properties and broad applications. However, semimetallic mesoporous structures cannot be obtained by the traditional template-mediated strategies due to the inevitable hydrolytic reaction of semimetal compounds. Therefore, it is yet challenging to fabricate mesoporous semimetal nanostructures, not even mention controlling their pore sizes. Here we develop a facile and robust selective etching route to synthesize monodispersed mesoporous antimony nanospheres (MSbNSs). The pore sizes of MSbNSs are tunable by carefully controlling the partial oxidation of Sb nuclei and the selective etching of the as-formed Sb 2 O 3 . MSbNSs show a wide absorption from visible to second near-infrared (NIR-II) region. Moreover, PEGylated MSbNSs are degradable and the degradation mechanism is further explained. The NIR-II photothermal performance of MSbNSs is promising with a high photothermal conversion efficiency of ~44% and intensive NIR-II photoacoustic signal. MSbNSs show potential as multifunctional nanomedicines for NIR-II photoacoustic imaging guided synergistic photothermal/chemo therapy in vivo. Our selective etching process would contribute to the development of various semimetallic mesoporous structures and efficient multimodal nanoplatforms for theranostics., (© 2022. The Author(s).)

Cell penetrating peptides (CPPs) are peptides that can directly adapt to cell membranes and then permeate into cells. CPPs are usually covalently linked to the surface of nanocarriers to endow their permeability to the whole system. However, hybrids with lipids or polymers make the metabolism much more sophisticated and even more difficult to determine. In this study, we present a continuous sequence of 18 amino acids (FFAARTMIWY(d-P)GAWYKRI). It forms nanospheres around 170 nm, which increase slightly after loading with siRNA and DOX. Notably, it can be internalized by cancer cells mainly through electronic interactions and PD-L1-mediated endocytosis. Compared with poly-l-lysine and polyethyleneimine, it has a much higher efficiency (about four times) of gene transduction while lowering toxicity. In the treatment of cancer, it causes apoptosis (21%) and inhibits the expression of SURVIVIN protein in vitro. In vivo, it shows good biocompatibility as there are no changes in mice's body weight. When administering peptide-siRNA-DOX, tumor growth is inhibited the most (about three times). These results above prove the sequence to be a good candidate for gene therapy and drug delivery.

Chemodynamic therapy (CDT) that utilizes Fenton-type reactions to convert endogenous hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals ( • OH) is a promising strategy in anticancer treatment, but the overexpression of glutathione (GSH) and limited endogenous H 2 O 2 make the efficiency of CDT unsatisfactory. Here, an intelligent nanoplatform CuO 2 @mPDA/DOX-HA (CPPDH), which induced the depletion of GSH and the self-supply of H 2 O 2 , was proposed. When CPPDH entered tumor cells through the targeting effect of hyaluronic acid (HA), a release of Cu 2+ and produced H 2 O 2 were triggered by the acidic environment of lysosomes. Then, the Cu 2+ was reduced by GSH to Cu + , and the Cu + catalyzed H 2 O 2 to produce • OH. The generation of • OH could be distinctly enhanced by the GSH depletion and H 2 O 2 self-sufficiency. Besides, an outstanding photothermal therapy (PTT) effect could be stimulated by NIR irradiation on mesoporous polydopamine (mPDA). Meanwhile, mPDA was an excellent photoacoustic reagent, which could monitor the delivery of nanocomposite materials through photoacoustic (PA) imaging. Moreover, the successful delivery of doxorubicin (DOX) realized the integration of chemotherapy, PTT, and CDT. This strategy could solve the problem of insufficient CDT efficacy caused by the limited H 2 O 2 and overexpression of GSH. This multifunctional nanoplatform may open a broad path for self-boosting CDT and synergistic therapy.

Curcumin, a hydrophobic polyphenol of turmeric, has a variety of biological functions as an herbal supplement, but its poor gastric absorption rate is one of the major factors limiting its oral bioavailability. In the present study, we investigated the functional role of nanospheres loaded with curcumin (nCur) with regard to the motility of gut epithelial HCT116 cells and enterocyte migration along the crypt-villus axis. nCur significantly increased the motility of HCT116 cells and showed much higher migration efficacy than the curcumin. nCur stimulated the small GTPases Rac1 and the phosphorylation of protein kinase C, responsible for the distinctive activation of the mitogen-activated protein kinases. Interestingly, nCur significantly induced the expression of α-actinin, profilin-1, and filamentous (F)-actin as regulated by the phosphorylation of nuclear factor-kappa B during its promotion of cell migration. In mouse models of gut epithelial migration, treatment with nCur had an enhancing effect on the movement of enterocytes along the crypt-villus axis and the expression of cytoskeletal reorganization-related factors. These results indicate that nCur is a functional agent that promotes gut epithelial motility through F-actin-related migration signaling events., Competing Interests: Conflicts of Interest The authors have declared that there is no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Common chemotherapeutic drugs exhibit no specificity for cancer cells and destroy simultaneously healthy cells exhibiting high toxicity and reduced efficacy. The use of nanotechnology, especially of drug delivery systems to the size of the nanoscale, provides rational drug design solutions. Such nanomaterials may have a range of desired characteristics (lack of toxicity, response to certain characteristics of the cancer cells, antimicrobial properties, specific activity, etc.) in order to achieve targeted cancer therapy. In this chapter, polymeric systems with core-shell structure are synthesized, characterized, and studied as potent drug delivery devices for targeted cancer therapy. These polymeric systems are based on natural polysaccharides like cellulose, chitosan, and their derivatives, in combination with synthetic polymer. Polymethylmethacrylate (PMMA) nanospheres are used as a core in order to coat the surface with multiple layers of polysaccharides via layer-by-layer deposition. This design is advantageous due to the use of water as the appropriate solvent. Fabricated polymeric carriers are characterized structurally by AT-IR spectroscopy and morphologically by transmission (TEM) and scanning electron microscopy (SEM). Finally, daunorubicin, an anticancer agent, was encapsulated as a drug model into the carriers.

