Synergistic Enhancement of Photodynamic Cancer Therapy with Mesenchymal Stem Cells and Theranostic Nanoparticles.

Nanoparticles engineered to combat cancer and other life-threatening diseases may significantly improve patient outcomes. However, inefficient nanoparticle delivery to tumors limits their use and necessitates the development of complex delivery approaches. Here, we examine this issue by harnessing the tumor-homing abilities of human mesenchymal stem cells (MSCs) to deliver a decoupled theranostic complex of rare earth-doped nanoparticles (dNPs) and photosensitizer chlorin e6 (Ce6) to tumors. We show that both bone-marrow- and skin-derived MSCs can transport the dNP-Ce6 complex inside tumor spheroids, which is challenging to accomplish by passive delivery alone. MSCs deliver the dNP-Ce6 complex across the tumor spheroid, facilitating more effective photodynamic damage and tumor destruction than passively accumulated dNP-Ce6. The dNP-Ce6 complex also provides the built-in ability to monitor the MSC migration without causing undesired phototoxicity, which is essential for maximal and side-effect-free delivery of nanoparticles. Our results demonstrate how MSCs can be used as delivery vehicles for the transportation of the dNP-Ce6 complex, addressing the limitations of passive nanoparticle delivery and providing light-based theranostics.

Early in vivo detection of denervation-induced atrophy by luminescence transient nanothermometry.

Denervation induces skeletal muscle atrophy due to the loss of control and feedback with the nervous system. Unfortunately, muscle atrophy only becomes evident days after the denervation event when it could be irreversible. Alternative diagnosis tools for early detection of denervation-induced muscle atrophy are, thus, required. In this work, we demonstrate how the combination of transient thermometry, a technique already used for early diagnosis of tumors, and infrared-emitting nanothermometers makes possible the in vivo detection of the onset of muscle atrophy at short (<1 day) times after a denervation event. The physiological reasons behind these experimental results have been explored by performing three dimensional numerical simulations based on the Pennes' bioheat equation. It is concluded that the alterations in muscle thermal dynamics at the onset of muscle atrophy are consequence of the skin perfusion increment caused by the alteration of peripheral nervous autonomous system. This work demonstrates the potential of infrared luminescence thermometry for early detection of diseases of the nervous system opening the venue toward the development of new diagnosis tools.

Optomagnetic nanofluids for controlled brain hyperthermia: a critical study.

Optomagnetic nanofluids (OMNFs) are colloidal dispersions of nanoparticles (NPs) with combined magnetic and optical properties. They are especially appealing in biomedicine since they can be used as minimally invasive platforms for controlled hyperthermia treatment of otherwise difficultly accessible tumors such as intracranial ones. On the one hand, magnetic NPs act as heating mediators when subjected to alternating magnetic fields or light irradiation. On the other hand, suitably tailored luminescent NPs can provide a precise and remote thermal readout in real time. The combination of heating and thermometric properties allows, in principle, to precisely monitor the increase in the temperature of brain tumors up to the therapeutic level, without causing undesired collateral damage. In this work we demonstrate that this view is an oversimplification since it ignores the presence of relevant interactions between magnetic (γ-Fe2O3 nanoflowers) and luminescent nanoparticles (Ag2S NPs) that result in a detrimental alteration of their physicochemical properties. The magnitude of such interactions depends on the interparticle distance and on the surface properties of nanoparticles. Experiments performed in mouse brains (phantoms and ex vivo) revealed that OMNFs cannot induce relevant heating under alternating magnetic fields and fail to provide reliable temperature reading. In contrast, we demonstrate that the use of luminescent nanofluids (containing only Ag2S NPs acting as both photothermal agents and nanothermometers) stands out as a better alternative for thermally monitored hyperthermia treatment of brain tumors in small animal models.

Quantitative Comparison of the Light-to-Heat Conversion Efficiency in Nanomaterials Suitable for Photothermal Therapy.

Functional colloidal nanoparticles capable of converting between various energy types are finding an increasing number of applications. One of the relevant examples concerns light-to-heat-converting colloidal nanoparticles that may be useful for localized photothermal therapy of cancers. Unfortunately, quantitative comparison and ranking of nanoheaters are not straightforward as materials of different compositions and structures have different photophysical and chemical properties and may interact differently with the biological environment. In terms of photophysical properties, the most relevant information to rank these nanoheaters is the light-to-heat conversion efficiency, which, along with information on the absorption capacity of the material, can be used to directly compare materials. In this work, we evaluate the light-to-heat conversion properties of 17 different nanoheaters belonging to different groups (plasmonic, semiconductor, lanthanide-doped nanocrystals, carbon nanocrystals, and metal oxides). We conclude that the light-to-heat conversion efficiency alone is not meaningful enough as many materials have similar conversion efficiencies─in the range of 80-99%─while they significantly differ in their extinction coefficient. We therefore constructed their qualitative ranking based on the external conversion efficiency, which takes into account the conventionally defined light-to-heat conversion efficiency and its absorption capacity. This ranking demonstrated the differences between the samples more meaningfully. Among the studied systems, the top-ranking materials were black porous silicon and CuS nanocrystals. These results allow us to select the most favorable materials for photo-based theranostics and set a new standard in the characterization of nanoheaters.

