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.

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One of the rapidly developing directions of biomedical research and nanotechnology is the design of new delivery systems, in particular, for the delivery of genetic information. Majority of the established immortalized cells lines broadly used by the scientific community allow efficient RNA and DNA transfer using lipid-, polysaccharide-, polymer-, or calcium precipitation-based commercially available reagents. However, manipulation of gene expression in primary cells, including adult and embryonic stem cells and cancer stem cells representing attractive tools for regenerative medicine, cancer therapy, and immune disease treatment, remains still an Efficient delivery of genetic material to primary cells remains challenging. Here, efficient transfer of genetic material is presented using synthetic biodegradable nanocarriers, resembling extracellular vesicles in their biomechanical properties. This is based on two main technological achievements: generation of soft biodegradable polyelectrolyte capsules in nanosize and efficient application of the nanocapsules for co-transfer of different RNAs to tumor cell lines and primary cells, including hematopoietic progenitor cells and primary T cells. Near to 100% efficiency is reached using only 2.5 × 10 −4 pmol of siRNA, and 1 × 10 −3 nmol of mRNA per cell, which is several magnitude orders below the amounts reported for any of methods published so far. The data show that biodegradable nanocapsules represent a universal and highly efficient biomimetic platform for the transfer of genetic material with the utmost potential to revolutionize gene transfer technology in vitro and in vivo.

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.

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.

While DNA and messenger RNA (mRNA) based therapies are currently changing the biomedical field, the delivery of genetic material remains the key problem preventing the wide introduction of these methods...

Actinium-225 (225Ac) radiolabeled submicrometric core–shell particles (SPs) made of calcium carbonate (CaCO3) coated with biocompatible polymers [tannic acid–human serum albumin (TA/HSA)] have been developed to improve the efficiency of local α-radionuclide therapy in melanoma models (B16-F10 tumor-bearing mice). The developed 225Ac-SPs possess radiochemical stability and demonstrate effective retention of 225Ac and its daughter isotopes. The SPs have been additionally labeled with zirconium-89 (89Zr) to perform the biodistribution studies using positron emission tomography–computerized tomography (PET/CT) imaging for 14 days after intratumoral injection. According to the PET/CT analysis, a significant accumulation of 89Zr-SPs in the tumor area is revealed for the whole investigation period, which correlates with the direct radiometry analysis after intratumoral administration of 225Ac-SPs. The histological analysis has revealed no abnormal changes in healthy tissue organs after treatment with 225Ac-SPs (e.g., no acute pathologic findings are detected in the liver and kidneys). At the same time, the inhibition of tumor growth has been observed as compared with control samples [nonradiolabeled SPs and phosphate-buffered saline (PBS)]. The treatment of mice with 225Ac-SPs has resulted in prolonged survival compared to the control samples. Thus, our study validates the application of 225Ac-doped core–shell submicron CaCO3 particles for local α-radionuclide therapy.