Cancer cells immersed in inherent oxidative stress are more vulnerable to exogenous oxidative damages than normal cells. Reactive oxygen species (ROS)-mediated oxidation therapy preferentially aggravating tumor oxidative stress to disrupt redox homeostasis, has emerged as an effective and specific anticancer treatment. Herein, following an ingenious strategy of "broaden sources and reduce expenditure", we designed a versatile tumor-specific oxidative stress nanoamplifier enabling economized photodynamic therapy (PDT), to achieve synergistic oxidative stress explosion for superior oxidation therapy. Methods: Cinnamaldehyde (CA) as a therapeutic ROS generator was first conjugated to hyaluronic acid (HA) through acid-labile hydrazone bond to synthesize tailored amphiphilic HA@CA conjugates, which could surprisingly self-assemble into uniform nanofibers in aqueous media. Photosensitizer protoporphyrin (PpIX) was efficiently encapsulated into HA@CA nanofibers and transformed HA@CA nanofibers to final spherical HA@CAP. Results: With beneficial pH-responsiveness and morphology transformation, improved bioavailability and selective tumor accumulation, HA@CAP combining ROS-based dual chemo/photodynamic treatment modalities could induce cytotoxic ROS generation in a two-pronged approach to amplify tumor oxidative stress, termed "broaden sources". Moreover, utilizing CA-induced H 2 O 2 production and cascaded Fenton reaction in mitochondria to consume intracellular overloaded Fe(II), HA@CAP could skillfully block endogenic heme biosynthesis pathway on site to restrain undesired elimination of PpIX for economized PDT, termed "reduce expenditure". Both in vitro and in vivo results demonstrated the superior antitumor performance of HA@CAP. Conclusion: This study offered an inspiring strategy of "broaden sources and reduce expenditure" to specifically boost tumor oxidative stress for reinforced oxidation therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Introduction: Although carbon nanospheres (CNPs) are promising nanomaterials in cancer treatment, how they affect prostate cancer (PCa) remains unclear., Methods: In this study, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy were used to confirm the successful synthesis of CNPs. CCK-8, flow cytometry, Transwell, wound healing, Western blot and immunohistochemistry (IHC) assays were performed to evaluate the antitumor effect of CNPs toward the two kinds of prostate cancer cell lines PC3 and DU145., Results: Our results showed that CNPs inhibited cell growth, invasion, and migration and induced apoptosis and autophagy in PCa cells. Multifactor detection of a single Akt phosphorylation pathway and Western blot results suggested the suppression of 4E-BP1 in PCa cells after incubation with CNPs. The results from animal experiments also suggested the antitumor effect of CNPs and reduced 4E-BP1 expression in PCa tissue samples from BALB/c nude mice administered a local subcutaneous injection of CNPs., Competing Interests: The authors declare no conflicts of interest for this work., (© 2020 Dong et al.)

Inflammatory bowel disease (IBD) refers to progressive inflammatory disorders that impair the gastrointestinal tract's structure and function. Given their selective accumulation in inflamed tissues, nanoparticles are promising drug delivery systems for IBD treatment. The hypothesis here was that drug-free nanoscaled cationic ammonio methacrylate copolymers (AMCNP) may have a beneficial therapeutic effect in murine TNBS-induced colitis. Type A and B AMCNP (RLNP and RSNP, respectively) were prepared and characterized in vitro, and were rectally administered in two concentrations (5 and 25 mg ml -1 ) for the treatment of two grades of murine experimental colitis. The impact of the nanoparticles upon the inflammatory markers, circulating LPS, intestinal permeability and colonic leukocyte populations was examined. Both RLNP and RSNP led to a significant mitigation of mild to moderate experimental colitis, as evident from the substantial reduction of myeloperoxidase (MPO) and alkaline phosphatase (AP) activities (more than two-fold, P < 0.05) and various pro-inflammatory cytokine concentrations (TNF-α, IL-1β, IL-6, IL-12). The best therapeutic efficiency was observed when the particles were used at 5 mg ml -1 , while the more cationic RLNP performed superior. When used against a severe grade of colitis, RLNP (5 mg ml -1 ) resulted in a significant decrease of tissue MPO and TNF-α. It was found that treatment with AMCNP resulted in significant intestinal immune cell depletion, intestinal barrier function improvement, and 1.5-2.5 times reduction of the systemic endotoxin concentration. These findings highlighted the fact that nanoscaling endows the cationic amphiphilic AMCs unique therapeutic properties, which help mitigate murine experimental colitis in the absence of any drug load. The results also provided a glimpse of possible underlying mechanisms through which nanoscaled AMCs might have exerted their therapeutic effect within this context.

Background: The development of highly efficient nanoparticles to convert light to heat for anti-cancer applications is quite a challenging field of research., Methods: In this study, we synthesized unique pimpled gold nanospheres (PGNSs) for plasmonic photothermal therapy (PPTT). The light-to-heat conversion capability of PGNSs and PPTT damage at the cellular level were investigated using a tissue phantom model. The ability of PGNSs to induce robust cellular damage was studied during cytotoxicity tests on colorectal adenocarcinoma (DLD-1) and fibroblast cell lines. Further, a numerical model of plasmonic (COMSOL Multiphysics) properties was used with the PPTT experimental assays., Results: A low cytotoxic effect of thiolated polyethylene glycol (SH-PEG 400 -SH-) was observed which improved the biocompatibility of PGNSs to maintain 89.4% cell viability during cytometry assays (in terms of fibroblast cells for 24 hrs at a concentration of 300 µg/mL). The heat generated from the nanoparticle-mediated phantom models resulted in ΔT=30°C, ΔT=23.1°C and ΔT=21°C for the PGNSs, AuNRs, and AuNPs, respectively (at a 300 µg/mL concentration and for 325 sec). For the in vitro assays of PPTT on cancer cells, the PGNS group induced a 68.78% lethality (apoptosis) on DLD-1 cells. Fluorescence microscopy results showed the destruction of cell membranes and nuclei for the PPTT group. Experiments further revealed a penetration depth of sufficient PPTT damage in a physical tumor model after hematoxylin and eosin (H&E) staining through pathological studies (at depths of 2, 3 and 4 cm). Severe structural damages were observed in the tissue model through an 808-nm laser exposed to the PGNSs., Conclusion: Collectively, such results show much promise for the use of the present PGNSs and photothermal therapy for numerous anti-cancer applications., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Nasseri et al.)

Immunosuppressive chemoresistance is a major barrier in lung cancer treatment. However, the immunosuppressive mechanisms responsible for lung cancer cell chemoresistance and tumor relapse are still unknown. In this study, we introduce a model of precise immunosuppressive-based nanotherapy by designing and delivering biocompatible MDSC-targeted nanocarriers (NCs) into the lung tumor microenvironment. This is accomplished by conjugating l-Norvaline and Sunitinib integrated into biodegradable nanosomes in order to facilitate inhibition of tumor-supporting immunosuppression. Findings show that treatment with NCs increased apoptosis and significantly reduced tumor volume and Ki-67 antigen expression respectively. Biodistribution analysis revealed an increase in drug circulation time, as well as a greater accumulation in lung and peripheral tissues. Furthermore, an upregulation of tumor infiltrating lymphocytes expression was observed, especially CD8+ T cells by 27%, and CD4+ T cells by 7% compared to PBS treatment. The presence of CD161+ (NK1.1) cells revealed NK cell activation followed by decreased MDSC infiltration and MDSC subsets were characterized by the reduction of Gr/CD11b cell population in blood and tissue samples. In addition, these nanospheres, showed increased PTT efficiency and tumour targeting ability as evidenced by highly efficient tumour ablation under near infrared (NIR) exposure. Significant tumor reduction was observed due to recruitment of cytotoxic T-lymphocytes, followed by downregulation of immunosuppressive Foxp3+ Treg cells. Taken together, our findings provide a novel nanodrug delivery strategy for the inhibition of MDSC-related immunosuppression in lung tumor microenvironment and provide a new approach for the efficient treatment of metastatic cancer.

