Biphasic synthesis of biodegradable urchin-like mesoporous organosilica nanoparticles for enhanced cellular internalization and precision cascaded therapy.

It is widely accepted that a small particle size and rough surface can enhance tumor tissue accumulation and tumor cellular uptake of nanoparticles, respectively. Herein, sub-50 nm urchin-inspired disulfide bond-bridged mesoporous organosilica nanoparticles (UMONs) featured with a spiky surface and glutathione (GSH)-responsive biodegradability were successfully synthesized by a facile one-pot biphasic synthesis strategy for enhanced cellular internalization and tumor accumulation. l-Arginine (LA) is encapsulated into the mesopores of UMONs, whose outer surface is capped with the gatekeeper of ultrasmall gold nanoparticles, i.e., UMONs-LA-Au. On the one hand, the mild acidity-activated uncapping of ultrasmall gold can realize a tumor microenvironment (TME)-responsive release of LA. On the other hand, the unique natural glucose oxidase (GOx)-mimicking catalytic activity of ultrasmall gold can catalyze the decomposition of intratumoral glucose to produce acidic hydrogen peroxide (H2O2) and gluconic acid. Remarkably, these products can not only further facilitate the release of LA, but also catalyze the LA-H2O2 reaction for an increased nitric oxide (NO) yield, which realizes synergistic catalysis-enhanced NO gas therapy for tumor eradication. The judiciously fabricated UMONs-LA-Au present a paradigm of TME-responsive nanoplatforms for both enhanced cellular uptake and tumor-specific precision cascaded therapy, which broadens the range of practical biomedical applications and holds a significant promise for the clinical translation of silica-based nanotheranostics.

Perfluorocarbon Nanodroplets with Deep Tumor Penetration and Controlled Drug Delivery for Ultrasound/Fluorescence Imaging Guided Breast Cancer Therapy.

Some impediments, including insufficient drug release, poor tumor penetration, and lack of real-time imaging guidance, still limited the therapeutic efficiency of nanotechnology-based drug delivery systems. Here, light-responsive perfluoropentane (PFP) based nanodroplets as doxorubicin (DOX) nanocarriers that could achieve deep tumor delivery under multimodal imaging guidance were developed. Triggered by laser irradiation, the liquid PFP with low boiling point could go through small-to-big size change and liquid-to-gas phase transformation. At the same time, the accompanied cavitation effect led to not only the disruption of dense extracellular matrix for deep penetration but also the disruption of endo-/lysosome for nucleus delivery of released DOX. Furthermore, different from many imaging approaches which were always "on", only upon laser stimulation could the nanodroplets act as ultrasound/fluorescence probes due to the echogenic PFP bubbles and the recovered fluorescence of DOX itself after released from nanodroplets, which was highly desirable to indicate the DOX state in real time. Therefore, such PFP nanodroplets with phase/size tunable properties enable site-specific drug delivery efficiently and exhibit their potent in cancer theranostics.

Artificial Nanotargeted Cells with Stable Photothermal Performance for Multimodal Imaging-Guided Tumor-Specific Therapy.

Organic-inorganic hybrid materials have drawn increasing attention as photothermal agents in tumor therapy due to the advantages of green synthesis, high loading efficiency of hydrophobic drugs, facile incorporation of theranostic iron, and excellent photothermal efficiency without inert components or additives. Herein, we proposed a strategy for biomimetic engineering-mediated enhancement of photothermal performance in the tumor microenvironment (TME). This strategy is based on the specific characteristics of organic-inorganic hybrid materials and endows these materials with homologous targeting ability and photothermal stability in the TME. The hybrid materials perform the functions of cancer cells to target homolytic tumors (acting as "artificial nanotargeted cells (ANTC)"). Inspired by the pH-dependent disassembly behaviors of tannic acid (TA) and ferric ion (FeIII) and subsequent attenuation of photothermal performance, cancer cell membranes were self-deposited onto the surfaces of protoporphyrin-encapsulated TA and FeIII nanoparticles to achieve ANTC with TME-stable photothermal performance and tumor-specific phototherapy. The resulting ANTC can be used as contrast agents for concurrent photoacoustic imaging, magnetic resonance imaging, and photothermal imaging to guide the treatment. Importantly, the high loading efficiency of protoporphyrin enables the initiation of photodynamic therapy to enhance photothermal therapeutic efficiency, providing antitumor function with minimal side effects.

A Phototheranostic Strategy to Continuously Deliver Singlet Oxygen in the Dark and Hypoxic Tumor Microenvironment.

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT-induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell-killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE@PEG-Py NPs) prepared by using a 2-pyridone-based diblock polymer (PEG-Py) to encapsulate a semiconducting, heavy-atom-free pyrrolopyrrolidone-tetraphenylethylene (DPPTPE) with high singlet-oxygen-generation ability both in dichloromethane and water. The PEG-Py can trap the 1 O2 generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release 1 O2 in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence-imaging-guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.

