Biodegradable pH-responsive amorphous calcium carbonate nanoparticles as immunoadjuvants for multimodal imaging and enhanced photoimmunotherapy.

Development of bioresponsive theranostic nanoparticles to enhance cancer diagnostics and control cancer metastasis is highly desirable. In this study, we developed such a bioresponsive theranostic nanoparticle for synergistic photoimmunotherapy. In particular, these nanoparticles were constructed by embedding indocyanine green (ICG) into Mn2+-doped amorphous calcium carbonate (ACC(Mn)) nanoparticles, followed by loading of the Toll-like-receptor-7 agonist imiquimod (IMQ). The IMQ@ACC(Mn)-ICG/PEG nanoparticles respond to the acidic pH of the tumor microenvironment (TME) and co-deliver ICG and IMQ into the tumor. Selective phototherapy was achieved upon activation using a near-infrared laser. In the presence of IMQ and arising from phototherapeutically treated tumor cells, tumor-associated antigens give rise to a strong antitumor immune response. Reversal of the immunosuppressive TME via H+ scavenging of the tumor through ACC nanoparticles effectively inhibits tumor metastases. Moreover, the combination of ICG and Mn2+ also serves as an advanced contrast agent for cancer multimode imaging. Overall, these bioresponsive nanoparticles provide a promising approach for cancer theranostics with promising potential for future clinical translation.

NaGdF4:Yb,Er-Ag nanowire hybrid nanocomposite for multifunctional upconversion emission, optical imaging, MRI and CT imaging applications.

The effect of novel silver nanowire encapsulated NaGdF4:Yb,Er hybrid nanocomposite on the upconversion emission and bioimaging properties has been investigated. The upconvension nanomaterials were synthesised by polyol method in the presence of ethylene glycol, PVP and ethylenediamine. The NaGdF4:Yb,Er-Ag hybrid was formed with upconverting NaGdF4:Yb,Er nanoparticles of size ~ 80 nm and silver nanowires of thickness ~ 30 nm. The surface plasmon induced by the silver ion in the NaGdF4:Yb,Er-Ag nanocomposite resulted an intense upconversion green emission at 520 nm and red emission at 660 nm by NIR diode laser excitation at 980 nm wavelength. The UV-Vis-NIR spectral absorption at 440 nm and 980 nm, the intense Raman vibrational modes and the strong upconversion emission results altogether confirm the localised surface plasmon resonance effect of silver ion in the hybrid nanocomposite. MRI study of both NaGdF4:Yb,Er nanoparticle and NaGdF4:Yb,Er-Ag nanocomposite revealed the T1 relaxivities of 22.13 and 10.39 mM-1 s-1, which are larger than the commercial Gd-DOTA contrast agent of 3.08 mM-1 s-1. CT imaging NaGdF4:Yb,Er-Ag and NaGdF4:Yb,Er respectively showed the values of 53.29 HU L/g and 39.51 HU L/g, which are higher than 25.78 HU L/g of the CT contrast agent Iobitridol. The NaGdF4:Yb,Er and NaGdF4:Yb,Er-Ag respectively demonstrated a negative zeta potential of 54 mV and 55 mV, that could be useful for biological application. The in vitro cytotoxicity of the NaGdF4:Yb,Er tested in HeLa and MCF-7 cancer cell line by MTT assay demonstrated a cell viability of 90 and 80 %, respectively. But, the cell viability of NaGdF4:Yb,Er-Ag slightly decreased to 80 and 78%. The confocal microscopy imaging showed that the UCNPs are effectively up-taken inside the nucleolus of the cancer cells, and it might be useful for NIR laser-assisted phototherapy for cancer treatment. Graphical abstract.

Multifunctional siRNA-Laden Hybrid Nanoplatform for Noninvasive PA/IR Dual-Modal Imaging-Guided Enhanced Photogenetherapy.

Small interfering RNA (siRNA)-induced gene therapy has been recognized as a promising avenue for effective cancer treatment, while easy enzymatic degradation, poor transfection efficiency, nonspecific biodistribution, and uncontrolled release hinder its extensive clinical applications. Zeolitic imidazolate frameworks-8 (ZIF-8) have emerged as promising drug carriers without an in-depth exploration in programmable siRNA delivery. Herein, we report a multifunctional PDAs-ZIF-8 (PZ) nanoplatform for delivering siRNA with combined photothermal therapy (PTT) and gene therapy (GT) via the noninvasive guidance of photoacoustic (PA)/near-infrared (IR) dual-modal imaging. The ingenious PZ nanocarriers mediated the tumor-specific accumulation of therapeutic siRNA without undesired degradation and preleakage. The pH-responsive ZIF-8 decomposed in an acidic tumor microenvironment that was accompanied by the release of siRNA payloads for cleaving target mRNA in gene silencing therapy. Meanwhile, the polydopamine nanoparticles (PDAs) could simultaneously serve as a powerful noninvasive PA/IR imaging contrast agent and versatile photothermal agent for diagnosis-guided photogenetherapy. The systematic in vitro and in vivo experimental explorations demonstrated that our PDAs-siRNA-ZIF-8 (PSZ) could greatly enhance the therapeutic efficiency as compared with the corresponding PTT or GT monotherapy. This work holds great potential to advance the development of more intelligent diagnosis and therapeutic strategies, thus supplying promising smart nanomedicines in the near future.

