Photothermal-modulated reversible volume transition of wireless hydrogels embedded with redox-responsive carbon dots.

The reversible volume transition of redox-responsive hydrogels by near-infrared (NIR) irradiation has recently attracted significant attention as a novel therapy matrix for tracking and treating cancer via stimuli-responsive fluorescence on/off with controllable volume transition via a wireless sensing system. Herein, a NIR-induced redox-sensitive hydrogel was synthesized by blending a hydrogel with IR825-loaded carbon dots (CD) to achieve enhanced mobility of nanoparticles inside a gel network, and reversible volume phase transitions remotely controlled by a smartphone application via the induction of different redox environments. The presence of CD-IR825 in the thermosensitive poly(N-isopropylacrylamide) hydrogel network imparted fluorescence, electronic and photothermal properties to the hydrogels, which resulted in volume shrinkage behavior of the hydrogel upon exposure to NIR laser irradiation due to the redox-sensitive CDs. Under the NIR on/off cycles, the photothermal temperature, fluorescence, and porous structure were reversed after turning off the NIR laser. The hydrogel responsiveness under GSH and NIR light was studied using a wireless device based on the changes in the resistance graph on a smartphone application, generating a fast and simple method for the investigation of hydrogel properties. The in vitro cell viabilities of the MDA-MB cancer cells incubated with the composite hydrogel in the presence of external GSH exhibited a higher photothermal temperature, and the cancer cells were effectively killed after the NIR irradiation. Therefore, the NIR-induced redox-responsive nanocomposite hydrogel prepared herein has potential for use in cancer treatment and will enable the study of nanoparticle motion in hydrogel networks under multiple stimuli via a wireless device using a faster and more convenient method.

Zwitterionic carbon dot-encapsulating pH-responsive mesoporous silica nanoparticles for NIR light-triggered photothermal therapy through pH-controllable release.

Here, we designed a pH-responsive Indocyanine Green (ICG)-loaded zwitterion fluorescent carbon dot (CD)-encapsulating mesoporous silica nanoparticle (MSN) for pH-tunable image-guided photothermal therapy. ICG was loaded into MSN(CD) via hydrophobic and electrostatic interactions between zwitterionic CDs and ICG to achieve a controlled photothermal temperature with a fluorescent "off/on" system. The porosity of the MSNs was altered after ICG loading because of intermolecular interactions between the CDs and ICG inside the MSN shell and core, which blocked the MSN pore. The acidic environment pH affected the fluorescent signals of the ICG-MSN(CD), reflecting the "off-on" characteristics of the synthesized MSN, which then induced the release of ICG from the matrices. Moreover, the photothermal conversion of ICG-MSN(CD) showed sufficient heat generation to kill cancer cells at an acidic pH with low-temperature elevation at physiological pH. ICG-MSN(CD) demonstrated good cell viability of MDA-MB-231 cells without irradiation; however, high necrosis was observed when the environment was adjusted to acidic pH and after near-infrared irradiation. These pH-responsive photothermal mesoporous silica nanoparticles may have applications in biomedicine, particularly for cancer treatment.

pH/Redox-Triggered Photothermal Treatment for Cancer Therapy Based on a Dual-Responsive Cationic Polymer Dot.

In the present study, a pH/redox-responsive cationic polymer dot (CD) was successfully prepared for a near-infrared (NIR)-mediated, simultaneously controllable photothermal temperature guided imaging off/on system to monitor therapeutic delivery. Carbonized disulfide cross-linked branched polyethyleneimine (bPEI) was conjugated with folic acid (FA) as a targeting moiety and partially formed an ionic complex with anionic indocyanine green (ICG) to afford a bPEI-based CD (ICG-CD). This was responsive to mild reductive (glutathione, GSH) and acidic tumor conditions, which enabled the simultaneous biodegradation of those hydrophobic and complex sites. The ICG-CD internalized readily into the cytoplasm of cancer cells by a FA receptor and cationic-mediated endocytosis in the off state, whereas if ICG-CD met intracellular GSH at high concentrations, GSH contributed partially to the recovery of fluorescence and was then internalized into acidic endosomes to induce complete restoration of fluorescence. This tumor-sensitive degradability of the CD not only facilitated ICG release in the tumor location but also allowed controllable photothermal therapy effects of nanoparticles under NIR irradiation, which resulted in improved cancer therapy. Taken together, the results indicate great potential in tumor targeting, intracellular imaging, and controllable therapeutic delivery through a fluorescence off/on assay under the pH/redox conditions of cancer cells.

