Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal-Immunotherapy Efficiency of Solid Tumors.

Although photothermal therapy (PTT) is preclinically applied in solid tumor treatment, incomplete tumor removal of PTT and heat endurance of tumor cells induces significant tumor relapse after treatment, therefore lowering the therapeutic efficiency of PTT. Herein, a programmable therapeutic strategy that integrates photothermal therapeutic agents (PTAs), DNAzymes, and artificial engineered natural killer (A-NK) cells for immunotherapy of hepatocellular carcinoma (HCC) is designed. The novel PTAs, termed as Mn-CONASHs, with 2D structure are synthesized by the coordination of tetrahydroxyanthraquinone and Mn2+ ions. By further adsorbing polyetherimide/DNAzymes on the surface, the DNAzymes@Mn-CONASHs exhibit excellent light-to-heat conversion ability, tumor microenvironment enhanced T1 -MRI guiding ability, and antiheat endurance ability. Furthermore, the artificial engineered NK cells with HCC specific targeting TLS11a-aptamer decoration are constructed for specifically eliminating any possible residual tumor cells after PTT, to systematically enhance the therapeutic efficacy of PTT and avoid tumor relapse. Taken together, the potential of A-NK cells combined with antiheat endurance as a powerful strategy for immuno-enhancing photothermal therapy efficiency of solid tumors is highlighted, and the current strategy might provide promising prospects for cancer therapy.

Near-Infrared Light Activated Thermosensitive Ion Channel to Remotely Control Transgene System for Thrombolysis Therapy.

Current antithrombotic therapeutic strategies often suffer from severe post-thrombotic syndromes (PTS), inconvenient daily subcutaneous injections for a long time and short circulation times accompanied by a dose-dependent risk of intracranial hemorrhage. Aiming at noninvasive, on-demand, and sustained antithrombotic therapy, a new thrombolysis approach based on the transgene system has been developed to remotely and precisely control the expression of urokinase plasminogen activator (uPA) by bioengineered cells for antithrombotic therapy both in vitro and in vivo. In this design, the near-infrared (NIR) light could activate the expression of the thermosensitive TRPV1 channel in response to photothermal responsive nanotransducers to trigger the synthetic signaling pathway to secret uPA. By encapsulating bioengineered cells in injectable hydrogel to ensure long-term survival and convenience for injection, the engineered cells could noninvasively and precisely control the production of uPA protein in situ via an NIR laser to significantly enhance the thrombolysis therapeutic effects by spatiotemporally controlling the local temperature, in both the microfluidic blood circulation mimic and the murine tail thrombus model. This novel thrombolysis approach could overcome some key limitations that are associated with conventional antithrombotic therapy, thus opening a new direction for developing remotely and precisely controllable continuous thrombolysis through artificially designed signaling.

Folic acid-modified Prussian blue/polydopamine nanoparticles as an MRI agent for use in targeted chemo/photothermal therapy.

Fabricating multifunctional theranostic nanoparticles is highly pursued but still challenging for effective cancer treatment. Herein is reported a new theranostic nanoagent as both an MRI and targeted chemo/photothermal therapeutic agent. Prussian blue nanoparticles (PB) were first decorated with polydopamine (PDA), then conjugated with polyethylene glycol (PEG) and folic acid (FA), and finally loaded with doxorubicin (DOX) (denoted as PB@PDA@PEG-FA-DOX). The nanoagent was estimated to have an average size of 40 nm with a DOX-loading capacity of 36%, photothermal conversion efficiency of 45.7% and a transverse relaxation rate of 0.366 mM-1 s-1. In vitro release investigations showed a dual-responsive release by a mild acid and near-infrared (NIR) laser irradiation. PB@PDA@PEG-FA illustrated negligible cytotoxicity against the HL-7702 cell line and 38.2% cell viability under NIR against the HeLa cell line. PB@PDA@PEG-FA-DOX exhibited 45.2% cell viability. In contrast, the cell viability of PB@PDA@PEG-FA-DOX was dramatically decreased to 18.4% under NIR. Exclusive of folic acid, PB@PDA@PEG-DOX demonstrated 40.5% cell viability. These results demonstrated the potential of the nanoagent for integrated photothermal therapy (PTT) and chemotherapy, also embracing the FA targeting effect. In vivo MRI confirmed the effective nanoparticle accumulation, while infrared thermal images revealed the dramatically increased temperature under NIR at a tumor site. In vivo combination treatment-induced tumors were nearly completely destroyed without significant body weight loss after 14 days. H&E and Ki67 staining indicated remarkable necrosis and weak cell proliferation in the tumor area. Histologic examination revealed a lower toxicity in the vital organs. Therefore, this combination of chemo/photothermal therapy could provide an efficient route for cancer treatment.