Photonic cancer nanomedicine using the near infrared-II biowindow enabled by biocompatible titanium nitride nanoplatforms.

Light-activated photoacoustic imaging (PAI) and photothermal therapy (PTT) using the second near-infrared biowindow (NIR-II, 1000-1350 nm) hold great promise for efficient tumor detection and diagnostic imaging-guided photonic nanomedicine. In this work, we report on the construction of titanium nitride (TiN) nanoparticles, with a high photothermal-conversion efficiency and desirable biocompatibility, as an alternative theranostic agent for NIR-II laser-excited photoacoustic (PA) imaging-guided photothermal tumor hyperthermia. Working within the NIR-II biowindow provides a larger maximum permissible exposure (MPE) and desirable penetration depth of the light, which then allows detection of the tumor to the full extent using PA imaging and complete tumor ablation using photothermal ablation, especially in deeper regions. After further surface polyvinyl-pyrrolidone (PVP) modification, the TiN-PVP photothermal nanoagents exhibited a high photothermal conversion efficiency of 22.8% in the NIR-II biowindow, and we further verified their high penetration depth using the NIR-II biowindow and their corresponding therapeutic effect on the viability of tumor cells in vitro. Furthermore, these TiN-PVP nanoparticles were developed as a contrast agent for NIR-II-activated PA imaging both in vitro and in vivo for the first time and realized efficient photothermal ablation of the tumor in vivo within both the NIR-I and NIR-II biowindows. This work not only provides a paradigm for TiN-PVP photothermal nanoagents working in the NIR-II biowindow both in vitro and in vivo, but also proves the feasibility of PAI and PTT cancer theranostics using NIR-II laser excitation.

Quantitative guidelines for the prediction of ultrasound contrast agent destruction during injection.

Experiments and theory were undertaken on the destruction of ultrasound contrast agent microbubbles on needle injection, with the aim of predicting agent loss during in vivo studies. Agents were expelled through a variety of syringe and needle combinations, subjecting the microbubbles to a range of pressure drops. Imaging of the bubbles identified cases where bubbles were destroyed and the extent of destruction. Fluid-dynamic calculations determined the pressure drop for each syringe and needle combination. It was found that agent destruction occurred at a critical pressure drop that depended only on the type of microbubble. Protein-shelled microbubbles (sonicated bovine serum albumin) were virtually all destroyed above their critical pressure drop of 109 ± 7 kPa Two types of lipid-shelled microbubbles were found to have a pressure drop threshold above which more than 50% of the microbubbles were destroyed. The commercial lipid-shelled agent Definity was found to have a critical pressure drop for destruction of 230 ± 10 kPa; for a previously published lipid-shelled agent, this value was 150 ± 40 kPa. It is recommended that attention to the predictions of a simple formula could preclude unnecessary destruction of microbubble contrast agent during in vivo injections. This approach may also preclude undesirable release of drug or gene payloads in targeted microbubble therapies. Example values of appropriate injection rates for various agents and conditions are given.

Heat-sensitive microbubbles for intraoperative assessment of cancer ablation margins.

A heat-sensitive microbubble (HSM) agent, comprising a core of liquid perfluorocarbon (PFC) compound and a shell of biodegradable poly lactic-co-glycolic acid (PLGA), was fabricated using an emulsion evaporation method. Optical microscopic imaging showed that heating the HSM suspension to 55 degrees C activated the HSMs for significant volumetric expansion. After placing a HSM-dispersed agar-agar gel phantom in a 55 degrees C water bath for 10 min, the phantom became ultrasonically hyperechoic due to the HSM expansion. In an ex vivo test, a porcine tissue sample was injected with the HSM suspension and placed in a 55 degrees C water bath for 10 min. US imaging clearly identified the hyperechoic regions resulted from the HSM activation. The hyperechoic regions in the tissue sample kept a strong US contrast for more than 1 h. In a simulated ablation process, a HSM-dispersed agar-agar gel phantom was ablated by a cylindrical heating element. US imaging accurately estimated the ablation margin propagation while thermographic imaging underestimated the ablation margin. Our experiments demonstrated that the HSM agent could be used as a novel contrast agent for intraoperative assessment of ablation margins in cancer thermal ablation therapies.

Thermal response of contrast agent microbubbles: preliminary results from physico-chemical and US-imaging characterization.

Hyperthermia (HT) is a therapeutic strategy based on the selective damaging of tumoral cells when heated at temperatures in the range 41-45 degrees C. We are currently investigating the feasibility of Ultrasound (US) imaging to perform a non-invasive, efficient and cost effective temperature monitoring of heated tissues. Commercial US contrast agents (Sonovue, Bracco), consisting in microbubbles of SF(6) coated with a phospholipidic shell, greatly improve the US echo signal from tissues. Further investigations have been performed, consisting in physico-chemical and US-imaging characterization. In conclusion, we demonstrate that Sonovue microbubbles reach their maximal diameter at 40 degrees C, and then a sharp decrease is observed, possible due to the occurrence of gel-sol transition of the phospholipidic shell. At the same temperature the maximal backscattering intensity is predicted and actually experimentally observed. Sonovue, as well as other contrast agents based only on phospholipids, are, therefore, not suitable for use as non-invasive temperature monitoring medium since it is sensitive to temperatures below the hyperthermic range. Although microbubbles are in principle thermally effective, other coating materials should be investigated in order to increase their operative thermal range.