In-Brain Multiphoton Imaging of Vaterite Cargoes Loaded with Carbon Dots.

Biocompatible fluorescent agents are key contributors to the theranostic paradigm by enabling real-time in vivo imaging. This study explores the optical properties of phenylenediamine carbon dots (CDs) and demonstrates their potential for fluorescence imaging in cells and brain blood vessels. The nonlinear absorption cross-section of the CDs was measured and achieved values near 50 Goeppert-Mayer (GM) units with efficient excitation in the 775-895 nm spectral range. Mesoporous vaterite nanoparticles were loaded with CDs to examine the possibility of a biocompatible imaging platform. Efficient one- and two-photon imaging of the CD-vaterite composites uptaken by diverse cells was demonstrated. For an in vivo scenario, CD-vaterite composites were injected into the bloodstream of a mouse, and their flow was monitored within the blood vessels of the brain through a cranial window. These results show the potential of the platform for high-brightness biocompatible imaging with the potential for both sensing and simultaneous drug delivery.

One-Pot Synthesis of Affordable Redox-Responsive Drug Delivery System Based on Trithiocyanuric Acid Nanoparticles.

Redox-responsive drug delivery systems present a promising avenue for drug delivery due to their ability to leverage the unique redox environment within tumor cells. In this work, we describe a facile and cost-effective one-pot synthesis method for a redox-responsive delivery system based on novel trithiocyanuric acid (TTCA) nanoparticles (NPs). We conduct a thorough investigation of the impact of various synthesis parameters on the morphology, stability, and loading capacity of these NPs. The great drug delivery potential of the system is further demonstrated in vitro and in vivo by using doxorubicin as a model drug. The developed TTCA-PEG NPs show great drug delivery efficiency with minimal toxicity on their own both in vivo and in vitro. The simplicity of this synthesis, along with the promising characteristics of TTCA-PEG NPs, paves the way for new opportunities in the further development of redox-responsive drug delivery systems based on TTCA.

Overcoming the blood-brain barrier for the therapy of malignant brain tumor: current status and prospects of drug delivery approaches.

Besides the broad development of nanotechnological approaches for cancer diagnosis and therapy, currently, there is no significant progress in the treatment of different types of brain tumors. Therapeutic molecules crossing the blood-brain barrier (BBB) and reaching an appropriate targeting ability remain the key challenges. Many invasive and non-invasive methods, and various types of nanocarriers and their hybrids have been widely explored for brain tumor treatment. However, unfortunately, no crucial clinical translations were observed to date. In particular, chemotherapy and surgery remain the main methods for the therapy of brain tumors. Exploring the mechanisms of the BBB penetration in detail and investigating advanced drug delivery platforms are the key factors that could bring us closer to understanding the development of effective therapy against brain tumors. In this review, we discuss the most relevant aspects of the BBB penetration mechanisms, observing both invasive and non-invasive methods of drug delivery. We also review the recent progress in the development of functional drug delivery platforms, from viruses to cell-based vehicles, for brain tumor therapy. The destructive potential of chemotherapeutic drugs delivered to the brain tumor is also considered. This review then summarizes the existing challenges and future prospects in the use of drug delivery platforms for the treatment of brain tumors.

Correction to: Current outlook on radionuclide delivery systems: from design consideration to translation into clinics.

After publication of this article, an error was found in the description of the holmium isotopes. 165Ho is a stable isotope a fraction of which is activated to 166Ho by neutron activation in a nuclear reactor [2]. In one paragraph of the published article, describing holmium containing QuiremSpheres, 165Ho should be replaced with 166Ho. The correct description is given below.

Current outlook on radionuclide delivery systems: from design consideration to translation into clinics.

Radiopharmaceuticals have proven to be effective agents, since they can be successfully applied for both diagnostics and therapy. Effective application of relevant radionuclides in pre-clinical and clinical studies depends on the choice of a sufficient delivery platform. Herein, we provide a comprehensive review on the most relevant aspects in radionuclide delivery using the most employed carrier systems, including, (i) monoclonal antibodies and their fragments, (ii) organic and (iii) inorganic nanoparticles, and (iv) microspheres. This review offers an extensive analysis of radionuclide delivery systems, the approaches of their modification and radiolabeling strategies with the further prospects of their implementation in multimodal imaging and disease curing. Finally, the comparative outlook on the carriers and radionuclide choice, as well as on the targeting efficiency of the developed systems is discussed.

