Fate of Linear and Branched Polyether-Lipids In Vivo in Comparison to Their Liposomal Formulations by ¹⁸F‑Radiolabeling and Positron Emission Tomography

In this study, linear poly­(ethylene glycol) (PEG) and novel linear-hyperbranched, amphiphilic polyglycerol (<i>hb</i>PG) polymers with cholesterol (Ch) as a lipid anchor moiety were radiolabeled with fluorine-18 via copper-catalyzed click chemistry. In vivo investigations via positron emission tomography (PET) and ex vivo biodistribution in mice were conducted. A systematic comparison to the liposomal formulations with and without the polymers with respect to their initial pharmacokinetic properties during the first hour was carried out, revealing remarkable differences. Additionally, cholesterol was directly labeled with fluorine-18 and examined likewise. Both polymers, Ch-PEG₂₇-CH₂-triazole-TEG-¹⁸F and Ch-PEG₃₀-<i>hb</i>PG₂₄-CH₂-triazole-TEG-¹⁸F (TEG: triethylene glycol), showed rapid renal excretion, whereas the ¹⁸F-cholesten displayed retention in lung, liver, and spleen. Liposomes containing Ch-PEG₂₇-CH₂-triazole-TEG-¹⁸F revealed a hydrodynamic radius of 46 nm, liposomal Ch-PEG₃₀-<i>hb</i>PG₂₄-CH₂-triazole-TEG-¹⁸F showed a radius of 84 nm and conventional liposomes with ¹⁸F-cholesten 204 nm, respectively. The results revealed fast uptake of the conventional liposomes by liver, spleen, and lung. Most importantly, the novel <i>hb</i>PG-polymer stabilized liposomes showed similar behavior to the PEG-shielded vesicles. Thus, an advantage of multifunctionality is achieved with retained pharmacokinetic properties. The approach expands the scope of polymer tracking in vivo and liposome tracing in mice via PET

Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages

Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system