Search

In this study, we described physico-chemical properties of novel nanoformulation of photosensitizer-pyropheophorbide α 17-diethylene glycol ester (XL) (chlorophyll α derivative), revealing insights into antitumor activity and maintaining quality, meeting the pharmaceutical approach of new nanoformulation design. Our formulation, based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles, increased XL solubility and selective tumor-targeted accumulation. In our research, we revealed, for the first time, that XL binding to polyvinyl alcohol (PVA) enhances XL photophysical activity, providing the rationale for PVA application as a stabilizer for nanoformulations. Results of FTIR, DSC, and XRD revealed the physical interactions between XL and excipients, including PVA, indicating that the encapsulation maintained XL binding to PVA. The encapsulated XL exhibited higher photophysical activity compared to non-encapsulated substance, which can be attributed to the influence of residual PVA. Gamma-irradiation led to degradation of XL; however, successful sterilization of the samples was achieved through the filtration. Importantly, the encapsulated and sterilized XL retained cytotoxicity against both 2D and 3D tumor cell models, demonstrating the potential of the formulated NP-XL for photodynamic therapy applications, but lacked the ability to reactivate epigenetically silenced genes. These findings provide valuable insights into the design and characterization of PLGA-based nanoparticles for the encapsulation of photosensitizers.

Unsaturated fatty acids, such as oleic acid (OA) and linoleic acid (LA), are promising antimicrobial and cytostatic agents. We modified OA and LA with thymol (TOA and TLA, respectively) to expand their bioavailability, stability, and possible applications, and encapsulated these derivatives in polymeric nanoparticles (TOA-NPs and TLA-NPs, respectively). Prior to synthesis, we performed mathematical simulations with PASS and ADMETlab 2.0 to predict the biological activity and pharmacokinetics of TOA and TLA. TOA and TLA were synthesized via esterification in the presence of catalysts. Next, we formulated nanoparticles using the single-emulsion solvent evaporation technique. We applied dynamic light scattering, Uv-vis spectroscopy, release studies under gastrointestinal (pH 1.2-6.8) and blood environment simulation conditions (pH 7.4), and in vitro biological activity testing to characterize the nanoparticles. PASS revealed that TOA and TLA have antimicrobial and anticancer therapeutic potential. ADMETlab 2.0 provided a rationale for TOA and TLA encapsulation. The nanoparticles had an average size of 212-227 nm, with a high encapsulation efficiency (71-93%), and released TOA and TLA in a gradual and prolonged mode. TLA-NPs possessed higher antibacterial activity against B. cereus and S. aureus and pronounced cytotoxic activity against MCF-7, K562, and A549 cell lines compared to TOA-NPs. Our findings expand the biomedical application of fatty acids and provide a basis for further in vivo evaluation of designed derivatives and formulations.

Photodynamic therapy (PDT) in oncology is characterized by low invasiveness, minimal side effects, and little tissue scarring. Increasing the selectivity of PDT agents toward a cellular target is a new approach intended to improve this method. This study is devoted to the design and synthesis of a new conjugate based on meso-arylporphyrin with a low-molecular-weight tyrosine kinase inhibitor, Erlotinib. A nano-formulation based on Pluronic F127 micelles was obtained and characterized. The photophysical and photochemical properties and biological activity of the studied compounds and their nano-formulation were studied. A significant, 20-40-fold difference between the dark and photoinduced activity was achieved for the conjugate nanomicelles. After irradiation, the studied conjugate nanomicelles were 1.8 times more toxic toward the EGFR-overexpressing cell line MDA-MB-231 compared to the conditionally normal NKE cells. The IC50 was 0.073 ± 0.014 μM for the MDA-MB-231 cell line and 0.13 ± 0.018 μM for NKE cells after irradiation for the target conjugate nanomicelles.

A novel amphiphilic cationic chlorin e 6 derivative was investigated as a promising photosensitizer for photodynamic therapy. Two cationic -N(CH 3 ) 3 + groups on the periphery of the macrocycle provide additional hydrophilization of the molecule and ensure its electrostatic binding to the mitochondrial membranes and bacterial cell walls. The presence of a hydrophobic phytol residue in the same molecule results in its increased affinity towards the phospholipid membranes while decreasing its stability towards aggregation in aqueous media. In organic media, this chlorin e 6 derivative is characterized by a singlet oxygen quantum yield of 55%. Solubilization studies in different polymer- and surfactant-based supramolecular systems revealed the effective stabilization of this compound in a photoactive monomolecular form in micellar nonionic surfactant solutions, including Tween-80 and Cremophor EL. A novel cationic chlorin e 6 derivative also demonstrates effective binding towards serum albumin, which enhances its bioavailability and promotes effective accumulation within the target tissues. Laser confocal scanning microscopy demonstrates the rapid intracellular accumulation and distribution of this compound throughout the cells. Together with low dark toxicity and a rather good photostability, this compound demonstrates significant phototoxicity against HeLa cells causing cellular damage most likely through reactive oxygen species generation. These results demonstrate a high potential of this derivative for application in photodynamic therapy.

Currently, molecular dynamics simulation is being widely applied to predict drug-polymer interaction, and to optimize drug delivery systems. Our study describes a combination of in silico and in vitro approaches aimed at improvement in polymer-based nanoparticle design for cancer treatment. We applied the PASS service to predict the biological activity of novel carboplatin derivatives. Subsequent molecular dynamics simulations revealed the dependence between the drug-polymer binding energy along with encapsulation efficacy, drug release profile, and the derivatives' chemical structure. We applied ICP-MS analysis, the MTT test, and hemolytic activity assay to evaluate drug loading, antitumor activity, and hemocompatibility of the formulated nanoparticles. The drug encapsulation efficacy varied from 0.2% to 1% and correlated with in silico modelling results. The PLGA nanoparticles revealed higher antitumor activity against A549 human non-small-cell lung carcinoma cells compared to non-encapsulated carboplatin derivatives with IC 50 values of 1.40-23.20 µM and 7.32-79.30 µM, respectively; the similar cytotoxicity profiles were observed against H69 and MCF-7 cells. The nanoparticles efficiently induced apoptosis in A549 cells. Thus, nanoparticles loaded with novel carboplatin derivatives demonstrated high application potential for anticancer therapy due to their efficacy and high hemocompatibility. Our results demonstrated the combination of in silico and in vitro methods applicability for the optimization of encapsulation and antitumor efficacy in novel drug delivery systems design.

Capsules with shells based on nanoparticles of different nature co-assembled at the interface of liquid phases of emulsion are promising carriers of lipophilic drugs. To obtain such capsules, theoretically using the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory and experimentally using dynamic light-scattering (DLS) and transmission electron microscopy (TEM) methods, the interaction of like-charged silica nanoparticles and detonation nanodiamonds in an aqueous solution was studied and their ratios selected for the formation of submicron-sized colloidosomes. The resulting colloidosomes were modified with additional layers of nanoparticles and polyelectrolytes, applying LbL technology. As a model anti-cancer drug, thymoquinone was loaded into the developed capsules, demonstrating a significant delay of the release as a result of colloidosome surface modification. Fluorescence flow cytometry and confocal laser scanning microscopy showed efficient internalization of the capsules by MCF7 cancer cells. The obtained results demonstrated a high potential for nanomedicine application in the field of the drug-delivery system development.