Development of Nanocarrier-Based Radionuclide and Photothermal Therapy in Combination with Chemotherapy in Melanoma Cancer Treatment.

Conventional cancer therapy methods have serious drawbacks that are related to the nonspecific action of anticancer drugs that leads to high toxicity on normal cells and increases the risk of cancer recurrence. The therapeutic effect can be significantly enhanced when various treatment modalities are implemented. Here, we demonstrate that the radio- and photothermal therapy (PTT) delivered through nanocarriers (gold nanorods, Au NRs) in combination with chemotherapy in a melanoma cancer results in complete tumor inhibition compared to the single therapy. The synthesized nanocarriers can be effectively labeled with 188Re therapeutic radionuclide with a high radiolabeling efficiency (94-98%) and radiochemical stability (>95%) that are appropriate for radionuclide therapy. Further, 188Re-Au NRs, mediating the conversion of laser radiation into heat, were intratumorally injected and PTT was applied. Upon the irradiation of a near-infrared laser, dual photothermal and radionuclide therapy was achieved. Additionally, the combination of 188Re-labeled Au NRs with paclitaxel (PTX) has significantly improved the treatment efficiency (188Re-labeled Au NRs, laser irradiation, and PTX) compared to therapy in monoregime. Thus, this local triple-combination therapy can be a step toward the clinical translation of Au NRs for use in cancer treatment.

Ligand-free template-assisted synthesis of stable perovskite nanocrystals with near-unity photoluminescence quantum yield within the pores of vaterite spheres.

Ligand-free methods for the synthesis of halide perovskite nanocrystals are of great interest because of their excellent performance in optoelectronics and photonics. In addition, template-assisted synthesis methods have become a powerful tool for the fabrication of environmentally stable and bright nanocrystals. Here we develop a novel approach for the facile ligand-free template-assisted fabrication of perovskite nanocrystals with a near-unity absolute quantum yield, which involves CaCO3 vaterite micro- and submicrospheres as templates. We show that the optical properties of the obtained nanocrystals are affected not mainly by the template morphology, but strongly depend on the concentration of precursor solutions, anion and cation ratio, as well as on adding defect-passivating rare-earth dopants. The optimized samples are further tested as infrared radiation visualizers exhibiting promising characteristics comparable to those that are commercially available.

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.

Halide Perovskite Nanocrystals with Enhanced Water Stability for Upconversion Imaging in a Living Cell.

Halide perovskite nanomaterials are widely used in optoelectronics and photonics due to their outstanding luminescent properties, whereas their strong multiphoton absorption makes them prospective for bioimaging. Nonetheless, instability of perovskites in aqueous solutions is an important limitation that prevents their application in biology and medicine. Here, we demonstrate fluorescence and upconversion imaging in living cells by employing CsPbBr3 nanocrystals (NCs) that show an improved water-resistance (at least for 24 h) after their coating as individual particles with various silica-based shells. The obtained phTEOS-TMOS@CsPbBr3 NCs possess high quality, which we confirm with high-resolution transmission and scanning transmission electron microscopy, X-ray diffraction analysis, Fourier-transform infrared and energy-dispersive X-ray spectroscopies, as well as with fluorescence optical microscopy. The developed platform can make the halide perovskite NCs suitable for various bioimaging applications.

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.

Comprehensive Characterization of Titania Nanotubes Fabricated on Ti-Nb Alloys: Surface Topography, Structure, Physicomechanical Behavior, and a Cell Culture Assay.