Photocatalysis Enhancement for Programmable Killing of Hepatocellular Carcinoma through Self-Compensation Mechanisms Based on Black Phosphorus Quantum-Dot-Hybridized Nanocatalysts.

Recently reported black phosphorus quantum dots (BPQDs) possess unique photocatalysis activities. However, the environmental instability accompanied by a hypoxic tumor microenvironment (TME) seriously hindered the bioapplications of BPQDs, especially in oxygen-dependent photodynamic therapy (PDT). Here, we construct a hepatocellular carcinoma (HCC)-specific targeting aptamer "TLS11a"-decorated BPQDs-hybridized nanocatalyst, which can specifically target HCC tumor cells and self-compensate oxygen (O2) into hypoxic TME for enhancing PDT efficiency. The BPQD-hybridized mesoporous silica framework (BMSF) with in situ synthesized Pt nanoparticles (PtNPs) in the BMSF is simply prepared. After being decorated by TLS11a aptamer/Mal-PEG-NHS, the resultant nanosystem (refer as Apt-BMSF@Pt) exhibits excellent environmental stability, active targeting ability to HCC cells, and self-compensation ability of oxygen. Compared with the PEG-BMSF@Pt without H2O2 incubation, the PEG-BMSF@Pt nanocatalyst exhibits 4.2-folds O2 and 1.6-folds 1O2 generation ability in a mimetic closed-system in the presence of both H2O2 and near-infrared laser. In a mouse model, the Apt-BMSF@Pt can effectively accumulate into tumor sites, and the core of BMSF subsequently can act as a photosensitizer to generate reactive oxygen species, while the PtNPs can serve as a catalyst to convert H2O2 into O2 for enhancing PDT through self-compensation mechanisms in hypoxic TME. By comparison of the tumor volume/weight, H&E, and immunohistochemical analysis, the excellent antitumor effects with minimized side effects of our Apt-BMSF@Pt could be demonstrated in vivo. Taken together, the current study suggests that our Apt-BMSF@Pt could act as an active targeting nanocatalyst for programmable killing of cancer cells in hypoxic TME.

Self-Luminescing Theranostic Nanoreactors with Intraparticle Relayed Energy Transfer for Tumor Microenvironment Activated Imaging and Photodynamic Therapy.

The low tissue penetration depth of external excitation light severely hinders the sensitivity of fluorescence imaging (FL) and the efficacy of photodynamic therapy (PDT) in vivo; thus, rational theranostic platforms that overcome the light penetration depth limit are urgently needed. To overcome this crucial problem, we designed a self-luminescing nanosystem (denoted POCL) with near-infrared (NIR) light emission and singlet oxygen (1O2) generation abilities utilizing an intraparticle relayed resonance energy transfer strategy. Methods: Bis[3,4,6-trichloro-2-(pentyloxycarbonyl) phenyl] oxalate (CPPO) as a chemical energy source with high reactivity toward H2O2, poly[(9,9'-dioctyl-2,7-divinylene-fluorenylene)-alt-2-methoxy- 5-(2-ethyl-hexyloxy)-1,4-phenylene] (PFPV) as a highly efficient chemiluminescence converter, and tetraphenylporphyrin (TPP) as a photosensitizer with NIR emission and 1O2 generation abilities were coencapsulated by self-assembly with poly(ethyleneglycol)-co-poly(caprolactone) (PEG-PCL) and folate-PEG-cholesterol to form the POCL nanoreactor, with folate as the targeting group. A series of in vitro and in vivo analyses, including physical and chemical characterizations, tumor targeting ability, tumor microenvironment activated imaging and photodynamic therapy, as well as biosafety, were systematically investigated to characterize the POCL. Results: The POCL displayed excellent NIR luminescence and 1O2 generation abilities in response to H2O2. Therefore, it could serve as a specific H2O2 probe to identify tumors through chemiluminescence imaging and as a chemiluminescence-driven PDT agent for inducing tumor cell apoptosis to inhibit tumor growth due to the abnormal overproduction of H2O2 in the tumor microenvironment. Moreover, the folate ligand on the POCL surface can further improve the accumulation at the tumor site via a receptor-mediated mechanism, thus enhancing tumor imaging and the therapeutic effects both in vitro and in vivo but without any observable systemic toxicity. Conclusion: The nanosystem reported here might serve as a targeted, smart, precise, and noninvasive strategy triggered by the tumor microenvironment rather than by an outside light source for cancer NIR imaging and PDT treatment without limitations on penetration depth.

pH/hypoxia programmable triggered cancer photo-chemotherapy based on a semiconducting polymer dot hybridized mesoporous silica framework.