A novel nanocarrier based-on hollow mesoporous carbon nanospheres (HMCNs) with primary amines on its surface, a large cavity, and good hydrophilicity was synthesized by a hydrothermal reaction. The primary amine functionalities on the mesoporous carbon were used as the initiation sites for growing poly (epichlorohydrin) (PCH) chains. The chlorine groups in the side chain of PCH were replaced with imidazole as the pendant groups. Calcium chloride (CaCl 2 ) was applied as a capping agent. The coordination bonding was formed between pendant imidazole groups and calcium ions. Doxorubicin (DOX) was selected as a model of hydrophilic anticancer drug and was loaded onto the nanocarrier and released through the cleavage of the pH-sensitive coordination bonding. The gating mechanism enables the nanocarrier to store and release the calcium ions and the DOX molecules trapped in the pores. MTT assay toward HeLa cells indicated that the nanocarrier had low toxicity because of the surface modification with the oxygen-rich polymer. The cellular uptake of the pH-sensitive nanocarrier for HeLa cancer cell lines was confirmed by CLSM images and flow cytometry. So, the novel pH-sensitive nanocarrier can be applicable to carry and release both DOX drug and calcium ions for cancer treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2019. Published by Elsevier B.V.)

Gold nanoparticles can act as photothermal agents to generate local tumor heating and subsequent depletion upon laser exposure. Herein, photothermal heating of four gold nanoparticles and the resulting induced cancer cell death are systematically assessed, within extra- or intracellular localizations. Two state-of-the-art gold nanorods are compared with small nanospheres (single-core) and nanoraspberries (multicore). Heat generation is measured in water dispersion and in cancer cells, using lasers at wavelengths of 680, 808, and 1064 nm, covering the entire range used in photothermal therapy, defined as near infrared first (NIR-I) and second (NIR-II) windows, with NIR-II offering more tissue penetration. When dispersed in water, gold nanospheres provide no significant heating, gold nanorods are efficient in NIR-I, and only gold nanoraspberries are still heating in NIR-II. However, in cells, due to endosomal confinement, all nanoparticles present an absorption red-shift translating visible and NIR-I absorbing nanoparticles into effective NIR-I and NIR-II nanoheaters, respectively. The gold nanorods then become competitive with the multicore nanoparticles (nanoraspberries) in NIR-II. Similarly, once in cells, gold nanospheres can be envisaged for NIR-I heating. Remarkably, nanoraspberries are efficient nanoheaters, whatever the laser applied, and the extra- versus intra-cellular localization demonstrates treatment versatility., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Curcumin, a hydrophobic polyphenol of turmeric, has a variety of biological functions as a herbal supplement, but its poor gastric absorption rate is one of the major factors limiting its oral bioavailability. In the present study, we have investigated the functional role of a nanosphere loaded with curcumin (CN) during host cell death elicited by the Gram-negative bacterium V. vulnificus in human gastrointestinal epithelial HT-29 cells and an ileal-ligated mouse model. The recombinant protein (r) VvhA produced by V. vulnificus significantly reduced the viability of HT-29 cells. The cytotoxic effect of rVvhA was restored upon a treatment with CN (100 ng/mL), which had shown 1000-fold higher anti-apoptotic efficacy than curcumin. CN inhibited the phosphorylation of c-Src and PKC mediated by intracellular ROS responsible for the distinctive activation of the MAPKs in rVvhA-treated HT-29 cells. Interestingly, CN significantly restored the expression of Bax, Bcl-2, and cleaved caspase-3 as regulated by the phosphorylation of NF-κB. In mouse models of V. vulnificus infection, treatment with CN had a blocking effect that elevated the levels of TUNEL-positive DNA fragmentation and apoptosis-related proteins. These results indicate that CN is a functional agent that manipulates the V. vulnificus VvhA signaling pathway responsible for gastrointestinal cell death.

Timely diagnosis of acute myocardial infarction (AMI) strongly impacts the survival rate of patients. The authors report the development of a two-shell hollow silica contrast agent useful for ultrasound (US) imaging, which is able to provide ultra-early diagnosis of AMI. To target the characterization of fast blood flow and high blood pressure in the heart, two shells of hollow silica are adopted with opposite polarities, which assemble based on amino and perfluorodecyl silanes. The external amino silane facilitates the attachment of disease-targeted groups, while the internal perfluorodecyl silane provides great US imaging contrast. The material also possesses superior water dispersity, controllable morphology, low toxicity, and biodegradability both in vitro and in vivo, thus promoting its applications in the ultra-early diagnosis of AMI in rats, and is particularly useful for delineation of myocardial necrosis sites., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An important objective of cancer nanomedicine is to improve the delivery efficacy of functional agents to solid tumors for effective cancer imaging and therapy. Stimulus-responsive nanoplatforms can target and regulate the tumor microenvironment (TME) for the optimization of cancer theranostics. Here, we developed magnetic manganese oxide sweetgum-ball nanospheres (MMOSs) with large mesopores as tools for improved cancer theranostics. MMOSs contain magnetic iron oxide nanoparticles and mesoporous manganese oxide (MnO 2 ) nanosheets, which are assembled into gumball-like structures on magnetic iron oxides. The large mesopores of MMOSs are suited for cargo loading with chlorin e6 (Ce6) and doxorubicin (DOX), thus producing so-called CD@MMOSs. The core of magnetic iron oxides could achieve magnetic targeting of tumors under a magnetic field (0.25 mT), and the targeted CD@MMOSs may decompose under TME conditions, thereby releasing loaded cargo molecules and reacting with endogenous hydrogen peroxide (H 2 O 2 ) to generate oxygen (O 2 ) and manganese (II) ions (Mn 2+ ). Investigation in vivo in tumor-bearing mice models showed that the CD@MMOS nanoplatforms achieved TME-responsive cargo release, which might be applied in chemotherapy and photodynamic therapy. A remarkable in vivo synergy of diagnostic and therapeutic functionalities was achieved by the decomposition of CD@MMOSs and coadministration with chemo-photodynamic therapy of tumors using the magnetic targeting mechanism. Thus, the result of this study demonstrates the feasibility of smart nanotheranostics to achieve tumor-specific enhanced combination therapy.