Dual-Responsive Carbon Dot for pH/Redox-Triggered Fluorescence Imaging with Controllable Photothermal Ablation Therapy of Cancer.

Herein we describe fluorescence resonance energy transfer (FRET) for a pH/redox-activatable fluorescent carbon dot (FNP) to realize "off-on" switched imaging-guided controllable photothermal therapy (PTT). The FNP is a carbonized self-crosslinked polymer that allows IR825 loading (FNP[IR825]) via hydrophobic interactions for cancer therapy. Fluorescence bioimaging was achieved by the internalization of FNP(IR825) into tumor cells, wherein glutathione (GSH) disulfide bonds are reduced, and benzoic imine groups are cleaved under acidic conditions. The release of IR825 from the FNP core in this system may be used to efficiently control PTT-mediated cancer therapy via its photothermal conversion after near-infrared (NIR) irradiation. In vitro and in vivo cellular uptake studies revealed efficient uptake of FNP(IR825) by tumor cells to treat the disease site. In this way we demonstrated in mice that our smart nanocarrier can effectively kill tumor cells under exposure to a NIR laser, and that the particles are biocompatible with various organs. This platform responds sensitively to the exogenous environment inside the cancer cells and may selectively induce the release of PTT-mediated cytotoxicity. Furthermore, this platform may be useful for monitoring the elimination of cancer cells through the fluorescence on/off switch, which can be used for various applications in the field of cancer cell therapy and diagnosis.

pH-Responsible fluorescent carbon nanoparticles for tumor selective theranostics via pH-turn on/off fluorescence and photothermal effect in vivo and in vitro.

We developed nanoparticles comprising a photothermal dye (IR825)-loaded carbonized zwitterionic polymer [FNP-I] as "switch-on" pH-responsive fluorescence probes to sense intracellular cancer cells and for near-infrared (NIR) controllable photothermal therapy (PTT) in vivo and in vitro. The fluorescent "off" of FNP-I was activated after reaching the cancer cell environment, where the zwitterionic compartment of FNP lost its hydrophobicity to induce PTT-mediated heat release of IR825 under NIR irradiation in the tumor. Approximately 100% of the IR825 was released from the FNP core to generate high thermal conversion to completely kill the cancer cells. Furthermore, after intravenous treatment of FNP-I into MDAMB-231-cell bearing mice, pH-responsive photothermal therapy was observed, achieving marked ablation of tumor cells with release of IR825 under tumor environment conditions. In addition, fluorescent signals were clearly found at the tumor site after 3 h, decreasing at the 6 h time point. The in vitro and in vivo detection system demonstrated good cellular uptake and biocompatibility as a potential imaging-guided photothermal therapy nanotool for cancer treatment. Interestingly, the synergism of the biosensor and PTT in single FNP-I platform led to more effective cancer cell killing than either monotherapy, providing a new approach for cancer treatment.

In Vitro and In Vivo Tumor Targeted Photothermal Cancer Therapy Using Functionalized Graphene Nanoparticles.

