BACKGROUND: Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, trigger biodegradation of polymer-based nanoparticles (NPs) bearing pinacol-type boronic ester groups. These NPs may selectively release their cargo, in this case paclitaxel (PTX), at the high levels of ROS present in the intracellular environment of inflamed tissues and most tumors. PURPOSE: The main objective was to determine anti-tumor efficacy of PTX-loaded ROS-sensitive NPs and to examine whether macrophage infiltration had any impact on treatment efficacy. METHODS: NPs were synthesized and their characteristics in the presence of H2O2 were demonstrated. Both confocal microscopy as well as flow cytometry approaches were used to determine degradation of ROS-sensitive NPs. HeLa cells were cultured in vitro and used to establish tumor xenografts in nude mice. In vivo experiments were performed to understand toxicity, biodistribution and anti-tumor efficacy of the NPs. Moreover, we performed immunohistochemistry on tumor sections to study infiltration of M1 and M2 subsets of macrophages. RESULTS: We demonstrated that PTX delivered in NPs containing a ROS-sensitive polymer exhibits a better anti-tumor efficacy than PTX in NPs containing ROS-non-sensitive polymer, free PTX or Abraxane® (nab-PTX). The biodistribution revealed that ROS-sensitive NPs exhibit retention in liver, spleen and lungs, suggesting a potential to target cancer metastasizing to these organs. Finally, we demonstrated a correlation between infiltrated macrophage subsets and treatment efficacy, possibly contributing to the efficient anti-tumor effects. CONCLUSION: Treatment with ROS-sensitive NPs containing PTX gave an improved therapeutic effect in HeLa xenografts than their counterpart, free PTX or nab-PTX. Our data revealed a correlation between macrophage infiltration and efficiency of the different antitumor treatments, as the most effective NPs resulted in the highest infiltration of the anti-tumorigenic M1 macrophages.

• Klíčová slova
• ROS-sensitive nanoparticles, macrophage infiltration, paclitaxel, reactive oxygen species, treatment efficacy,
• MeSH
• albuminy farmakologie   terapeutické užití   MeSH
• HeLa buňky MeSH
• hydrodynamika MeSH
• lidé MeSH
• makrofágy účinky léků   metabolismus   MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• nanočástice terapeutické užití   MeSH
• paclitaxel farmakologie   terapeutické užití   MeSH
• paklitaxel vázaný na albumin terapeutické užití   MeSH
• polymery chemie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• tkáňová distribuce účinky léků   MeSH
• velikost částic MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 130-nm albumin-bound paclitaxel MeSH Prohlížeč
• albuminy MeSH
• paclitaxel MeSH
• paklitaxel vázaný na albumin MeSH
• polymery MeSH
• reaktivní formy kyslíku MeSH

BACKGROUND: To investigate the impact of perioperative chemo(radio)therapy in advanced primary urethral carcinoma (PUC). PATIENTS AND METHODS: A series of 124 patients (86 men, 38 women) were diagnosed with and underwent surgery for PUC in 10 referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank testing was used to investigate the impact of perioperative chemo(radio)therapy on overall survival (OS). The median follow-up was 21 months (mean: 32 months; interquartile range: 5-48). RESULTS: Neoadjuvant chemotherapy (NAC), neoadjuvant chemoradiotherapy (N-CRT) plus adjuvant chemotherapy (ACH), and ACH was delivered in 12 (31%), 6 (15%) and 21 (54%) of these patients, respectively. Receipt of NAC/N-CRT was associated with clinically node-positive disease (cN+; P = 0.033) and lower utilization of cystectomy at surgery (P = 0.015). The objective response rate to NAC and N-CRT was 25% and 33%, respectively. The 3-year OS for patients with objective response to neoadjuvant treatment (complete/partial response) was 100% and 58.3% for those with stable or progressive disease (P = 0.30). Of the 26 patients staged ≥cT3 and/or cN+ disease, 16 (62%) received perioperative chemo(radio)therapy and 10 upfront surgery without perioperative chemotherapy (38%). The 3-year OS for this locally advanced subset of patients (≥cT3 and/or cN+) who received NAC (N = 5), N-CRT (N = 3), surgery-only (N = 10) and surgery plus ACH (N = 8) was 100%, 100%, 50% and 20%, respectively (P = 0.016). Among these 26 patients, receipt of neoadjuvant treatment was significantly associated with improved 3-year relapse-free survival (RFS) (P = 0.022) and OS (P = 0.022). Proximal tumor location correlated with inferior 3-year RFS and OS (P = 0.056/0.005). CONCLUSION: In this series, patients who received NAC/N-CRT for cT3 and/or cN+ PUC appeared to demonstrate improved survival compared with those who underwent upfront surgery with or without ACH.

• Klíčová slova
• adjuvant, chemoradiotherapy, chemotherapy, neoadjuvant, primary urethral carcinoma,
• MeSH
• adenokarcinom mortalita   terapie   MeSH
• adjuvantní chemoterapie metody   MeSH
• chemoradioterapie metody   MeSH
• cisplatina aplikace a dávkování   MeSH
• cystektomie MeSH
• deoxycytidin aplikace a dávkování   analogy a deriváty   MeSH
• diverze moči MeSH
• fluoruracil aplikace a dávkování   MeSH
• gemcitabin MeSH
• ifosfamid aplikace a dávkování   MeSH
• Kaplanův-Meierův odhad MeSH
• karboplatina aplikace a dávkování   MeSH
• karcinom z přechodných buněk mortalita   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitomycin aplikace a dávkování   MeSH
• nádory močové trubice mortalita   terapie   MeSH
• neoadjuvantní terapie metody   MeSH
• paclitaxel aplikace a dávkování   MeSH
• paklitaxel vázaný na albumin aplikace a dávkování   MeSH
• perioperační péče MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• spinocelulární karcinom mortalita   terapie   MeSH
• uretra chirurgie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Názvy látek
• cisplatina MeSH
• deoxycytidin MeSH
• fluoruracil MeSH
• gemcitabin MeSH
• ifosfamid MeSH
• karboplatina MeSH
• mitomycin MeSH
• paclitaxel MeSH
• paklitaxel vázaný na albumin MeSH