No abstract

A novel reduced graphene oxide/poly(2-acrylamido-2-methylpropanesulfonic acid-co-acrylamide) (rGO/poly(AMPS-co-AAm)) nanocomposite hydrogel that possesses excellent electro-response and mechanical properties has been successfully developed. The rGO nanosheets that homogeneously dispersed in the hydrogels could provide prominent conductive platforms for promoting the ion transport inside the hydrogels to generate significant osmotic pressure between the outside and inside of such nanocomposite hydrogels. Thus, the electro-responsive rate and degree of the hydrogel for both deswelling and bending performances become rapid and remarkable. Moreover, the enhanced mechanical properties including both the tensile strength and compressive strength of rGO/poly(AMPS-co-AAm) hydrogels are improved by the hydrogen-bond interactions between the rGO nanosheets and polymer chains, which could dissipate the strain energy in the polymeric networks of the hydrogels. The proposed rGO/poly(AMPS-co-AAm) nanocomposite hydrogels with improved mechanical properties exhibit rapid, significant, and reversible electro-response, which show great potential for developing remotely controlled electro-responsive hydrogel systems, such as smart actuators and soft manipulators.

Novel near-infrared (NIR) light-responsive poly(N-isopropylacrylamide)/graphene oxide (PNIPAM-GO) nanocomposite hydrogels with ultrahigh tensibility are prepared by incorporating sparse chemical cross-linking of small molecules with physical cross-linking of graphene oxide (GO) nanosheets. Combination of the GO nanosheets and thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) polymeric networks provides the hydrogels with an excellent NIR light-responsive property. The ultrahigh tensibility of PNIPAM-GO nanocomposite hydrogels is achieved by simply using a very low concentration of N,N'-methylenebis(acrylamide) (BIS) molecules as chemical cross-linkers to generate a relatively homogeneous structure with flexible long polymer chains and rare chemically cross-linked dense clusters. Moreover, the oxidized groups of GO nanosheets enable the formation of a hydrogen bond interaction with the amide groups of PNIPAM chains, which could physically cross-link the PNIPAM chains to increase the toughness of the hydrogel networks. The prepared PNIPAM-GO nanocomposite hydrogels with ultrahigh tensibility exhibit rapid, reversible, and repeatable NIR light-responsive properties, which are highly promising for fabricating remote light-controlled devices, smart actuators, artificial muscles, and so on.

In this study, a series of injectable thermoreversible and thermogelling PDLLA-PEG-PDLLA copolymers were developed and a systematic evaluation of the thermogelling system both in vitro and in vivo was performed. The aqueous PDLLA-PEG-PDLLA solutions above a critical gel concentration could transform into hydrogel spontaneously within 2 minutes around the body temperature in vitro or in vivo. Modulating the molecular weight, block length and polymer concentration could adjust the sol-gel transition behavior and the mechanical properties of the hydrogels. The gelation was thermally reversible due to the physical interaction of copolymer micelles and no crystallization formed during the gelation. Little cytotoxicity and hemolysis of this polymer was found, and the inflammatory response after injecting the hydrogel to small-animal was acceptable. In vitro and in vivo degradation experiments illustrated that the physical hydrogel could retain its integrity as long as several weeks and eventually be degraded by hydrolysis. A rat model of sidewall defect-bowel abrasion was employed, and a significant reduction of post-operative adhesion has been found in the group of PDLLA-PEG-PDLLA hydrogel-treated, compared with untreated control group and commercial hyaluronic acid (HA) anti-adhesion hydrogel group. As such, this PDLLA-PEG-PDLLA hydrogel might be a promising candidate of injectable biomaterial for medical applications.

