Fast Fourier Transform-weighted Photoacoustic Imaging by In Vivo Magnetic Alignment of Hybrid Nanorods.

Photoacoustic (PA) imaging uses photon-phonon conversion for high-resolution tomography of biological tissues and functions. Exogenous contrast agents are often added to improve the image quality, but the interference from endogenous molecules diminishes the imaging sensitivity and specificity. We report a background-free PA imaging technique based on the active modulation of PA signals via magnetic alignment of Fe3O4@Au hybrid nanorods. Switching the field direction creates enhanced and deactivated PA imaging modalities, enabling a simple pixel subtraction to effectively minimize background noises. Under an alternating magnetic field, the nanorods exhibit PA signals of coherently periodic changes that can be converted into a sharp peak in a frequency domain via the fast Fourier transform. Automatic pixel-wise screening of nanorod signals performed using a computational algorithm across a time-sequence set of PA images regenerates a background-free PA image with significantly improved contrast, specificity, and fidelity.

Nanovaccines with cell-derived components for cancer immunotherapy.

Cancer nanovaccines as one of immunotherapeutic approaches are able to attack tumors by stimulating tumor-specific immunological responses. However, there still exist multiple challenges to be tackled for cancer nanovaccines to evoke potent antitumor immunity. Particularly, the administration of exogenous materials may cause the off-target immunotherapy responses. In recent years, biomimetic nanovaccines by using cell lysates, cell-derived nanovesicles, or extracted cell membranes as the functional components have received extensive attention. Such nanovaccines based on cell-derived components would show many unique advantages including inherent biocompatibility and the ability to trigger immune responses against a range of tumor-associated antigens. In this review article, we will introduce the recent research progresses of those cell-derived biomimetic nanovaccines for cancer immunotherapy, and discuss the perspectives and challenges associated with the future clinical translation of these emerging vaccine platforms.

Ultra-small natural product based coordination polymer nanodots for acute kidney injury relief.

Acute kidney injury (AKI) is frequently associated with reactive oxygen species (ROS) and causes high mortality in clinics annually, and nanotechnology-mediated antioxidative therapy is emerging as a novel strategy for AKI treatment. Herein, four kinds of natural antioxidants are able to coordinate with iron (Fe) ions to form ultra-small coordination polymer nanodots (CPNs) with good water dispersibility and strong ROS scavenging ability. In particular, Fe-curcumin CPNs (Fe-Cur CPNs) are applied for cellular ROS scavenging and rhabdomyolysis-induced AKI relief.

Ultrasound-Mediated Remotely Controlled Nanovaccine Delivery for Tumor Vaccination and Individualized Cancer Immunotherapy.

Vaccines are one of utmost important weapons in modern medicine to fight a wide range of diseases. To achieve optimal vaccination effects, repeated injections of vaccines are often required, which would largely decrease patient comfort. Herein, an ultrasound-responsive self-healing hydrogel system loaded with nanovaccines is designed for remotely controlled tumor vaccine release and individualized cancer immunotherapy. The gel could be transformed into sol status in response to ultrasound treatment, allowing a burst release of nanovaccines, and self-healed to gel afterward. For mice with a single subcutaneous injection of nanovaccine-loaded gel and multiple ultrasound treatments, repeatedly released nanovaccines could elicit antitumor immune responses, which in combination with immune checkpoint blockade could effectively inhibit established tumors, and prevent postoperative tumor metastases and recurrence based on our personalized nanovaccine system. This work presents an easy-to-operate strategy to realize controllable and durable delivery of vaccines against cancer and potentially other types of diseases.

Thermo-Triggered In Situ Chitosan-Based Gelation System for Repeated and Enhanced Sonodynamic Therapy Post a Single Injection.

Sonodynamic therapy (SDT) by utilizing ultrasonic waves triggers the generation of reactive oxygen species (ROS) with the help of sonosensitizers to destruct deep-seated tumors has attracted great attention. However, the efficacy of SDT may not be robust enough due to the insufficient oxygen supply within solid tumors. Additionally, repeated injections and treatments, which are often required to achieve the optimal therapeutic responses, may cause additional side effects and patient incompliance. Herein, a thermo-triggered in situ hydrogel system is developed in which catalase (CAT) conjugated with sonosensitizer meso-tetra (4-carboxyphenyl) porphine (TCPP) is mixed into chitosan (CS) and beta-glycerol phosphate disodium (GP) to form the precursor solution. After injection of the precursor solution into tumors, the in situ sol-gel transformation will occur as triggered by the body temperature, resulting in the localized tumor retention of TCPP-CAT. The locally restrained TCPP-CAT not only produces ROS under ultrasonic treatment, but also sustainably reverses the oxygen-deficient status in solid tumors by triggering the O2 generation from the decomposition of endogenous H2 O2 , further promoting the efficacy of SDT. As a result, the repeated SDT after a single dose injection of such a hydrogel can offer robust treatment effects to effectively eradicate tumors.

