Hypoxia is a characteristic property of locally advanced solid tumors, resulting from an imbalance between the supply and consumption of oxygen. Major pathogenetic mechanisms for the development of hypoxia are (1) structural and functional abnormalities of the tumor microvasculature, (2) increased diffusion distances, and (3) tumor-associated and therapy-induced anemia. The oxygenation status is independent of clinical tumor size, stage, grade, and histopathological type, but is affected by the hemoglobin level. Hypoxia is intensified in anemic patients, especially in tumors with low perfusion rates. Hypoxia and anemia (most probably via worsening of tumor hypoxia) can lead to therapeutic problems, as they make solid tumors resistant to sparsely ionizing radiation and some forms of chemotherapy. In addition to more direct mechanisms involved in the development of therapeutic resistance, there are also indirect machineries that can cause barriers to therapies. These include hypoxia-driven proteome and genome changes and clonal selection. These, in turn, can drive subsequent events that are known to further increase resistance to therapy (in addition to critically affecting long-term prognosis). Treatment resistance in anemic patients can be, at least partially, prevented or overcome by anemia correction, resulting in better locoregional tumor control and overall survival of patients.

F on: Fluorotriorganosilyl‐derivatized Tyr3‐octreotate was labeled with 18F− providing the first practical formulation in 18F‐radiochemistry for the labeling of a peptide (see scheme). The very mild reaction conditions and the fast labeling make this strategy a valuable tool for the synthesis of 18F‐radiopharmaceuticals.

The expression and activity of P-glycoprotein (pGP) play a role in the multidrug resistance of tumors. Because solid-growing tumors often show pronounced hypoxia or extracellular acidosis, this study attempted to analyze the impact of an acidic environment on the expression and activity of pGP and on the cytotoxicity of chemotherapeutic agents. For this, prostate carcinoma cells were exposed to an acidic extracellular environment (pH 6.6) for up to 24 hours. pGP activity was more than doubled after 3 to 6 hours of incubation in acidic medium, whereas cellular pGP expression remained constant, indicating that increased transport rate is the result of functional modulation. In parallel, the cytotoxic efficacy of daunorubicin showed pronounced reduction at low pH, an effect that was reversible on coincubation with a pGP inhibitor. A reduction of intracellular Ca2+ concentration by 35% under acidic conditions induced a higher transport rate of pGP, an effect comparable to that found on inhibition of protein kinase C (PKC). These data indicate that pGP activity is increased by low extracellular pH presumably as a result of lowered intracellular calcium levels and inhibition of PKC. These findings may explain the reduced cytotoxicity of chemotherapeutic agents in hypoxic/acidic tumors.

During the last decades polymer-based nanomedicine has turned out to be a promising tool in modern pharmaceutics. The following article describes the synthesis of well-defined random and block copolymers by RAFT polymerization with potential medical application. The polymers have been labeled with the positron-emitting nuclide fluorine-18. The polymeric structures are based on the biocompatible N-(2-hydroxypropyl)-methacrylamide (HPMA). To achieve these structures, functional reactive ester polymers with a molecular weight within the range of 25,000-110,000 g/mol were aminolyzed by 2-hydroxypropylamine and tyramine (3%) to form (18)F-labelable HPMA-polymer precursors. The labeling procedure of the phenolic tyramine moieties via the secondary labeling synthon 2-[(18)F]fluoroethyl-1-tosylate ([(18)F]FETos) provided radiochemical fluoroalkylation yields of ∼80% for block copolymers and >50% for random polymer architectures within a synthesis time of 10 min and a reaction temperature of 120 °C. Total synthesis time including synthon synthesis, (18)F-labeling, and final purification via size exclusion chromatography took less than 90 min and yielded stable (18)F-labeled HPMA structures in isotonic buffer solution. Any decomposition could be detected within 2 h. To determine the in vivo fate of (18)F-labeled HPMA polymers, preliminary small animal positron emission tomography (PET) experiments were performed in healthy rats, demonstrating the renal clearance of low molecular weight polymers. Furthermore, low metabolism rates could be detected in urine as well as in the blood. Thus, we expect this new strategy for radioactive labeling of polymers as a promising approach for in vivo PET studies.

This study suggests that cHb values of between 12 and 14 g/dl are optimal with regard to the oxygenation status in the tumor entities investigated, a finding which may have far-reaching implications in the clinical setting.

There is a recognized need to create well-defined polymer probes for in vivo and clinical positron emission tomography (PET) imaging to guide the development of new generation polymer therapeutics. Using the RAFT polymerization technique in combination with the reactive ester approach, here we have synthesized well-defined and narrowly distributed N-(2-hydroxypropyl)methacrylamide homopolymers (pHPMA) (P1* and P2*) and random HPMA copolymers consisting of hydrophilic HPMA and hydrophobic lauryl methacrylate comonomers (P3* and P4*). The polymers had molecular weights below (P1* and P3*) and above the renal threshold (P2* and P4*). Whereas the homopolymers dissolve in isotonic solution as individual coils, the random copolymers form larger aggregates above their critical micelle concentration (∼ 40 nm), as determined by fluorescence correlation spectroscopy. Structure-property relationships of the pharmacokinetics and biodistribution of the different polymer architectures were monitored in the living organism following radiolabeling with the positron emitter (18)F via fluoroethylation within a few hours. Ex vivo organ biodistribution and in vivo μPET imaging studies in male Copenhagen rats revealed that both size and the nature of the aggregate formation (hydrophobically modified copolymers) played a major role in blood clearance and biodistribution, especially concerning liver and kidney accumulation. The high-molecular-weight random copolymer P4* (hydrophobically modified), in particular, combines low liver uptake with enhanced blood circulation properties, showing the potential of hydrophobic interactions, as seen for the represented model system, that are valuable for future drug carrier design.

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Tumor micromilieu often shows pronounced acidosis forcing cells to adapt their phenotype towards enhanced tumorigenesis induced by altered cellular signalling and transcriptional regulation. In the presents study mechanisms and potential consequences of the crosstalk between extra- and intracellular pH (pHe, pHi) and mitogen-activated-protein-kinases (ERK1/2, p38) was analyzed. Data were obtained mainly in AT1 R-3327 prostate carcinoma cells, but the principle importance was confirmed in 5 other cell types. Extracellular acidosis leads to a rapid and sustained decrease of pHi in parallel to p38 phosphorylation in all cell types and to ERK1/2 phosphorylation in 3 of 6 cell types. Furthermore, p38 phosphorylation was elicited by sole intracellular lactacidosis at normal pHe. Inhibition of ERK1/2 phosphorylation during acidosis led to necrotic cell death. No evidence for the involvement of the kinases c-SRC, PKC, PKA, PI3K or EGFR nor changes in cell volume in acidosis-induced MAPK activation was obtained. However, our data reveal that acidosis enhances the formation of reactive oxygen species (ROS), probably originating from mitochondria, which subsequently trigger MAPK phosphorylation. Scavenging of ROS prevented acidosis-induced MAPK phosphorylation whereas addition of H2O2 enhanced it. Finally, acidosis increased phosphorylation of the transcription factor CREB via p38, leading to increased transcriptional activity of a CRE-reporter even 24 h after switching the cells back to a normal environmental milieu. Thus, an acidic tumor microenvironment can induce a longer lasting p38-CREB-medited change in the transcriptional program, which may maintain the altered phenotype even when the cells leave the tumor environment.