The combination of chemotherapy with photodynamic therapy (PDT) has attracted broad attention as it can overcome limitations of conventional chemo-treatment by using different modes of action. However, the efficacy of PDT to treat solid tumors is severely affected by hypoxia in tumors.Methods: In this study, we developed oxygen-generating theranostic nanoparticles (CDM NPs) by hierarchically assembling doxorubicin (DOX), chlorin e6 (Ce6) and colloidal manganese dioxide (MnO2) with poly (ε-caprolactone-co-lactide)-b-poly (ethylene glycol)-b-poly (ε-caprolactone-co-lactide) for treating breast cancer. The in vitro and in vivo antitumor efficacy and imaging performance were investigated.Results: The theranostic nanoparticles showed high stability and biocompatibility both in vitro and in vivo. MnO2 within the nanoparticles could trigger decomposition of excessive endogenous H2O2 in the tumor microenvironment to generate oxygen in-situ to relieve tumor hypoxia. With enhanced oxygen generation, the PDT effect was significantly improved under laser-irradiation. More importantly, this effect together with that of DOX was able to dramatically promote the combined chemotherapy-PDT efficacy of CDM NPs in an MCF-7 tumor-bearing mouse model. Furthermore, the real-time tumor accumulation of the nanocomposites could be monitored by fluorescence imaging, photoacoustic (PA) imaging and magnetic resonance imaging (MRI).Conclusion: The designed CDM NPs are expected to provide an alternative way of improving antitumor efficacy by combined chemo-PDT further enhanced by oxygen generation, and would have broad applications in cancer theranostics.

Protease activated receptor (PAR)‐1 expression in tumor cells is associated with disease progression and overall survival in a variety of cancers of epithelial origin; however, the importance of PAR‐1 in the tumor microenvironment remains unexplored. Utilizing an orthotopic pancreatic cancer model in which tumor cells are PAR‐1 positive whereas stromal cells are PAR‐1 negative, we show that PAR‐1 expression in the microenvironment drives progression and induces chemoresistance of pancreatic cancer. PAR‐1 enhances monocyte recruitment into the tumor microenvironment by regulating monocyte migration and fibroblast dependent chemokine production thereby inducing chemoresistance. Overall, our data identify a novel role of PAR‐1 in the pancreatic tumor microenvironment and suggest that PAR‐1 may be an attractive target to reduce drug resistance in pancreatic cancer.

For breast cancer patients who have undergone breast‐conserving surgery, effective treatments to prevent local recurrences and metastases is very essential. Here, a local injectable therapeutic platform based on a thermosensitive PLEL hydrogel with near‐infrared (NIR)‐stimulated drug release is developed to achieve synergistic photothermal immunotherapy for prevention of breast cancer postoperative relapse. Self‐assembled multifunctional nanoparticles (RIC NPs) are composed of three therapeutic components including indocyanine green, a photothermal agent; resiquimod (R848), a TLR‐7/8 agonist; and CPG ODNs, a TLR‐9 agonist. RIC NPs are physically incorporated into the thermosensitive PLEL hydrogel. The RIC NPs encapsulated PLEL hydrogel (RIC NPs@PLEL) is then locally injected into the tumor resection cavity for local photothermal therapy to ablate residue tumor tissues and produce tumor‐associated antigens. At the same time, NIR also triggers the release of immune components CPG ODNs and R848 from thermoresponsive hydrogels PLEL. The released immune components, together with tumor‐associated antigens, work as an in situ cancer vaccine for postsurgical immunotherapy by inducing effective and sustained antitumor immune effect. Overall, this work suggests that photothermal immunotherapy based on local hydrogel delivery system has great potential as a promising tool for the postsurgical management of breast cancer to prevent recurrences and metastases.

Nanomedicine constructed by therapeutics has unique and irreplaceable advantages in biomedical applications, especially in drug delivery for cancer therapy. The strategy, however, used to construct the therapeutics-based nanomedicines with tumor microenvironmental factor responsiveness is still sophisticated. In this study, an easy-operating procedure is used to construct a therapeutics-based nanosystem with active tumor-targeting, enhanced penetration, and stimuli-responsive drug release behavior as well as programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blockading mediated immunomodulation to enhance tumor immunotherapy. The matrix metalloproteinase-2 responsive peptide with the existence of Lyp-1 sequence contributes to the success of active tumor-targeting and the enhancement of the penetration of the nanoparticles in tumor tissue. The obtained nanosystem strikingly inhibits the primary tumor growth in the first 24 h (more than 97.5% of tumor cells are inhibited), and total inhibition can be achieved with the combination of photothermal therapy. IR820, which is served as the carrier for the therapeutics, is used as a photosensitizer for photothermal therapy. The progress and aggression of distal tumor has further been alleviated by a d-peptide which is an antagonist for PD-1/PD-L1 blockage. Therefore, a therapeutics-constructed multifunctional nanosystem is provided to realize a combinational therapeutic strategy to enhance the therapeutic outcome.