Copresentation of Tumor Antigens and Costimulatory Molecules via Biomimetic Nanoparticles for Effective Cancer Immunotherapy.

Nanoparticle (NP)-based cancer immunotherapy has been extensively explored. However, the efficacy of existing strategies is often limited by the lack of effective tumor-specific antigens or the inability to present costimulatory signal or both. Here, we report a novel approach to overcoming these limitations through surface coating with dendritic-tumor fusion cell membranes, which present whole repertories of tumor-associated antigens in the presence of costimulatory molecules. Because antigen-presenting and costimulatory molecules are displayed on their surface, these NPs can efficiently penetrate immune organs and activate T cells. We show that these NPs can be utilized to prevent tumor development and regress established tumors, including tumors in the brain. We demonstrate that encapsulation of immune adjuvants further improves their efficacy. Due to their significant efficacy, the whole tumor antigen-presenting costimulatory NPs have the potential to be translated into clinical applications for treatment of various cancers.

Near-Infrared Light-Responsive Nitric Oxide Delivery Platform for Enhanced Radioimmunotherapy.

Radiotherapy (RT) is a widely used way for cancer treatment. However, the efficiency of RT may come with various challenges such as low specificity, limitation by resistance, high dose and so on. Nitric oxide (NO) is known a very effective radiosensitizer of hypoxic tumor. However, NO cannot circulate in body with high concentration. Herein, an NIR light-responsive NO delivery system is developed for controlled and precisely release of NO to hypoxic tumors during radiotherapy. Tert-Butyl nitrite, which is an efficient NO source, is coupled to Ag2S quantum dots (QDs). NO could be generated and released from the Ag2S QDs effectively under the NIR irradiation due to the thermal effect. In addition, Ag is also a type of heavy metal that can benefit the RT therapy. We demonstrate that Ag2S NO delivery platforms remarkably maximize radiotherapy effects to inhibit tumor growth in CT26 tumor model. Furthermore, immunosuppressive tumor microenvironment is improved by our NO delivery system, significantly enhancing the anti-PD-L1 immune checkpoint blockade therapy. 100% survival rate is achieved by the radio-immune combined therapy strategy based on the Ag2S NO delivery platforms. Our results suggest the promise of Ag2S NO delivery platforms for multifunctional cancer radioimmunotherapy.

Renal Clearable Ru-based Coordination Polymer Nanodots for Photoacoustic Imaging Guided Cancer Therapy.

Rationale: Despite the promises of applying theranostic nanoagents for imaging-guided cancer therapy, the chronic retention of these nanoagents may cause safety concerns that hinder their future clinical applications. The metabolizable nanoagents with rapid renal excretion to avoid long-term toxicity is a possible solution for this issue. Method: Herein, we synthesize ultra-small metal-organic coordination polymer nanodots based on ruthenium ion (Ru3+) / phenanthroline (Phen) (Ru-Phen CPNs) with superior near-infrared (NIR) absorption. The size, photothermal conversion, cytotoxicity, photoacoustic imaging, in vivo & in vitro cancer treatment efficiency and biosafety are tested. Results: The size of the ultra-small Ru-Phen CPNs is 6.5 nm. The photothermal conversion efficiency is measured to be ~ 60.69 %, much higher than that of previously reported photothermal agents. The Ru-Phen CPNs could be employed for photoacoustic (PA, 808 nm) imaging-guided photothermal therapy (PTT, 808 nm, 0.5 W/cm2) with great performance. Notably, the intrinsic PA signals (808 nm) of Ru-Phen CPNs are observed in kidneys of treated mice, illustrating efficient renal clearance of those ultra-small CPNs. Moreover, the clearance of CPNs is further confirmed by detecting Ru levels in urine and feces. Conclusion: Our work presents a new type of ultra-small Ru-based CPNs with a record high photothermal conversion efficiency, efficient tumor retention after systemic administration, and rapid renal excretion to avoid long-term toxicity, promising for imaging-guided photothermal therapy.

Ultrasound-Responsive Conversion of Microbubbles to Nanoparticles to Enable Background-Free in Vivo Photoacoustic Imaging.

Photoacoustic (PA) imaging based on the photon-to-ultrasound conversion allows the imaging of optical absorbers in deep tissues with high spatial resolution. However, the inherent optical absorbance of biomolecules (e.g., hemoglobin, melanin, etc.) would show up as tissue background signals to interfere with signals from the contrast agent during in vivo PA imaging, limiting the imaging sensitivity. Herein, an ultrasound (US)-responsive PA imaging probe based on microbubbles (MBs) containing gold nanoparticles (Au NPs) is designed for in vivo "background-free" PA imaging. The obtained Au@lip MBs with separated Au NPs decorated within the lipid shell of MBs show low PA signals under near-infrared (NIR) excitation. Interestingly, under exposure to US pulses, those Au@lip MBs would burst to form nanoscale aggregates of Au@lip NPs, which exhibit significantly enhanced NIR PA signals due to their red-shifted surface plasmon resonance. Therefore, by subtracting the PA image captured pre-US burst from that captured post-US burst, the tissue background PA signals could be deducted to enable background-free PA imaging with high sensitivities as demonstrated by multiple ex vivo and in vivo experiments. This work presents a simple yet effective strategy to deduct background signals during PA imaging, which is promising for accurate PA detection of targets in tissues with a strong background.