In this study, hybrid composites based on ß-alloy Ti-xNb and oxide nanotubes (NTs) have been successfully prepared. NTs of different sizes were grown on Ti-Nb substrates with different Nb contents (5, 25, and 50 wt %) via electrochemical anodization at 30 and 60 V. Scanning electron microscopy imaging revealed that vertically aligned nanotubular structures form on the surface of Ti-Nb alloy substrates and influence Nb content in alloys based on NT length. X-ray diffraction analysis confirmed the formation of the anodized TiO2 layer and revealed several phases as the Nb content increased, starting with α' for low Nb content (5 wt %), the martensite α″ for intermediate Nb content (25 wt %), and the ß phase for the highest Nb content (50 wt %). Nanoindentation testing was used to evaluate the changes in mechanical properties of oxide NTs grown on Ti-Nb alloys with different compositions. NT arrays showed wide variations in Young's modulus and hardness depending upon the anodization voltage and the Nb content. The hardness and Young's modulus strongly correlated with NT morphology and structure. The highly dense morphology formed at a lower anodization voltage results in increased elastic modulus and hardness values compared with the surfaces prepared at higher anodization voltages. The nanostructurization of Ti-Nb surface substrates favored improved surface properties for the enhanced adhesion and proliferation of human mesenchymal stem cells (hMSCs). In vitro adhesion, spreading, and proliferation of hMSCs revealed the improved surface properties of the NTs prepared at an anodization voltage of 30 V compared with the NTs prepared at 60 V. Thus it can be concluded that NTs with diameters of ∼50 nm (at 30 V) are more favorable for cell adhesion and growth compared with NTs with diameters of 80 ± 20 nm (at 60 V). The surfaces of Ti-25Nb substrates anodized at 30 V promoted enhanced cell growth, as the further increase in Nb content in Ti-Nb substrate (Ti-50Nb) led to reduced cell proliferation. The application of NTs on Ti-Nb substrates leads to significant reductions in mechanical properties compared with those on the Ti-Nb alloy and improves cell adhesion and proliferation, which is vitally important for successful application in regenerative medicine.

Biomimetic drug delivery platforms based on mesenchymal stem cells impregnated with light-responsive submicron sized carriers.

Synthetic organic and inorganic carriers often have limitations associated with problematic targeting ability or non-optimized pharmacokinetics, and, therefore, they have restricted therapeutic potential. Natural drug carriers (e.g. mesenchymal stem cells, MSCs) are able to migrate towards the tumor site and penetrate cancerous cells. These biomimetic features make MSCs an attractive delivery platform that allows achieving maximal therapeutic efficiency with minimal toxic side effects. A combination of MSCs exhibiting a homing effect on tumors with stimuli-responsive nanostructured carriers is foreseen to have a huge impact in the field of personalized oncology. Here we develop for the first time a light-sensitive biomimetic delivery platform based on MSCs impregnated with submicron sized composite capsules containing an antitumor drug. This cell-based delivery system triggers the release of the drug upon near-infrared (NIR) laser irradiation due to gold nanorods (Au NRs) incorporated into the capsule wall. The NIR-triggered release of the antitumor drug such as vincristine leads to the effective mortality of tumor spheroids made of primary melanoma cells. Encapsulated vincristine delivered by MSCs into the tumor spheroids and deployed over the whole spheroid upon NIR exposure represents a promising therapy for the improved treatment of malignant neoplasms.

Development of Optimized Strategies for Growth Factor Incorporation onto Electrospun Fibrous Scaffolds To Promote Prolonged Release.

Growth factor incorporation in biomedical constructs for their local delivery enables specific pharmacological effects such as the induction of cell growth and differentiation. This has enabled a promising way to improve the tissue regeneration process. However, it remains challenging to identify an appropriate approach that provides effective growth factor loading into biomedical constructs with their following release kinetics in a prolonged manner. In the present work, we performed a systematic study, which explores the optimal strategy of growth factor incorporation into sub-micrometric-sized CaCO3 core-shell particles (CSPs) and hollow silica particles (SiPs). These carriers were immobilized onto the surface of the polymer scaffolds based on polyhydroxybutyrate (PHB) with and without reduced graphene oxide (rGO) in its structure to examine the functionality of incorporated growth factors. Bone morphogenetic protein-2 (BMP-2) and ErythroPOietin (EPO) as growth factor models were included into CSPs and SiPs using different entrapping strategies, namely, physical adsorption, coprecipitation technique, and freezing-induced loading method. It was shown that the loading efficiency, release characteristics, and bioactivity of incorporated growth factors strongly depend on the chosen strategy of their incorporation into delivery systems. Overall, we demonstrated that the combination of scaffolds with drug delivery systems containing growth factors has great potential in the field of tissue regeneration compared with individual scaffolds.