Photothermal therapy mediated by phase-transformation nanoparticles facilitates delivery of anti-PD1 antibody and synergizes with antitumor immunotherapy for melanoma.

Melanoma remains one of the most challenging malignant tumor related deaths worldwide and alternative approaches to efficiently treat melanoma are eagerly needed. Anti-PD1 antibody (aPD1) immunotherapy is the most significant and impactful therapy for melanoma by immune checkpoint inhibition and T cell stimulation to mediate tumor killing. But the clinical remission rate of aPD1 immunotherapy is limited in melanoma. Here we show a potent combination of aPD1 and photothermal therapy (PTT) by effective delivery of a multifunctional phase-transformation nanocarrier to melanoma tumor. We successfully synthesized multifunctional nanoparticles (NPs) encapsulated with aPD1, iron oxide and perfluoropentane (PFP) in lactic-co-glycolic acid (PLGA) shell modified with poly ethylene glycol (PEG) and Gly-Arg-Gly-Asp-Ser (GRGDS) peptides (GOP@aPD1). In vitro, GOP@aPD1 NPs were characterized for particle size and drug-loading efficiency. The NPs were also tested for photothermal property, optical droplet vaporization (ODV) capacity and the ability of aPD1 release profile. In vivo, GOP@aPD1 NPs were systemically administered to melanoma-bearing mice demonstrated no toxicity and accumulation at tumor site. When mediated with PTT, this synergistic treatment achieved enhanced antitumor efficacy, due to combination of the effective aPD1 release and increased CD8+ T cell infiltration in tumor site. In conclusion, GOP@aPD1 NPs combined with PTT could potentiate the efficacy of aPD1 not only by tumor-targeted delivery of aPD1 but also by activating the immune system in the tumor microenvironment, which is a highly effective approach to treat melanoma.

Wet/Sono-Chemical Synthesis of Enzymatic Two-Dimensional MnO2 Nanosheets for Synergistic Catalysis-Enhanced Phototheranostics.

2D nanomaterials have attracted broad interest in the field of biomedicine owing to their large surface area, high drug-loading capacity, and excellent photothermal conversion. However, few studies report their "enzyme-like" catalytic performance because it is difficult to prepare enzymatic nanosheets with small size and ultrathin thickness by current synthetic protocols. Herein, a novel one-step wet-chemical method is first proposed for protein-directed synthesis of 2D MnO2 nanosheets (M-NSs), in which the size and thickness can be easily adjusted by the protein dosage. Then, a unique sono-chemical approach is introduced for surface functionalization of the M-NSs with high dispersity/stability as well as metal-cation-chelating capacity, which can not only chelate 64 Cu radionuclides for positron emission tomography (PET) imaging, but also capture the potentially released Mn2+ for enhanced biosafety. Interestingly, the resulting M-NS exhibits excellent enzyme-like activity to catalyze the oxidation of glucose, which represents an alternative paradigm of acute glucose oxidase for starving cancer cells and sensitizing them to thermal ablation. Featured with outstanding phototheranostic performance, the well-designed M-NS can achieve effective photoacoustic-imaging-guided synergistic starvation-enhanced photothermal therapy. This study is expected to establish a new enzymatic phototheranostic paradigm based on small-sized and ultrathin M-NSs, which will broaden the application of 2D nanomaterials.

IR780-based light-responsive nanocomplexes combining phase transition for enhancing multimodal imaging-guided photothermal therapy.

Near-infrared (NIR) light-triggered photothermal therapy (PTT) has been widely applied for treating cancer. The combination of nanotechnology and NIR has shown great promise for promoting the efficacy of PTT. However, PTT alone could not completely ablate the tumors and easily causes tumor recurrence. To overcome this challenge, many studies have been performed to enhance PTT, including combining chemical therapy and radiotherapy, both of which have side effects on the body. To reduce the side effects and enhance PTT, a new infrared IR780-based nanocomplex combining liquid fluorocarbon perfluoropentane (PFP) has been synthesized for enhancing multimodal imaging-guided PTT. Under NIR irradiation, the size changes of PFP-loaded nanobubbles transforming into microbubbles allow ultrasound (US) imaging, showing boundaries and internal information of tumors. The breakup process and cascade reaction of phase transition can improve intratumoral permeation and retention of nanoparticles in nonmicrovascular tissue and damage the cell membranes of tumors, further enhancing PTT to kill tumor cells. The strong absorption in the NIR field of IR780-loaded NPs allows not only photoacoustic (PA) imaging but also NIR fluorescence (NIRF) imaging, which provides more anatomical information about tumors. This nanocomplex exhibits good biocompatibility and nontoxicity, strong PA/US/NIRF imaging contrast, excellent liquid-gas transition and a photothermal effect. This finding provides a new method to enhance multimodal imaging-guided cancer nanotheranostics.