Despite the tremendous progress that photothermal therapy (PTT) has recently achieved, it still has a long way to go to gain the effective targeted photothermal ablation of tumor cells. Driven by this need, we describe a new class of targeted photothermal therapeutic agents for cancer cells with pH responsive bioimaging using near-infrared dye (NIR) IR825, conjugated poly(ethylene glycol)-g-poly(dimethylaminoethyl methacrylate) (PEG-g-PDMA, PgP), and hyaluronic acid (HA) anchored reduced graphene oxide (rGO) hybrid nanoparticles. The obtained rGO nanoparticles (PgP/HA-rGO) showed pH-dependent fluorescence emission and excellent near-infrared (NIR) irradiation of cancer cells targeted in vitro to provide cytotoxicity. Using intravenously administered PTT agents, the time-dependent in vivo tumor target accumulation was exactly defined, presenting eminent photothermal conversion at 4 and 8 h post-injection, which was demonstrated from the ex vivo biodistribution of tumors. These tumor environment responsive hybrid nanoparticles generated photothermal heat, which caused dominant suppression of tumor growth. The histopathological studies obtained by H&E staining demonstrated complete healing from malignant tumor. In an area of limited successes in cancer therapy, our translation will pave the road to design stimulus environment responsive targeted PTT agents for the safe eradication of devastating cancer.

Functionalized biocompatible WO3 nanoparticles for triggered and targeted in vitro and in vivo photothermal therapy.

We report on dopamine-conjugated hyaluronic acid (HA-D), a mussel-inspired facile capping material that can modify tungsten oxide (WO3) nanoparticles to be both biocompatible and targetable, allowing precise delivery (WO3-HA) to a tumor site. Near-infrared (NIR) irradiated WO3-HA showed a rapid and substantial rise in photothermal heat to complete in vitro thermolysis of malignant MDAMB and A549 cancer cellsbut was found to be relatively less sensitive to normal MDCK cells. A long-term in vivo investigation of ~10 nm HA thickness on WO3 (WO3-HA) nanoparticles demonstrated efficient photo-thermal conversion with time-dependent tumor target accumulation. This long-termin vivo survival study ofWO3-HA showed promising biocompatibility, with a complete recovery from malignant tumor. Due to the importance of keeping simplicity in the design of therapeutic nanoparticles, we therefore expect that this facile scheme (HA-D) would contribute to the biocompatible development of versatile metallic nanoparticles for photothermal applications.

Fluorescent carbon nanoparticles derived from natural materials of mango fruit for bio-imaging probes.

Water soluble fluorescent carbon nanoparticles (FCP) obtained from a single natural source, mango fruit, were developed as unique materials for non-toxic bio-imaging with different colors and particle sizes. The prepared FCPs showed blue (FCP-B), green (FCP-G) and yellow (FCP-Y) fluorescence, derived by the controlled carbonization method. The FCPs demonstrated hydrodynamic diameters of 5-15 nm, holding great promise for clinical applications. The biocompatible FCPs demonstrated great potential in biological fields through the results of in vitro imaging and in vivo biodistribution. Using intravenously administered FCPs with different colored particles, we precisely defined the clearance and biodistribution, showing rapid and efficient urinary excretion for safe elimination from the body. These findings therefore suggest the promising possibility of using natural sources for producing fluorescent materials.

Injectable and sustained delivery of human growth hormone using chemically modified Pluronic copolymer hydrogels.

A new injectable biodegradable hydrogel system with thermosensitive sol-gel transition behavior was developed. A series of A-B-A triblock copolymers consisting of Pluronic copolymer end-capped with D- or L-lactic acid oligomers (PL-LA(n)) with various chain lengths (n = 5,12) was synthesized. It was assumed that a pair of two triblock copolymers with enantiomeric oligolactide chains, when blended in an equimolar mixture, would form more stable, self-assembled, and stereocomplexed (ST) hydrogels. A series of blend hydrogels encapsulating human growth hormone (hGH) was prepared by varying blend ratios between PL and stereocomplexed PL copolymers. They showed sustained release of hGH via an erosion-dependent mechanism. The hydrogel with a 5% blending ratio exhibited the most delayed mass erosion as well as sustained protein release patterns in vitro possibly due to the formation of a fish-net like 3-D mesh structure. The effect of incubation condition on hGH release and degradation behaviors was also assessed.