Theoretical simulation and experimental design of selenium and gold incorporated polymer-based microcarriers for ROS-mediated combined photothermal therapy.

Recently, multi-modal combined photothermal therapy (PTT) with the use of photo-active materials has attracted significant attention for cancer treatment. However, drug carriers enabling efficient heating at the tumor site are yet to be designed: this is a fundamental requirement for broad implementation of PTT in clinics. In this work, we design and develop hybrid carriers based on multilayer capsules integrated with selenium nanoparticles (Se NPs) and gold nanorods (Au NRs) to realize reactive oxygen species (ROS)-mediated combined PTT. We show theoretically and experimentally that cooperative interaction of Se NPs with Au NRs improves the heat release efficiency of the developed capsules. In addition, after uptake by tumor cells, intracellular ROS level amplified by Se NPs inhibits the tumor growth. As a consequence, the synergy between Se NPs and Au NRs exhibits the advantages of hybrid carriers such as (i) improved photothermal conversion efficiency and (ii) dual-therapeutic effect. The results of in vitro and in vivo experiments demonstrate that the combination of ROS-mediated therapy and PTT has a higher tumor inhibition efficiency compared to the single-agent treatment (using only Se-loaded or Au-loaded capsules). Furthermore, the developed hybrid carriers show negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys and spleen. This study not only provides a potential strategy for the design of multifunctional "all-in-one" carriers, but also contributes to the development of combined PTT in clinical practice.

Real-Time Temperature Monitoring of Photoinduced Cargo Release inside Living Cells Using Hybrid Capsules Decorated with Gold Nanoparticles and Fluorescent Nanodiamonds.

Real-time temperature monitoring within biological objects is a key fundamental issue for understanding the heating process and performing remote-controlled release of bioactive compounds upon laser irradiation. The lack of accurate thermal control significantly limits the translation of optical laser techniques into nanomedicine. Here, we design and develop hybrid (complex) carriers based on multilayered capsules combined with nanodiamonds (NV centers) as nanothermometers and gold nanoparticles (Au NPs) as nanoheaters to estimate an effective laser-induced temperature rise required for capsule rupture and further release of cargo molecules outside and inside cancerous (B16-F10) cells. We integrate both elements (NV centers and Au NPs) in the capsule structure using two strategies: (i) loading inside the capsule's cavity (CORE) and incorporating them inside the capsule's wall (WALL). Theoretically and experimentally, we show the highest and lowest heat release from capsule samples (CORE or WALL) under laser irradiation depending on the Au NP arrangement within the capsule. Applying NV centers, we measure the local temperature of capsule rupture inside and outside the cells, which is determined to be 128 ± 1.12 °C. Finally, the developed hybrid containers can be used to perform the photoinduced release of cargo molecules with simultaneous real-time temperature monitoring inside the cells.

Radiolabeling Strategies of Micron- and Submicron-Sized Core-Shell Carriers for In Vivo Studies.

Core-shell particles made of calcium carbonate and coated with biocompatible polymers using the Layer-by-Layer technique can be considered as a unique drug-delivery platform that enables us to load different therapeutic compounds, exhibits a high biocompatibility, and can integrate several stimuli-responsive mechanisms for drug release. However, before implementation for diagnostic or therapeutic purposes, such core-shell particles require a comprehensive in vivo evaluation in terms of physicochemical and pharmacokinetic properties. Positron emission tomography (PET) is an advanced imaging technique for the evaluation of in vivo biodistribution of drug carriers; nevertheless, an incorporation of positron emitters in these carriers is needed. Here, for the first time, we demonstrate the radiolabeling approaches of calcium carbonate core-shell particles with different sizes (CaCO3 micron-sized core-shell particles (MicCSPs) and CaCO3 submicron-sized core-shell particles (SubCSPs)) to precisely determine their in vivo biodistribution after intravenous administration in rats. For this, several methods of radiolabeling have been developed, where the positron emitter (68Ga) was incorporated into the particle's core (co-precipitation approach) or onto the surface of the shell (either layer coating or adsorption approaches). According to the obtained data, radiochemical bounding and stability of 68Ga strongly depend on the used radiolabeling approach, and the co-precipitation method has shown the best radiochemical stability in human serum (96-98.5% for both types of core-shell particles). Finally, we demonstrate the size-dependent effect of core-shell particles' distribution on the specific organ uptake, using a combination of imaging techniques, PET, and computerized tomography (CT), as well as radiometry of separate organs. Thus, our findings open up new perspectives of CaCO3-radiolabeled core-shell particles for their further implementation into clinical practice.