Improved therapeutic effects can be achieved by the delivery of combination of drugs through multifunctional cell targeted nanocarrier systems. The present investigation reports the preparation of Poly (D,L-lactic-co-glycolic acid) (PLGA) nanospheres loaded with the novel combination such as Rutin (R) and Benzamide (B) as drugs using water-oil-water (w/o/w) emulsion method. Dual drug loaded PLGA nanospheres (R/B@PLGA) were stabilized by poly (vinyl alcohol) (PVA) coating and characterized in terms of morphology, size, surface charge, and structural chemistry by Scanning electron microscopy (SEM), Dynamic light scattering (DLS), Zeta potential analysis, UV-vis and Fourier transform infrared (FT-IR) spectroscopy. The inhibitory effects of rutin and benzamide on MDA-MB-231 (triple negative breast cancer-TNBC) cells using the drug loaded PLGA nanospheres as well as their non-toxic features were evaluated in vivo. The anticancer activity of the R/B@PLGA nanospheres through cell cycle disruption and apoptotic induction was assessed in vitro by flow cytometry analysis. Further, the in vitro antioxidant capacity, pH-based drug release and hemocompatible property were also investigated. It was shown that the R/B@PLGA nanospheres lacked genotoxic potential and they did not alter the antioxidant enzyme activities and histological features of zebrafish. Hence, this dual drug delivery system (DDS) not only actively targets multidrug-resistance (MDR) associated phenotype but also improves the therapeutic efficiency by its non-toxic nature towards enhanced cancer cell focused delivery and sustained release of therapeutic agents., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cisplatin (CDDP) is the most commonly used chemotherapeutic drug and has an irreplaceable role in cancer treatment. However, CDDP-induced acute kidney injury (AKI) greatly limits its use. Abundant evidence has confirmed that apoptosis contributes to AKI caused by CDDP administration. The nanoparticle form of selenium, also known as Se@SiO2 nanocomposites (NPs), has been proven to be a potential agent to prevent apoptotic cell death. In this article, we established acute kidney injury models in vivo via a single injection of CDDP and used human kidney 2 (HK-2) cells for experiments in vitro. We demonstrated that NPs can improve CDDP-induced renal dysfunction. In addition, therapy with NPs attenuated apoptosis in cells and kidney tissues treated with CDDP. In terms of mechanism, we discovered that Sirt1, a deacetylase with an important role in CDDP-induced acute kidney injury, was remarkedly increased after NPs pretreatment, and the anti-apoptotic effect of the NPs was markedly abrogated after the inhibition of Sirt1. The results linked the protective effect of NPs on nephrotoxicity with Sirt1, suggesting the potential clinical importance of nanomaterials in alleviating the side effects of chemotherapy., (Copyright © 2019. Published by Elsevier Inc.)

Carbon-based light-activated materials can absorb optical energy to generate photoacoustic (PA) signals for imaging or transduce optical photons to thermal energy, which holds great promise for biomedical applications. Herein, we synthesize hollow and mesoporous carbon nanospheres (HMCNs) with uniform size on a large scale. The properties of hollow cavity and mesoporous structures make the HMCNs achieve high drug loading (480 mg DOX per g HMCNs). The present intense near infrared (NIR) absorbance achieves excellent photoacoustic imaging ability and photothermal conversion efficacy (32.0%). More interestingly, the encapsulated drugs can have a triggered release under NIR irradiation. The investigations in vitro and in vivo demonstrate that HMCNs have excellent biocompatibility, and accumulate in tumors by the enhanced permeability and retention (EPR) effect. Moreover, under NIR irradiation, in vivo evaluation shows that HMCNs can perform strong PA imaging, and induce great tumor inhibition by the combination of chemotherapy and PTT under the guidance of photoacoustic imaging. The present study provides new insight for design of novel biocompatible light-activated carbons for cancer nanotheranostics.

Due to the limitation of inorganic nanomaterials in present clinical applications induced by their inherent nonbiodegradability and latent long-term side effects, we successfully prepared double switch degradable and clearable trinickel monophosphide porous hollow nanospheres (NiP PHNPs) modified with bovine serum albumin (BSA). Attributed to their acidic and oxidative double switch degradation capacities, NiP PHNPs can be effectively excreted from mice without long-term toxicity. Moreover, because of the paramagnetic and high molar extinction coefficient property resulting from the strong absorption in the second near-infrared light (NIR II) biowindow, NiP PHNPs have potential to be used for photoacoustic imaging (PAI) and T 1 -weighted magnetic resonance imaging (MRI) guided photothermal ablation of tumors in the NIR II biowindow. Specifically, it is interesting that the hollow structure and acidic degradation property enable NiP PHNPs to act as intelligent drug carriers with an on-demand release ability. These findings highlight the great potential of NiP PHNPs in the cancer theranostics field and inspire us to further broaden the bioapplications of transition metal phosphides.

We previously showed that folate liposomes of 5FU made from Dipalmitoylphosphatidylcholine (DPPC) induced cell death in HT-29 and HeLa cells more potently than bulk 5FU. Also, a primary 5FU liposomal formulation with phosphatidyl choline (PC) exhibited higher cytotoxicity in murine colon cancer cells. In the present study, optimization of 5FU PC liposome, mechanism of cell death induction in human cancer cell lines and its safety along with other assays have been employed for targeted PC liposomes of 5FU. Liposomes were prepared using thin layer method and optimization of preparation was assessed using central composite design (CCD) of response surface methodology (RSM). Folic acid (FA) was employed as the targeting ligand. Morphology of 5FU loaded liposomes and changes in their thermal behavior were assessed by transmission electron microscopy (TEM) and differential scanning calorimetry (DSC), respectively. In vitro cytotoxicity was explored using MTT assay in HT-29, Caco-2, HeLa and MCF-7 cell lines. Cytotoxicity mechanism of the targeted delivery system was searched through the evaluation of reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (∆Ψ m ), the release of cytochrome c, the activity of caspase 3/7 and apoptosis and necrosis rate. Liposomes were spherical in shape and 5FU was successfully encapsulated into liposomes rather in an amorphous state. Our interesting results showed that in HT-29 cells targeted liposomes triggered the mitochondrial apoptotic pathway by decreasing the mitochondrial membrane potential, releasing of cytochrome c and promoting the substantial activity of caspase 3/7. In HeLa cells, however, targeted liposomes particularly activated necrosis pathway through the overproduction of ROS. Folate-liposomal 5FU showed significantly higher antitumor efficiency compared to free drug. The results of this study offer new prospects for cancer therapy with reducing systemic drug exposure and associated toxicities., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The integration of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhanced anticancer effects. Herein, we report biodegradable cancer cell membrane-coated mesoporous copper/manganese silicate nanospheres (mCMSNs) with homotypic targeting ability to the cancer cell lines and enhanced ROS generation through singlet oxygen ( 1 O 2 ) production and glutathione (GSH)-activated Fenton reaction, showing excellent CDT/PDT synergistic therapeutic effects. We demonstrate that mCMSNs are able to relieve the tumor hypoxia microenvironment by catalytic decomposition of endogenous H 2 O 2 to O 2 and further react with O 2 to produce toxic 1 O 2 with a 635 nm laser irradiation. GSH-triggered mCMSNs biodegradation can simultaneously generate Fenton-like Cu + and Mn 2+ ions and deplete GSH for efficient hydroxyl radical (•OH) production. The specific recognition and homotypic targeting ability to the cancer cells were also revealed. Notably, relieving hypoxia and GSH depletion disrupts the tumor microenvironment (TME) and cellular antioxidant defense system, achieving exceptional cancer-targeting therapeutic effects in vitro and in vivo. The cancer cells growth was significantly inhibited. Moreover, the released Mn 2+ can also act as an advanced contrast agent for cancer magnetic resonance imaging (MRI). Thus, together with photosensitizers, Fenton agent provider and MRI contrast effects along with the modulating of the TME allow mCMSNs to realize MRI-monitored enhanced CDT/PDT synergistic therapy. It provides a paradigm to rationally design TME-responsive and ROS-involved therapeutic strategies based on a single polymetallic silicate nanomaterial with enhanced anticancer effects.