Although photothermal therapy (PTT) has become a compelling strategy for cancer therapy, few studies concern the physiological consequences of PTT ablation. Herein, we discover that PTT-induced hyperthermia can aggravate tumor hypoxia, which may increase the risk of tumor recurrence and reduce PTT efficacy. We thus integrated the pH/hypoxia-triggered Fe(iii)-banoxantrone (AQ4N) prodrug and semiconducting polymer dots (SPs) for programmable triggered cancer photothermal-chemotherapy. A SP-hybridized mesoporous silica framework, decorated by dopamine and polyethylene glycol, named PPMSF, was synthesized by a simple method, and then served as an efficient photo-absorbing agent (PTA) and drug carrier. Fe(iii)-AQ4N and Mn(ii) were then coordinated with PPMSF (abbreviated Mn-APPMSF) via coordination effects. The nanohybrids exhibited tumor micro-environment pH triggered drug release. Under the irradiation of NIR light, magnetic resonance imaging (MRI) tracked the accumulation of the nanohybrids in tumors which then destroyed tumor cells by local hyperthermia, this can consequently aggravate the tumor hypoxia levels. Intriguingly, the aggravated hypoxia can further enhance the reduction of AQ4N to significantly improve therapeutic efficacy and effectively inhibit tumor growth when compared with traditional PTT. These results indicate the potential of our nanohybrids as a programmable synergistic agent for cancer therapy.

Semiconducting polymer-based nanoparticles for photothermal therapy at the second near-infrared window.

We designed novel diketopyrrolopyrrole polymer based nanoparticles (DPP-IID-FA), which exhibited strong light absorption and excellent photothermal conversion in the NIR optical window, and displayed high biocompatibility and photostability. Furthermore, our nanoparticles could be efficiently uptaken by cancer cells and exhibited outstanding anticancer ability both in vitro and in vivo under NIR-II laser irradiation.

Light-Enhanced Hypoxia-Response of Conjugated Polymer Nanocarrier for Successive Synergistic Photodynamic and Chemo-Therapy.

The tumor hypoxic environment as well as photodynamic therapy (PDT)-induced hypoxia could severely limit the therapeutic efficacy of traditional PDT. Fortunately, the smart integration of hypoxia-responsive drug delivery system with PDT might be a promising strategy to enhance the PDT efficiency that is hindered by the hypoxic environment. Herein, a novel azobenzene (AZO) containing conjugated polymers (CPs)-based nanocarriers (CPs-CPT-Ce6 NPs) was constructed for the combination of PDT with chemotherapy, as well as to enhance the hypoxia-responsive drug release by light. The conjugated polymer chains, used as a matrix to prepare the CPs-CPT-Ce6 NPs, were beneficial for loading hydrophobic photosensitizers and chemotherapy drugs, to improve their cellular uptake. Moreover, the AZO group (-N═N-) in CPs, which can be reduced and cleaved by azoreductase (a typical biomarker of hypoxia) under the hypoxic environment of tumor cells, acts as the hypoxia-responsive linker component. Upon laser irradiation, the CPs-CPT-Ce6 NPs could produce ROS for PDT and then facilitate the enhancement of tumor hypoxic condition, which could further promote the dissociation of CPs via reductive cleavage of AZO bridges to subsequently release cargos (chemotherapeutic drug, CPT) and then significantly enhance the killing effects to tumor cells that were resistant to PDT. Both in vitro and in vivo studies confirmed the improvement of synergistic therapeutic effects of our CPs-CPT-Ce6 NPs. This cascade responsive approach provides an excellent complementary mode for PDT and could open new insights for constructing programmable and controllable responsive systems in biomedical applications.

Facile preparation of biocompatible Ti2O3 nanoparticles for second near-infrared window photothermal therapy.

Photothermal therapy (PTT) is emerging as a powerful tool for the treatment of cancer. However, typical photothermal agents are excited by conventional near-infrared light (NIR-I, 700-900 nm), which leads to low tissue penetration and significantly hinders their further application. Compared with NIR-I light, the second NIR optical window light (NIR-II, 1000-1700 nm) can remarkably increase the tissue penetration depth; however, photothermal agents in this optical window are extremely limited and need to be further explored. Herein, we prepared Ti2O3 nanoparticles through a ball milling method, and to further improve their biocompatibility and targeting efficiency, the Ti2O3 nanoparticles were modified with hyaluronic acid. The as-prepared nanoparticles exhibited strong light absorption and excellent photothermal conversion efficiency in the NIR-II optical window. Both in vitro and in vivo studies clearly demonstrated that the Ti2O3@HA nanoparticles not only exhibit high biocompatibility and photostability, but also can be efficiently taken up by cancer cells and display excellent anticancer ability in the NIR-II region. Thus, this study provides a novel photothermal agent for PTT in the NIR-II optical window, which may further advance cancer photo-treatment in future.