Light-Triggered In Situ Gelation to Enable Robust Photodynamic-Immunotherapy by Repeated Stimulations.

Photodynamic therapy (PDT) has shown the potential of triggering systemic antitumor immune responses. However, while the oxygen-deficient hypoxic tumor microenvironment is a factor that limits the PDT efficacy, the immune responses after conventional PDT usually are not strong enough to eliminate metastatic tumors. Herein, a light-triggered in situ gelation system containing photosensitizer-modified catalase together with poly(ethylene glycol) double acrylate (PEGDA) as the polymeric matrix is designed. Immune adjuvant nanoparticles are further introduced into this system to trigger robust antitumor immune responses after PDT. Following local injection of the mixed precursor solution into tumors and the subsequent light exposure, polymerization of PEGDA can be initiated to induce in situ gelation. Such hybrid hydrogel with long-term tumor retention of various agents and the ability to enable persistent tumor hypoxia relief can enable multiple rounds of PDT, which results in significantly enhanced immune responses by multiround stimulation. Further combination of such gel-based multiround PDT with anticytotoxic T-lymphocyte antigen-4 checkpoint blockade offers not only the abscopal effect to inhibit growth of distant tumors but also effective long-term immune memory protection from rechallenged tumors. Therefore, such a light-triggered in situ gelation system by a single-dose injection can enable greatly enhanced photoimmunotherapy by means of repeated stimulations.

Near-Infrared-Triggered in Situ Gelation System for Repeatedly Enhanced Photothermal Brachytherapy with a Single Dose.

Brachytherapy by the placing of therapeutic radioactive materials into or near tumors has been widely used in a clinical setting for cancer treatment. The efficacy of brachytherapy, however, may often be limited by the radiation resistance for tumor cells located in the hypoxic region of a solid tumor as well as the non-optimal distribution of radioactivity inside the tumor. Herein, a hybrid hydrogel system is developed by using 131I-labeled copper sulfide (CuS/131I) nanoparticles as the photothermal- and radiotherapeutic agent, poly(ethylene glycol) double acrylates (PEGDA) as the polymeric matrix, and 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) as the thermal initiator to realize light-induced in situ gelation in the tumor for the combined photothermal brachytherapy. After local injection, CuS/131I nanoparticles under irradiation by the 915 nm near-infrared (NIR) laser would produce heat to mildly raise the tumor temperature and initiate the polymerization of PEGDA by activating the AIPH thermal initiator, effectively fixing CuS/131I by in situ gelation within the tumor for the long term. By the repeated NIR irradiation of tumors, the tumor hypoxia could be relieved for a much-longer term, resulting in a significant synergistic photothermal brachytherapeutic effect to eliminate tumors. This work presents an efficient type of NIR-responsive nanoparticle-encapsulated hydrogel system, inspiring the design of a form of brachytherapy.

NIR-Laser-Switched In Vivo Smart Nanocapsules for Synergic Photothermal and Chemotherapy of Tumors.

In vivo MEO2 MA@MEO2 MA-co-OEGMA-CuS-DOX (G-CuS-DOX) nanocapsules increase the temperature of tumors from room temperature to 57 °C due to the photothermal effect under irradiation from a 915-nm laser. When the temperature exceeds 42 °C, photothermal therapy of G-CuS-DOX is switched on. Simultaneously, higher temperatures (>LCST, 42 °C) induce volume shrinkage of G-CuS-DOX in vivo, leading to the controllable release of the anticancer drug DOX. If the NIR laser is switched off, both therapy effects are interrupted immediately.

A novel nanocomposite hydrogel with precisely tunable UCST and LCST.

Novel thermosensitive nanocomposite (NC) hydrogels consisting of organic/inorganic networks are prepared via in situ free radical polymerization of 2-(2-methoxyethoxy) ethyl methacrylate (MEO2 MA) and oligo(ethylene glycol) methacrylate (OEGMA) in the presence of inorganic cross-linker clay in aqueous solution. The obtained clay/P(MEO2 MA-co-OEGMA) hydrogels exhibit double volume phase transition temperatures, an upper critical solution temperature (UCST), and a lower critical solution temperature (LCST), which can be controlled between 5 and 85 °C by varying the fraction of OEGMA units and the weight percentage of cross-linker clay. These new types of NC hydrogels with excellent reversible thermosensitivity are promising for temperature-sensitive applications such as smart optical switches.