Okara is a by-product of tofu manufacturing and is usually used as a feedstuff. Herein, we developed a methodology of using okara as a carbon source for the preparation of photothermal nano-materials. It's interesting to find that just after calcination, the carbonized okara forms sphere-shaped hollow particles (denoted as HCNS) with an average diameter of 200 nm. Owning to the existence of a cavity, the HCNS was found to exhibit not only a good photothermal conversion efficiency, but also an ideal photoacoustic imaging property, which makes it a promising agent for imaging-guided photothermal therapy (PTT). The high photothermal conversion efficiency can result from the high carbon content and its hollow morphology. The in vitro and in vivo results both demonstrated the biocompatibility and capacity of the plant source carbon spheres for NIR-triggered cancer treatment. Therefore, the current work suggests a new method to gain a safe and low-cost photothermal platform which could be further exploited in biomedical fields.

Biomedical application of boron nitride (BN) nanomaterials has recently attracted considerable attentions. BN nanospheres (BNNS) could safely deliver anti-cancer drug into tumor cells, which makes them potential nanocarrier for cancer therapy. However, the poor dispersity in physiological environments and low drug loading capacity severely limit their further applications. Herein, we developed a novel drug delivery system based on folate-conjugated mesoporous silica (MS)-functionalized BNNS (BNMS-FA). Dispersity and drug loading capacity of BNNS were highly improved by MS modification. BNMS-FA complexes were nontoxic up to a concentration of 100 μg/mL, and could be specifically internalized by HeLa and MCF-7 cells via folate receptor-mediated endocytosis. Doxorubicin (DOX) could be loaded onto BNMS-FA complexes with high efficiency via π-π stacking and hydrogen bonding, and showed a sustained release pattern under different pH conditions. BNMS-FA/DOX complexes exhibited superior drug internalization and antitumor efficacy over free DOX, BNNS/DOX and BNMS/DOX complexes, which were considered promising for targeted cancer therapy., (Copyright © 2018. Published by Elsevier B.V.)

Synergistic thermo-chemotherapy based multiple stimuli-responsive drug delivery systems have achieved significant improvement of cancer curative effects compared with single modality treatment. Nevertheless, the efficacy of thermo-chemotherapy is often reduced in drug-resistant tumors and the therapy method is unexpectedly associated with potential toxicity by utilizing poorly degradable materials. Here, we report a simple approach to encapsulate three drug payloads into multi-sensitive and degradable nanospheres (SDC@NS) to achieve anticancer effects. SDC@NS comprise a photothermal agent (cypate), an anticancer agent (doxorubicin), and a nitric oxide donor (SNAP) to achieve controllable drugs release in high concentration glutathione or under near-infrared light (NIR) irradiation. Hyperthermia from NIR-mediated cypate can accelerate cancer cell apoptosis in vitro and tumor tissue ablation in vivo. Furthermore, our results also confirmed that the nitric oxide-based SDC@NS showed significant cytotoxicity compared to the nitric oxide absent group (denoted as DC@NS) and an enhanced chemotherapy effect in vivo. The photothermal effect and payloads can synchronously realize cancer therapy and provide a new insight into the enhanced synergistic therapeutic effect.

To overcome the unfavorable effects of the hydrophobicity of drugs and cancer resistance, mesoporous NiS 2 nanospheres (mNiS 2 NSs) have been successfully developed here to package hydrophobic camptothecin (CPT) and realize the synergistic photothermal-chemotherapy of cancer. The mNiS 2 NSs which were prepared through a facile solvothermal method here exhibited not only considerable near-infrared (NIR) absorption and good photothermal conversion efficiency as high as 44.6%, but also achieved a NIR light induced CPT release property which were both beneficial for improving the cancer cell-killing efficacy. After a short period of NIR light illumination, a significant intensified cell killing efficacy was observed when 4T1 or HepG2 cancer cells were incubated with CPT@mNiS 2 NSs. Thus, mNiS 2 NSs have been demonstrated here to have potential as a novel NIR light-responsive hydrophobic drug delivery nanoplatform for realizing synergistic cancer treatment.

Despite great progress in photodynamic therapy (PDT), the therapeutic effect is still limited by some points, such as tumor hypoxia, the short lifetime and the limited action region of 1O2. Herein, a special kind of three-dimensional dendritic mesoporous silica nanosphere (3D-dendritic MSN) was synthesized and used as a robust nanocarrier to deliver abundant hydrophobic photosensitizer chlorin e6 (Ce6) to the A549 lung cancer cells. To address the tumor hypoxia issue, the nanozyme Pt nanoparticles (Pt NPs) were immobilized onto the channels of 3D-dendritic MSNs to catalyze the conversion of intracellular H2O2 to oxygen. Moreover, due to the in situ reduction process, the uniform Pt NPs distributed well on the surface of 3D-dendritic MSNs with high homogeneous dispersity. Additionally, a mitochondria-targeting ligand, triphenylphosphine (TPP), was conjugated to the Pt-decorated 3D-dendritic MSN composites to form a mitochondria targeted system for the PDT. In a combination of the peroxidase-like Pt NPs with mitochondria-targeting ability of TPP, a reactive oxygen species (ROS) burst in the mitochondria was achieved and resulted in the cell apoptosis. This well-designed system shows an enhanced PDT effect of killing A549 cells, and promotes a new H2O2-activatable strategy to overcome hypoxia for tumor PDT.

