I. M. Deygen

Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations

Exosomes have recently emerged as a promising drug delivery system with low immunogenicity, high biocompatibility, and high efficacy of delivery. We demonstrated earlier that macrophage-derived exosomes (exo) loaded with a potent anticancer agent paclitaxel (PTX) represent a novel nanoformulation (exoPTX) that shows high anticancer efficacy in a mouse model of pulmonary metastases. We now report the manufacture of targeted exosome-based formulations with superior structure and therapeutic indices for systemic administration. Herein, we developed and optimized a formulation of PTX-loaded exosomes with incorporated aminoethylanisamide-polyethylene glycol (AA-PEG) vector moiety to target the sigma receptor, which is overexpressed by lung cancer cells. The AA-PEG-vectorized exosomes loaded with PTX (AA-PEG-exoPTX) possessed a high loading capacity, profound ability to accumulate in cancer cells upon systemic administration, and improved therapeutic outcomes. The combination of targeting ability with the biocompatibility of exosome-based drug formulations offers a powerful and novel delivery platform for anticancer therapy.

Structure and stability of fluoroquinolone-(2-hydroxypropyl)-β-cyclodextrin complexes as perspective antituberculosis drugs

The formation of host–guest complexes of fluoroquinolones (FQs), such as levofloxacin, ofloxacin, and moxifloxacin with (2-hydroxypropyl)-β-cyclodextrin (HP–β–CD) was studied by spectroscopic methods. The stoichiometry and dissociation constants of the inclusion complexes were determined. The formation of complexes of FQs with HP–β–CD was confirmed by the solubility studies, the UV and FTIR spectra and the equilibrium dialysis. The use of the complex of levofloxacin with HP–β–CD leads to the prolonged release of the former observed in the dialysis experiments. The formation of inclusion complexes makes it possible to increase the solubility of FQs by two to five times. The research may provide a basis for the development of new FQ-containing drugs involving HP–β–CD as a nanocarrier system.

Micronization of levofloxacin by supercritical antisolvent precipitation

The process of micronization of levofloxacin (LF, an antibacterial agent of the fluoroquinolone group) by the supercritical antisolvent precipitation technique (SAS) was investigated. It was shown that LF particles of different sizes (from 1 to 10 μm) and of various morphologies (from thin plates to elongated parallelepipeds) can be produced depending on the type of solvent used for conducting micronization. Investigation of the micronized LF preparations using the methods of IR-Fourier spectroscopy, Raman scattering, and circular dichroism showed that the LF micronization caused neither changes in its chemical structure nor racemization. Micronization of LF significantly affects the rate of its dissolution in model systems exhibiting effects dependent on the type of the solvent used for micronization. For example, the highest rate of dissolution at pH 4 was observed for LF preparations micronized with the help of chlorohydrocarbons. It was shown that the rate of dissolution of all micronized LF preparations was higher by 15–30% in comparison with the initial LF, which likely was related to the changes in the degree of crystallinity/amorphousness, as well as of morphologies of microparticles formed in the SAS process.

Novel Prodrug of Doxorubicin Modified by Stearoylspermine Encapsulated into PEG-Chitosan-Stabilized Liposomes

Here, we report a new modification of doxorubicin based on an amphiphilic stearoylspermine anchor, enabling loading into liposomal membranes. Doxorubicin is coupled with stearoylspermine through an acid-labile hydrazone linker to ensure the release of the drug in the acidic interstitium of tumors. Using ATR-FTIR spectroscopy (Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy), the mechanism of interaction of doxorubicin with the anionic liposomal membrane was studied: incorporation of stearoyl chains leads to an increase in local microfluidity, and the amino groups of spermine interact with the phosphate groups of lipids. To stabilize liposomes against aggregation, we applied the copolymer PEG-chitosan as a coating: complex formation leads to charge neutralization, and the liposomes grow in size. According to MTT tests and confocal microscopy for cell lines A459 and Caco-2, PEG-chitosan-coated liposomes are as effective as neutral liposomes but are much more stable.

Moxifloxacin Micronization via Supercritical Antisolvent Precipitation

Supercritical antisolvent (SAS) precipitation is employed for micronization of moxifloxacin (MF), an antibiotic from the fluoroquinolone group, to develop new dosage forms of MF. With this technique, we produced, in a controllable fashion, MF particles with different sizes (0.6–8.0 μm) and morphologies (from polygonal sheets to elongated rectangular prisms). The infrared and circular dichroism spectroscopy data suggest that micronization of MF via SAS does not alter its chemical structure or cause racemization. We demonstrate that micronized forms of MF drug substance exhibit a 20 to 30% increase in the dissolution rate, as compared to the initial MF form, in a physiological medium (pH 7.4). The dissolution rate of the microparticles obtained via SAS micronization depends on their size, morphology, and degree of crystallinity. The various data obtained in this study will be used in formulating new dosage forms of MF for treatment of drug-resistant forms of tuberculoses.

Effect of glycol chitosan on functional and structural properties of anionic liposomes

The possibility of using glycol chitosan to obtain stabilized liposome containers for doxorubicin delivery is demonstrated. The dissociation constants of the liposome complexes with glycol chitosan (3.4 × 10–4 and 1.10 × 10–5 depending on the aggregation state of the liposomes) are determined. It is shown that the formation of liposome complexes with glycol chitosan has a significant prolongation effect on the release of doxorubicin from the liposomes at pH 7.4.