CCL2 chemokine inhibition primes the tumor vasculature for improved nanomedicine delivery and efficacy.

Blood vessel functionality is crucial for efficient tumor-targeted drug delivery. Heterogeneous distribution and perfusion of angiogenic blood vessels contribute to suboptimal accumulation of (nano-) therapeutics in tumors and metastases. To attenuate pathological angiogenesis, an L-RNA aptamer inhibiting the CC motif chemokine ligand 2 (CCL2) was administered to mice bearing orthotopic 4T1 triple-negative breast cancer tumors. The effect of CCL2 inhibition on tumor blood vessel functionality and tumor-targeted drug delivery was evaluated via multimodal and multiscale optical imaging, employing fluorophore-labeled polymeric (10 nm) and liposomal (100 nm) nanocarriers. Anti-CCL2 treatment induced a dose-dependent anti-angiogenic effect, reflected by a decreased relative blood volume, increased blood vessel maturity and functionality, and reduced macrophage infiltration, accompanied by a shift in the polarization of tumor-associated macrophages (TAM) towards a less M2-like and more M1-like phenotype. In line with this, CCL2 inhibitor treatment improved the delivery of polymers and liposomes to tumors, and enhanced the antitumor efficacy of free and liposomal doxorubicin. Together, these findings demonstrate that blocking the CCL2-CCR2 axis modulates TAM infiltration and polarization, resulting in vascular normalization and improved tumor-targeted drug delivery.

Effect of Cellular and Microenvironmental Multidrug Resistance on Tumor-Targeted Drug Delivery in Triple-Negative Breast cancer.

Multidrug resistance (MDR) reduces the efficacy of chemotherapy. Besides inducing the expression of drug efflux pumps, chemotherapy treatment alters the composition of the tumor microenvironment (TME), thereby potentially limiting tumor-directed drug delivery. To study the impact of MDR signaling in cancer cells on TME remodeling and nanomedicine delivery, we generated multidrug-resistant 4T1 triple-negative breast cancer (TNBC) cells by exposing sensitive 4T1 cells to gradually increasing doxorubicin concentrations. In 2D and 3D cell cultures, resistant 4T1 cells are presented with a more mesenchymal phenotype and produced increased amounts of collagen. While sensitive and resistant 4T1 cells showed similar tumor growth kinetics in vivo, the TME of resistant tumors was enriched in collagen and fibronectin. Vascular perfusion was also significantly increased. Fluorophore-labeled polymeric (∼10 nm) and liposomal (∼100 nm) drug carriers were administered to mice with resistant and sensitive tumors. Their tumor accumulation and penetration were studied using multimodal and multiscale optical imaging. At the whole tumor level, polymers accumulate more efficiently in resistant than in sensitive tumors. For liposomes, the trend was similar, but the differences in tumor accumulation were insignificant. At the individual blood vessel level, both polymers and liposomes were less able to extravasate out of the vasculature and penetrate the interstitium in resistant tumors. In a final in vivo efficacy study, we observed a stronger inhibitory effect of cellular and microenvironmental MDR on liposomal doxorubicin performance than free doxorubicin. These results exemplify that besides classical cellular MDR, microenvironmental drug resistance features should be considered when aiming to target and treat multidrug-resistant tumors more efficiently.

Gestational Diabetes: Physical Activity Before Pregnancy and Its Influence on the Cardiovascular System.

Objectives: Gestational diabetes mellitus (GDM) is a common complication in pregnancy, affecting around 14% of all pregnancies each year. It will likely further increase, as obesity becomes more prevalent. The impact of GDM on cardiovascular changes in pregnant women and her child is still unclear. The aim of the study was to measure the effects of physical activity before pregnancy on the cardiovascular system in patients with GDM in pregnancy. Methods: Two hundred and six pregnant women were included in this observational study. All participants were recruited at the tertiary level teaching University Hospital "Klinikum rechts der Isar" between 28 and 32 weeks gestation. Questionnaires dealing with pre-pregnancy daily and physical activity (PA) were evaluated. The cardiovascular status of the mothers included measurements of the intima-media thickness (IMT) of the carotid arteries. PA level was performed with a standardized 6-min-walking-test. Results: Ninety-nine women with GDM with a mean age of 33.84 (± 4.7) years were examined. One hundred seven healthy pregnant women aged 32.6 (± 4.2) years served as controls. The mean weight in the study group was 73.0 (± 20.3) kg and 61.7 (± 9.5) kg in the control group. Based on the higher weight in the study group, the Body Mass Index (BMI) was also significantly higher than in the control group (26.3 ± 7.1 vs. 21.6 ± 3; p < 0.001). The frequency of PA was significantly higher in the control group (p < 0.001). The objective fitness level was worse in pregnant women with GDM compared to healthy controls (472 vs. 523 m, p < 0.001). PA before and during pregnancy was less performed in the study group (86 vs. 64.5%, p = 0.002; 69 vs. 45.7%, p = 0.003). Women who were physically inactive before pregnancy had a 3-times higher risk to develop GDM compared to active women (OR = 2.67). The IMT was significantly thicker in the study group (0.48 ± 0.042 mm vs. 0.45 ± 0.042) mm; p = 0.006). Conclusion: Physical activity before pregnancy and a lower initial weight reduces the risk of developing GDM and cardiovascular risk factors in pregnancy. The development of prevention programs is certainly necessary.