It is of extreme importance to reduce side effects resulting from the nonspecific uptake of phototherapeutic agents by normal tissues. Currently, the single responsive strategy still cannot entirely satisfy the requirements of practical applications. In this study, we developed one kind of combination-responsive phototherapeutic nanoplatforms, where oxygen-deficient molybdenum oxide (MoO 3- x ) hybridized hyaluronic acid (HA) hollow nanospheres, namely, MoO 3- x @HA HNSs, were constructed via a facile one-step method. In MoO 3- x @HA HNSs, the reasonable combination of actively targeted specificity endowed by the HA component and tumor microenvironment-responsive phototherapy activity induced by the MoO 3- x component can effectively improve the precision of phototherapy. The in vitro and in vivo experimental results confirm that MoO 3- x @HA HNSs can selectively kill CD44-overexpressing cancer cells and inhibit tumor growth under an 808 nm laser irradiation, revealing their remarkable synergistic photothermal therapy/photodynamic therapy effect with CD44 receptor-targeted specificity and pH responsiveness in treating cancer. We also prove that MoO 3- x @HA HNSs can serve as one kind of contrast agent to achieve the computed tomography/photoacoustic imaging. Encouraged by these results, it is anticipated that the reasonable combination of active targeting and tumor microenvironment responsiveness can be a promising strategy to develop phototherapeutic nanoplatforms for precise multimodality cancer theranostics.

Photothermal therapy (PTT) is providing new opportunities for killing cancer cells. In this work, we introduce a new nanomedicine based on spherical MoS2 nanoparticles for PTT treatment of tumors, prepared using "green" bottom-up technology. To increase water solubility and avoid rapid clearance by the reticuloendothelial system, polyethylene glycol (PEG) was used to coat them. These MoS2-PEG nanospheres with an appropriate size (∼100 nm) exhibit high photothermal conversion efficiency (26.7%). In vitro cellular studies revealed that the MoS2-PEG nanospheres showed negligible cytotoxicity. Additionally, through combining the MoS2-PEG nanosphere samples with NIR irradiation at 808 nm, excellent in vitro tumor cell killing efficacy was achieved. In the 4T1 tumor model, the MoS2-PEG nanospheres exhibited good antitumor efficiency in vivo, displaying complete tumor inhibition over 16 days after treatment. Therefore, MoS2-PEG nanospheres played an important role in tumor destruction, and this concept for developing spherical MoS2-based nanomedicines can serve as a platform technology for the next generation of in vivo PTT agents.

Diabetic ischemic ulcer is an intractable diabetic complication. Angiogenesis is a critical factor for wound healing in patients with diabetic foot wounds. Sustained gene delivery could be notably necessary in modulating gene expression in chronic ulcer healing and might be a promising approach for diabetic foot ulcers. In the present study, Sprague-Dawley rats were used to establish diabetic foot ulcer models by streptozotocin and skin biopsy punch. The plasmids expressing VEGF-A and PDGF-B were prepared and then incorporated with polylactic-co-glycolic acid (PLGA) nanospheres to upregulate genes expression. The aim of this study was to explore whether the engineered VEGF-A and PDGF-B based plasmid-loaded nanospheres could be upregulated in streptozotocin-induced diabetic rats and improve the wound healing. The cultured fibroblasts could be effectively transfected by means of nanosphere/plasmid in vitro. In vivo, the expression of VEGF-A and PDGF-B was significantly upregulated at full-thickness foot dorsal skin wounds and the area of ulceration was progressively and significantly reduced following treatment with nanosphere/plasmid. These results indicated that combined gene transfer of VEGF-A and PDGF-B could improve reparative processes in the wounded skin of diabetic rats and nanosphere may be a potential non-viral vector for gene therapy of the diabetic foot ulcer.

Nanomaterials with intrinsic enzyme-like activities (nanozymes), have been widely used as artificial enzymes in biomedicine. However, how to control their in vivo performance in a target cell is still challenging. Here we report a strategy to coordinate nanozymes to target tumor cells and selectively perform their activity to destruct tumors. We develop a nanozyme using nitrogen-doped porous carbon nanospheres which possess four enzyme-like activities (oxidase, peroxidase, catalase and superoxide dismutase) responsible for reactive oxygen species regulation. We then introduce ferritin to guide nitrogen-doped porous carbon nanospheres into lysosomes and boost reactive oxygen species generation in a tumor-specific manner, resulting in significant tumor regression in human tumor xenograft mice models. Together, our study provides evidence that nitrogen-doped porous carbon nanospheres are powerful nanozymes capable of regulating intracellular reactive oxygen species, and ferritinylation is a promising strategy to render nanozymes to target tumor cells for in vivo tumor catalytic therapy.

About 40% of the world's population lives in malaria zones where it presents a challenging health problem. Malaria treatment and prevention have been hindered by drug resistance. Bisphosphonates have been found to be active against Trypanosoma cruzi and Plasmodium falciparum that cause Chaga's disease and malaria respectively. However, bisphosphonates have a shortcoming of being rapidly removed from the bloodstream through the kidneys before reaching the target sites due to their low molecular weight. In the current study, increased bisphosphonates' efficacy for malaria treatment was attempted by conjugating bisphosphonates onto carbon nanospheres (CNSs). The synthesis of the target compounds was confirmed by SEM, TEM, EDX, FTIR, Raman and TGA. The target CNSs containing bisphosphonates were evaluated for antimalarial activity against a chloroquine-resistant strain of P. falciparum. From the free bisphosphonates to the conjugates, the results obtained revealed that there were improvements in percentage parasite kill (from -10.71% to 18%, -18.93% to 28.09% and 10.47% to 28.33% for alendronate, pamidronate and neridronate, respectively). The haemolysis assays revealed that the synthesized compound did not have a toxic impact on healthy red blood cells. The results indicate that bisphosphonates conjugated CNSs are said to be promising P. falciparum blood stage inhibitors.

Radioresistance is one of the undesirable impediments in hypoxic tumors, which sharply diminishes the therapeutic effectiveness of radiotherapy and eventually results in the failure of their treatments. An attractive strategy for attenuating radioresistance is developing an ideal radiosensitization system with appreciable radiosensitization capacity to attenuate tumor hypoxia and reinforce radiotherapy response in hypoxic tumors. Therefore, we describe the development of Gd-containing polyoxometalates-conjugated chitosan (GdW 10 @CS nanosphere) as a radiosensitization system for simultaneous extrinsic and intrinsic radiosensitization, by generating an overabundance of cytotoxic reactive oxygen species (ROS) using high-energy X-ray stimulation and mediating the hypoxia-inducible factor-1a (HIF-1a) siRNA to down-regulate HIF-1α expression and suppress broken double-stranded DNA self-healing. Most importantly, the GdW 10 @CS nanospheres have the capacity to promote the exhaustion of intracellular glutathione (reduced GSH) by synergy W 6+ -triggered GSH oxidation for sufficient ROS generation, thereby facilitating the therapeutic efficiency of radiotherapy. As a result, the as-synthesized GdW 10 @CS nanosphere can overcome radioresistance of hypoxic tumors through a simultaneous extrinsic and intrinsic strategy to improve radiosensitivity. We have demonstrated GdW 10 @CS nanospheres with special radiosensitization behavior, which provides a versatile approach to solve the critical radioresistance issue of hypoxic tumors.