Perfluorooctyl bromide & indocyanine green co-loaded nanoliposomes for enhanced multimodal imaging-guided phototherapy.

As a highly biocompatible NIR dye, indocyanine green (ICG) has been widely explored for cancer treatment due to its various energy level transition pathways upon NIR light excitation simultaneously, which leads to different theranostic effects (eg. Photoacoustic (PA) and fluorescence imaging (FL), photodynamic and photothermal therapy (PDT&PTT)). However, the theranostic efficiency of ICG is restricted intrinsically, owing to the competitive relationship of its co-existing imaging and therapeutic effect. Moreover, the extrinsic hypoxia nature of tumor further limits its therapeutic effect, especially for the oxygen-dependent PDT. Herein, perfluorooctyl bromide (PFOB), another biocompatible chemical, was integrated with ICG in a nanoliposome structure via a facile two-step emulsion method. Such an ICG&PFOB co-loaded nanoliposomes (LIP-PFOB-ICG) realized computed tomography (CT) contrast imaging in vivo, providing better anatomical information of tumor in comparison to ICG enabled PA and FL imaging. More importantly, LIP-PFOB-ICG inhibited MDA-MB-231 tumor growth completely via intravenous injection through enhanced PDT&PTT synergistic therapy due to the excellent oxygen carrying ability of PFOB, which effectively attenuated tumor hypoxia, improved the efficiency of collisional energy transfer between ICG and oxygen and reduced the expression of heat shock protein (HSP). As expected, the introduction of PFOB within nanoliposomes with ICG has augmented the theranostic effect of ICG comprehensively, which makes this simple biocompatible liposome-based nanoagent a potential candidate for clinical imaging guided phototherapy of cancer.

A Laser-Activated Biocompatible Theranostic Nanoagent for Targeted Multimodal Imaging and Photothermal Therapy.

Multifunctional nanoparticles have been reported for cancer detection and treatment currently. However, the accurate diagnosis and efficient treatment for tumors are still not satisfied. Here we report on the development of targeted phase change multimodal polymeric nanoparticles for the imaging and treatment of HER2-positive breast cancer. METHODS: We evaluated the multimodal imaging capabilities of the prepared nanoparticles in vitro using agar-based phantoms. The targeting performance and cytotoxicity of the nanoparticles were examined in cell culture using SKBR3 (over-expressing HER2) and MDA-MB-231 (HER2 negative) cells. We then tested the magnetic resonance (MR)/ photoacoustic (PA)/ ultrasound (US)/ near-infrared fluorescence (NIRF) multimodal imaging properties and photothermal effect of the nanoparticles in vivo using a SKBR3 breast xenograft model in nude mice. Tissue histopathology and immunofluorescence were also conducted. RESULTS: Both in vitro and in vivo systematical studies validated that the hybrid nanoparticles can be used as a superb MR/US/PA/NIRF contrast agent to simultaneously diagnose and guide tumor photothermal therapy (PTT). When irradiated by a near infrared laser, the liquid PFP vaporizes to a gas, rapidly expelling the contents and damaging surrounding tissues. The resulting micro-sized bubbles provide treatment validation through ultrasound imaging. Localization of DIR and SPIO in the tumor region facilitate photothermal therapy for targeted tumor destruction. The mice treated with HER2 targeted nanoparticles had a nearly complete response to treatment, while the controls showed continued tumor growth. CONCLUSION: This novel theranostic agent may provide better diagnostic imaging and therapeutic potential than current methods for treating HER2-positive breast cancer.

Microwave-activated nanodroplet vaporization for highly efficient tumor ablation with real-time monitoring performance.

The fast development of nanotechnology has provided a new efficient strategy for enhancing the therapeutic efficiency of various treatment modalities against cancer. However, the improvement of minimally invasive microwave therapy based on nanomaterials has not been realized. In this work, we successfully designed and synthesized a novel folate-targeted nanodroplet (TPN) with a composite mixture of perfluorocarbons as the core and lipid as the shell, which exerts the distinctive dual functions as the adjuvant for highly efficient percutaneous ultrasound imaging-guided microwave ablation (MWA) of tumors. Based on the unique phase-changeable performance of TPN nanosystem, a novel microwave-droplet vaporization (MWDV) strategy was proposed, for the first time, to overcome the critical issues of traditional acoustic-droplet vaporization (ADV) and optical-droplet vaporization (ODV) for cancer theranostics. Especially, the elaborately designed TPN can overcome the challenges of indistinct imaging of ablation margin and the limited ablation zone of MWA modality against cancer. The high efficiency of this new MWDV strategy has been systematically elucidated in vitro, ex vivo and in vivo. Therefore, such a successful demonstration of the role of nanomaterials (TPN in this case) in ultrasound imaging-guided MWA therapy against cancer provides a highly feasible strategy to effectively enhance the MWA outcome with the specific features of high efficiency and biosafety.