A Mycobacterium tuberculosis (H37Rv)-infected guinea pig model was used to screen for targeted delivery to the lungs by insufflation (with lactose excipient) or nebulization, of either rifampicin alone, rifampicin within poly(lactide-co-glycolide) microspheres (R-PLGA) or polymer microparticles alone (PLGA). Animals treated with single and double doses of R-PLGA microspheres exhibited significantly reduced numbers of viable bacteria, inflammation and lung damage compared with lactose-, PLGA- or rifampicin-treated animals 28 days post-infection (P < 0.05). Two doses of R-PLGA resulted in reduced splenic enlargement. These studies support the potential of R-PLGA delivered to the lung to treat pulmonary tuberculosis.

These studies indicate the potential of R-PLGA, delivered by insufflation or nebulization directly to the lungs, to affect the early development of pulmonary TB.

Aerosolized RPLGA reduced most measures of tuberculosis (TB) infection. These studies are further evidence for the potential of inhaled aerosol therapy for the treatment of TB. However, additional studies are required to elucidate underlying mechanisms of action and optimize this route of drug delivery.

Aerosol delivery to the airways of the human respiratory tract, followed by absorption, constitutes an alternative route of administration for compounds unsuitable for delivery by conventional oral and parenteral routes. The target for aerosol drug delivery is the airways epithelium, i.e. tracheal, bronchial, bronchiolar and alveolar cells, which become the site of drug deposition. These epithelial layers also serve as a barrier to the penetration of inhaled material. An in vitro model for aerosol deposition and transport across epithelia in the human airways may be a good predictor of in vivo disposition. The present preliminary studies begin an investigation that blends the dynamics of aerosol delivery and the basis of an in vitro simulated lung model to evaluate the transport properties of a series of molecular weight marker compounds across human-derived bronchiolar epithelial cell monolayers. An Andersen viable cascade impactor was used as a delivery apparatus for the deposition of size-segregated particles onto monolayers of small airway epithelial cells and Calu-3 cells. It was shown that these cell layers can withstand placement in the impactor, and that permeability can be tested subsequent to removal from the impactor.

Liposomes, as vehicles alone or in combination with rifampicin (RIF) microparticles (RMs), were evaluated as vehicles to enhance the permeation of RIF into granulomas. RIF liposomes (RLs) were extruded through a 0.1 µm polypropylene membrane. RMs were prepared by the solvent evaporation method. Four weeks after infection, guinea pigs (GPs) were assigned to groups treated with a combination of RM-RLs or RLs alone. RLs were nebulized after extrusion whereas RMs were suspended in saline and nebulized to GPs in a nose-only inhalation chamber. Necropsy was performed after the treatment; the lungs and spleen were resected for bacteriology. RLs had mean diameters of 137.1 ± 33.7 nm whereas RMs had a projected area diameter of 2.48 µm. The volume diameter of RMs was 64 ± 1 µm, indicating that RMs were aggregated. The treatment of TB-infected GPs with RLs significantly reduced their lung bacterial burden and wet spleen weight compared with those treated with blank liposomes. The treatment of TB-infected animals with RM-RLs also reduced their lung bacterial burden and wet spleen weight even though these reductions were not statistically different. Based on these results, the permeation of RIF into granulomas appears to be enhanced when encapsulated into liposomes delivered by the pulmonary route.

Phagocytosis represents a crucial event in the host defense against pathogens. Experimental methods are required that allow a range of particle doses to be delivered. However, it is not clear that these methods result in the same sites of deposition or mechanisms of clearance. The effect of particle administration by nebulization or instillation on the uptake by guinea pig alveolar macrophages (AMs) has been studied. Suspensions of escalating quantities of 1-microm fluorescent polystyrene latex microspheres were delivered by 15 min of nebulization (1.4 x 10(7)-11.1 x 10(7) particles) or instillation (19 x 10(7)-152 x 10(7) particles) into the lungs of guinea pigs. These doses were selected to maximize delivery using each of these methods. Macrophages were collected by alveolar lavage 6 h postadministration. The total number of cells recovered was 3 x 10(6) and the cell viability was >97%, which was measured by trypan blue exclusion. Differential cell counts of lavaged cell suspensions were conducted and results showed no difference for the two methods of administration with various concentrations of latex particles and control samples. The uptake of particles was measured using epifluorescence, confocal microscopy, and flow cytometry. AMs showed a dose-dependent increase in associated particles measured by microscopy and flow cytometry. There was a direct correlation (R(2) =.99) in the phagocytic indices (PIs) measured by flow cytometry and fluorescence microscopy. The PI was 15 times higher after instillation than that obtained after particle nebulization. The percentage of AMs involved in phagocytosis observed after instillation was 55% and after nebulization 23%. The uptake of aerosolized particles by AMs and the number of cells involved in phagocytosis were dependent on the particle dose and the efficiency of aerosol delivery to the lungs.

Hepatocellular cancer (HCC) is a significant problem of modern Oncology. Until recently, sorafenib was the only drug in the treatment of locally advanced and metastatic HCC. Knowledge of the mechanisms of carcinogenesis and tumor escape from the immune response is the basis for immunotherapy in the treatment of malignant tumors and HCC, in particular. Сlinical trials have shown immunotherapy significantly improves the results of treatment of patients with locally advanced and metastatic HCC with controlled toxicity profile. Currently, nivolumab and pembrolizumab (сheckpoint inhibitors) have been registered as the second line of treatment after progression on sorafenib. Clinical trials are needed to identify optimal combinations of drugs and sequences of their use in different clinical situations.

Background. Treatment results for the patients with stage II–III triple negative breast cancer (TN BC) have to be improved. Not only the new treatment regimens, but new predictive and prognostic factors should to be developed.Materials and methods. We included 98 patients with stage II–III TN BC in our study. We studied efficacy and safety of PlaTax regimen (cisplatin 75 mg / m2 day 1 + paclitaxel 80 mg / m2 days 1, 8, 15, course every 4 weeks) in this cohort of patients. We assessed pathologic response, survival and factors, which were relevant for predicting response and prognose survival.Results. PlaTax regimen is characterized by high efficacy and tolerable toxicity. Clinical efficacy was 85.8 %, pCR achievement was 60.5 %, tpCR achievement was 58.1 %. The regimen has low haematological toxicity (neutropenia III–IV grades – 4.1 %); the most frequent adverse events were polyneuropathy (18.5 %) and decreased renal function (24.5 %). 3-year progression-free survival was 68.4 %, most of the relapses (92 %) occurred during first 2 years. 3 year overall survival was 77.6 %. The most relevant predictive factor was level of Ki-67 ≥50 % (pCR 38.5 % vs. 68.7 %, p = 0.038). pCR achievement was the most important prognostic factor, resulting in improved 3-year progressionfree survival (44.3 % vs. 89.1 %, p <0.0001), and 3-year overall survival (61.5 % vs. 91.6 %, p = 0.001). Not only the residual disease, but also the size of residual tumor was important from prognostic point of view. Other important prognostic factors were size of the tumor, status of regional lymph nodes, grade. Delay in surgical treatment more than a month lead to decreased 3-year progression-free survival: 87.1 % vs. 62.5 % (p = 0.047).Conclusions. Our data suggest that studied regimen could be an option for patients with stage II–III TN BC. The assessment of the predictive and prognostic factors will help improve the treatment results for patients with stage II–III TN BC.