NaYF 4 :Yb,Er upconversion nanoparticles (UCNPs) capped with long-chain carboxylic acid were synthesized and then conjugated with chitosan (CS) in the aid of N-hydroxysuccinimide. The resultant nanocompound was integrated with doxorubicin (DOX) and Roussin's black salt (RBS), a photosensitive nitric oxide (NO) donor to produce stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres as nanocarriers for controllable drug delivery. On the one hand, the encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible photons to trigger NO release. On the other hand, the entrapped DOX can be released at lowered pH from the swollen nanospheres caused by stretched oleoyl-CS chains under acidic conditions. The UCNPs(DOX)@CS-RBS nanospheres exhibit great therapeutic efficacy, which is attributable to the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study highlights the controllable release of NO and DOX from the same nanocarriers and the synergistic therapeutic effect on tumors, which could give new insights into improving cancer nanotherapeutics., Statement of Significance: In this paper, core-shell structured UCNPs(DOX)@CS-RBS nanospheres have been designed and synthesized via a step-by-step procedure. The stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres act as nanocarriers for controllable drug delivery towards cancer therapy. The encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible light to trigger NO release. Meanwhile, the entrapped DOX can be released from the swollen nanospheres caused by stretched oleoyl-CS chains at lowered pH typical of intracellular environment. Synergistic cancer therapy will be achieved through the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study provides new drug nanocarriers with high antitumor efficacy for synergistic cancer therapy., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Development of novel and effective drug delivery systems for controlled release of bioactive molecules is of critical importance in the field of regenerative medicine. Here, oppositely charged gelatin nanospheres are incorporated into silk fibroin nanofibers through a colloidal electrospinning technique. A novel fibrous nano-in-nano drug delivery system is fabricated without the use of any organic solvent. The distribution of fluorescently labeled gelatin A and B nanospheres inside the nanofibers can be fine-tuned by simple adjustment of the weight ratio between the nanospheres and the relative feeding rate of core and shell solutions containing nanospheres by using single and coaxial nozzle electrospinning, respectively. Incorporation of vancomycin-loaded gelatin B nanospheres into the silk fibroin nanofibrous membranes results in a more sustained release of vancomycin, compared to the gelatin nanospheres free membranes. In addition, these membranes exhibit excellent and prolonged antibacterial effects against Staphylococcus aureus. Moreover, these membranes support the attachment, spreading, and proliferation of periodontal ligament cells. These results suggest that the beneficial properties of gelatin nanospheres can be exploited to improve the biological functionality of electrospun nanofibrous silk fibroin membranes., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Combining controllable photothermal therapy and efficacious gene therapy in a single platform holds great promise in cancer therapy due to the enhanced combined therapeutic effects. Herein, polyethyleneimine-grafted oxidized mesoporous carbon nanospheres (OP) were developed for combined photothermal combined gene therapy in vitro and in vivo. The synthesized OP was characterized to have three dimensional spherical structure with uniformed diameter, ordered mesopores with graphitic domains, high water dispersion with zeta potential of +22 mV, and good biocompatibility. Consequently, OP was exploited as the photothermal convertor with strong NIR absorption and the gene vector via electrostatic interaction, which therefore cannot only deliver the therapeutic gene (pING4) to tumors for gene therapy, but also can eliminate the tumors by photothermal ablation. Moreover, the improved gene therapy accompanied by the NIR photothermally enhanced gene release was also well achieved based on OP. The excellent combined therapeutic effects demonstrated in vitro and in vivo suggested the OP's potential for cancer therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Unlabelled: Dual drug delivery of drugs with different therapeutic effects in a single system is an effective way to treat a disease. One of the main challenges in dual drug delivery is to control the release behavior of each drug independently. In this study, we devised thermo-responsive polymeric nanospheres that can provide simultaneous and independent dual drug delivery in the response to temperature change. The nanospheres based on chitosan oligosaccharide conjugated pluronic F127 grafting carboxyl group were synthesized to deliver kartogenin (KGN) and diclofenac (DCF) in a single system. To achieve the dual drug release, KGN was covalently cross-linked to the outer part of the nanosphere, and DCF was loaded into the inner core of the nanosphere. The nanospheres demonstrated immediate release of DCF and sustained release of KGN, which were independently controlled by temperature change. The nanospheres treated with cold temperature effectively suppressed lipopolysaccharide-induced inflammation in chondrocytes and macrophage-like cells. The nanospheres also induced chondrogenic differentiation of mesenchymal stem cells, which was further enhanced by cold shock treatment. Bioluminescence of the fluorescence-labeled nanospheres was significantly increased after cold treatment in vivo. The nanospheres suppressed the progression of osteoarthritis in treated rats, which was further enhanced by cold treatment. The nanospheres also reduced cyclooxygenase-2 expression in the serum and synovial membrane of treated rats, which were further decreased with cold treatment. These results suggest that the thermo-responsive nanospheres provide dual-function therapeutics possessing anti-inflammatory and chondroprotective effects which can be enhanced by cold treatment., Statement of Significance: We developed thermo-responsive nanospheres that can provide a useful dual-function of suppressing the inflammation and promoting chondrogenesis in the treatment of osteoarthritis. For a dual delivery system to be effective, the release behavior of each drug should be independently controlled to optimize their desired therapeutic effects. We employed rapid release of diclofenac for acute anti-inflammatory effects, and sustained release of kartogenin, a newly found molecule, for chondrogenic effects in this polymeric nanospheres. This nanosphere demonstrated immediate release of diclofenac and sustained release of kartogenin, which were independently controlled by temperature change. The effectiveness of this system to subside inflammation and regenerate cartilage in osteoarthritis was successful demonstrated through in vitro and in vivo experiments in this study. We think that this study will add a new concept to current body of knowledge in the field of drug delivery and treatment of osteoarthritis., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Carbon nanomaterials with small size and unique optical properties have attracted intensive interest for their promising biomedical applications. In this work, glucose-derived carbonaceous nanospheres (CNSs) with high photothermal conversion efficiency up to 35.1% are explored for the first time as a novel carbon-based theranostic agent. Different from most other carbon nanomaterials, the obtained CNSs are highly biocompatible and nontoxic because of their intrinsic hydrophilic property and the use of glucose as raw materials. Under near-infrared laser irradiation (808 nm, 6 W cm(-2)) for 10 min, less than 15% of PC-3M-IE8 cells exposed to CNSs aqueous dispersions (0.16 mg/mL) remained alive. After intravenous administration of CNSs aqueous dispersions into nude mice, the photoacoustic intensity of the tumor region is about 2.5 times higher than that of preinjection. These results indicate that CNSs are suitable for simultaneous photoacoustic imaging and photothermal ablation of cancer cells and can serve as promising biocompatible carbon-based agents for further clinical trials.