Safe and Effective Delivery of Antitumor Drug Using Mesenchymal Stem Cells Impregnated with Submicron Carriers.

An important area in modern malignant tumor therapy is the optimization of antitumor drugs pharmacokinetics. The use of some antitumor drugs is limited in clinical practice due to their high toxicity. Therefore, the strategy for optimizing the drug pharmacokinetics focuses on the generation of high local concentrations of these drugs in the tumor area with minimal systemic and tissue-specific toxicity. This can be achieved by encapsulation of highly toxic antitumor drug (vincristine (VCR) that is 20-50 times more toxic than widely used the antitumor drug doxorubicin) into nano- and microcarriers with their further association into therapeutically relevant cells that possess the ability to migrate to sites of tumor. Here, we fundamentally examine the effect of drug carrier size on the behavior of human mesenchymal stem cells (hMSCs), including internalization efficiency, cytotoxicity, cell movement, to optimize the conditions for the development of carrier-hMSCs drug delivery platform. Using the malignant tumors derived from patients, we evaluated the capability of hMSCs associated with VCR-loaded carriers to target tumors using a three-dimensional spheroid model in collagen gel. Compared to free VCR, the developed hMSC-based drug delivery platform showed enhanced antitumor activity regarding those tumors that express CXCL12 (stromal cell-derived factor-1 (SDF-1)) gene, inducing directed migration of hMSCs via CXCL12 (SDF-1)/CXCR4 pathway. These results show that the combination of encapsulated antitumor drugs and hMSCs, which possess the properties of active migration into tumors, is therapeutically beneficial and demonstrated high efficiency and low systematic toxicity, revealing novel strategies for chemotherapy in the future.

Multifunctional Scaffolds with Improved Antimicrobial Properties and Osteogenicity Based on Piezoelectric Electrospun Fibers Decorated with Bioactive Composite Microcapsules.

The incorporation of bioactive compounds onto polymer fibrous scaffolds with further control of drug release kinetics is essential to improve the functionality of scaffolds for personalized drug therapy and regenerative medicine. In this study, polymer and hybrid microcapsules were prepared and used as drug carriers, which are further deposited onto polymer microfiber scaffolds [polycaprolactone (PCL), poly(3-hydroxybutyrate) (PHB), and PHB doping with the conductive polyaniline (PANi) of 2 wt % (PHB-PANi)]. The number of immobilized microcapsules decreased with increase in their ζ-potential due to electrostatic repulsion with the negatively charged fiber surface, depending on the polymer used for the scaffold's fabrication. Additionally, the immobilization of the capsules in dynamic mechanical conditions at a frequency of 10 Hz resulted in an increase in the number of the capsules on the fibers with increase in the scaffold piezoelectric response in the order PCL < PHB < PHB-PANi, depending on the chemical composition of the capsules. The immobilization of microcapsules loaded with different bioactive molecules onto the scaffold surface enabled multimodal triggering by physical (ultrasound, laser radiation) and biological (enzymatic treatment) stimuli, providing controllable release of the cargo from scaffolds. Importantly, the microcapsules immobilized onto the surface of the scaffolds did not influence the cell growth, viability, and cell proliferation on the scaffolds. Moreover, the attachment of human mesenchymal stem cells (hMSCs) on the scaffolds revealed that the PHB and PHB-PANi scaffolds promoted adhesion of hMSCs compared to that of the PCL scaffolds. Two bioactive compounds, antibiotic ceftriaxone sodium (CS) and osteogenic factor dexamethasone (DEXA), were chosen to load the microcapsules and demonstrate the antimicrobial properties and osteogenesis of the scaffolds. The modified scaffolds had prolonged release of CS or DEXA, which provided an improved antimicrobial effect, as well as enhanced osteogenic differentiation and mineralization of the scaffolds modified with capsules compared to that of individual scaffolds soaked in CS solution or incubated in an osteogenic medium. Thus, the immobilization of microcapsules provides a simple, convenient way to incorporate bioactive compounds onto polymer scaffolds, which makes these multimodal materials suitable for personalized drug therapy and bone tissue engineering.