New opportunities for light-based tumor treatment with an "iron fist".

The efficacy of photodynamic treatments of tumors can be significantly improved by using a new generation of nanoparticles that take advantage of the unique properties of the tumor microenvironment.

Infrared-Emitting Multimodal Nanostructures for Controlled In Vivo Magnetic Hyperthermia.

Deliberate and local increase of the temperature within solid tumors represents an effective therapeutic approach. Thermal therapies embrace this concept leveraging the capability of some species to convert the absorbed energy into heat. To that end, magnetic hyperthermia (MHT) uses magnetic nanoparticles (MNPs) that can effectively dissipate the energy absorbed under alternating magnetic fields. However, MNPs fail to provide real-time thermal feedback with the risk of unwanted overheating and impeding on-the-fly adjustment of the therapeutic parameters. Localization of MNPs within a tissue in an accurate, rapid, and cost-effective way represents another challenge for increasing the efficacy of MHT. In this work, MNPs are combined with state-of-the-art infrared luminescent nanothermometers (LNTh; Ag2 S nanoparticles) in a nanocapsule that simultaneously overcomes these limitations. The novel optomagnetic nanocapsule acts as multimodal contrast agents for different imaging techniques (magnetic resonance, photoacoustic and near-infrared fluorescence imaging, optical and X-ray computed tomography). Most crucially, these nanocapsules provide accurate (0.2 °C resolution) and real-time subcutaneous thermal feedback during in vivo MHT, also enabling the attainment of thermal maps of the area of interest. These findings are a milestone on the road toward controlled magnetothermal therapies with minimal side effects.

Highly Efficient Copper Sulfide-Based Near-Infrared Photothermal Agents: Exploring the Limits of Macroscopic Heat Conversion.

Among the foreseeable therapeutic approaches at the cellular level, nanoplatform-driven photothermal therapy is a thriving tool for the selective eradication of malignant tissues with minimal side effects to healthy ones. Hence, chemically versatile, near-infrared absorbing plasmonic nanoparticles are distinctly appealing and most sought after as efficient photothermal agents. In this work, a straightforward method to synthesize monodisperse PEGylated copper sulfide nanoparticles of pure covellite (CuS) phase, featuring strong localized surface plasmonic resonance absorption in the near-infrared and flexible surface chemistry, imparted by monomethyl ether polyethylene glycol molecules, is developed and optimized. These nanoparticles show a remarkable photothermal heat conversion efficiency (HCE) of 71.4%, which is among the highest for CuS systems and rivals that of plasmonic noble metal nanostructures. Moreover, through critical evaluation and mathematical modeling of the material's properties and measurement methodology, it is assessed that the calculated HCE values drastically depend on experimental conditions such as wavelength-dependent solvent absorption properties, sol concentration, and optical path. These findings are of paramount relevance to the photothermal community, since they call for a standardization of the procedure for the evaluation of the HCE of proposed photothermal agents, in order to make the reported values universally and reliably comparable.

Small and Bright Lithium-Based Upconverting Nanoparticles.

In the context of light-mediated tumor treatment, the application of ultraviolet (UV) radiation can initiate drug release and photodynamic therapy. However, its limited penetration depth in tissues impedes the subcutaneous applicability of such radiation. On the contrary, near-infrared (NIR) light is not energetic enough to initiate secondary photochemical processes, but can pierce tissues at a significantly greater depth. Upconverting nanoparticles (UCNPs) unify the advantages of both extremes of the optical spectrum, they can be excited by NIR irradiation and emit UV light through the process of upconversion, effective NIR-to-UV generation being attained with UCNPs as large as 100 nm. However, in anticipation of biomedical applications, the size of UCNPs must be greatly minimized to favor their cellular internalization; yet straightforward size reduction negatively affects the NIR-to-UV upconversion efficiency. Herein, we propose a two-step strategy to obtain small yet bright lithium-based UCNPs. First, we synthesized UCNPs as small as 5 nm by controlling the relative amount of coordinating ligands, namely oleylamine (OM) and oleic acid (OA). Although these UCNPs were chemically unstable, particle coarsening via an annealing process in the presence of fresh OA yielded structurally stable and highly monodisperse sub-10 nm crystals. Second, we grew a shell with controlled thickness on these stabilized cores of UCNPs, improving the NIR-to-UV upconversion by orders of magnitude. Particularly in the case of LiYbF4:Tm3+/LiYF4 UCNPs, their NIR-to-UV upconversion surpassed the gold standard 90 nm-sized LiYF4:Tm3+, Yb3+ UCNPs. All in all, these UCNPs show great potential within the biomedical framework as they successfully combine the requirements of small size, deep tissue NIR penetration and bright UV emission.