This article describes an effect based on the wetting transparency of graphene; the morphology of a metallic film (≤20 nm) when deposited on graphene by evaporation depends strongly on the identity of the substrate supporting the graphene. This control permits the formation of a range of geometries, such as tightly packed nanospheres, nanocrystals, and island-like formations with controllable gaps down to 3 nm. These graphene-supported structures can be transferred to any surface and function as ultrasensitive mechanical signal transducers with high sensitivity and range (at least 4 orders of magnitude of strain) for applications in structural health monitoring, electronic skin, measurement of the contractions of cardiomyocytes, and substrates for surface-enhanced Raman scattering (SERS, including on the tips of optical fibers). These composite films can thus be treated as a platform technology for multimodal sensing. Moreover, they are low profile, mechanically robust, semitransparent and have the potential for reproducible manufacturing over large areas.

Multifunctional nanocomposites combining imaging and therapeutic functions have great potential for cancer diagnosis and therapy. In this work, we developed a novel theranostic agent based on hollow gold nanospheres (HGNs) and superparamagnetic iron oxide nanoparticles (SPIO). Taking advantage of the excellent magnetic properties of SPIO and strong near-infrared (NIR) absorption property of HGNs, such nanocomposites were applied to targeted magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) of cancer cells. In vitro results demonstrated they displayed significant contrast enhancement for T2-weighted MRI and strong PAI signal enhancement. Simultaneously, the nanocomposites exhibited a high photothermal effect under the irradiation of the near-infrared laser and can be used as efficient photothermal therapy (PTT) agents for selective killing of cancer cells. All these results indicated that such nanocomposites combined with MRI-PAI and PTT functionality can have great potential for effective cancer diagnosis and therapy.

Targeting nanocontainers to the pathological zone and controlling release of their cargoes, in particular delivery of anticancer drugs to specific tumor cells in a targeted and controlled manner, remain the key challenges in drug delivery. This paper reports the development of a traceable and tumor-targeted intracellular drug release nanocontainer. The nanocontainer is obtained by in situ growth of silver nanoparticles (AgNPs) on the surfaces of mesoporous silica nanospheres (MSNs) using a DNA-templated process. Additionally, drug release from the nanopores is achieved by selective glutathione (GSH)-triggered dismantle of the AgNPs, and the concurrent fluorescence change allows real-time monitoring of drug release efficacy and facile visualization of in vivo delivery events. After being functionalized with sgc8 aptamer on the outer shell of the AgNPs, the targeted nanocontainers are delivered into acute lymphoblastic leukemia cells by aptamer-mediated recognition and endocytosis. Moreover, the GSH-responsive process presents an improvement in the cell-specific drug release and chemotherapeutic inhibition of tumor growth.

Photothermal therapy (PTT) employs photosensitizing agents, which are taken up by cells and generate heat when irradiated with near-infrared (NIR) light, to enable the photoablation of cancer cells. High absorption in the NIR region is crucial for a photosensitizing agent to achieve efficient PTT. Different combinations between gold nanoparticles and fluorescent agents always influence their spectrum properties. Herein, we fabricated a novel combination of a fluorescent agent (doxorubicin, DOX, also a popular chemotherapeutic agent) with gold nanospheres by synthesizing hybridized DOX-Au nanospheres (DAuNS), where a part of the DOX molecules and Au co-formed a hybridized matrix as the shell and the remaining DOX molecules precipitated as the core. The unique structure of DAuNS induced interesting changes in the characteristics including spectrum properties, morphology, drug loading and antitumor activity. We observed that DAuNS exhibited a significantly enhanced surface plasmon absorption in the NIR region, inducing a more efficient photothermal conversion and stronger tumor-cell killing ability under NIR laser irradiation. In addition, our study presents a new and simple platform to load a drug into nanoparticles. DAuNS could be a promising nanoparticle with the "two punch" efficacy of PTT and chemotherapy and could be used in clinical applications due to its controllable synthesis, small size, and narrow size distribution.

Concerns related to pulmonary toxicity and non-specificity of nanoparticles have limited their clinical applications for aerosol delivery of chemotherapeutics in lung cancer. We hypothesized that pulmonary surfactant mimetic nanoparticles that offer pH responsive release specifically in tumor may be a possible solution to overcome these issues. We therefore developed lung surfactant mimetic and pH responsive lipid nanovesicles for aerosol delivery of paclitaxel in metastatic lung cancer. 100-200 nm sized nanovesicles showed improved fusogenicity and cytosolic drug release, specifically with cancer cells, thereby resulting in improved cytotoxicity of paclitaxel in B16F10 murine melanoma cells and cytocompatibility with normal lung fibroblasts (MRC 5). The nanovesicles showed airway patency similar to that of endogenous pulmonary surfactant and did not elicit inflammatory response in alveolar macrophages. Their aerosol administration while significantly improving the biodistribution of paclitaxel in comparison to Taxol (i.v.), also showed significantly higher metastastes inhibition (~75%) in comparison to that of i.v. Taxol and i.v. Abraxane. No signs of interstitial pulmonary fiborisis, chronic inflammation and any other pulmonary toxicity were observed with nanovesicle formulation. Overall, these nanovesicles may be a potential platform to efficiently deliver hydrophobic drugs as aerosol in metastatic lung cancer and other lung diseases, without causing pulmonary toxicity.

Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

Branched amphiphilic peptide capsules (BAPCs) are peptide nano-spheres comprised of equimolar proportions of two branched peptide sequences bis(FLIVI)-K-KKKK and bis(FLIVIGSII)-K-KKKK that self-assemble to form bilayer delimited capsules. In two recent publications we described the lipid analogous characteristics of our BAPCs, examined their initial assembly, mode of fusion, solute encapsulation, and resizing and delineated their capability to be maintained at a specific size by storing them at 4°C. In this report we describe the stability, size limitations of encapsulation, cellular localization, retention and, bio-distribution of the BAPCs in vivo. The ability of our constructs to retain alpha particle emitting radionuclides without any apparent leakage and their persistence in the peri-nuclear region of the cell for extended periods of time, coupled with their ease of preparation and potential tune-ability, makes them attractive as biocompatible carriers for targeted cancer therapy using particle emitting radioisotopes. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova., (Copyright © 2014 Elsevier B.V. All rights reserved.)