The exit of nanoparticles from solid tumours.

Nanoparticles enter tumours through endothelial cells, gaps or other mechanisms, but how they exit is unclear. The current paradigm states that collapsed tumour lymphatic vessels impair the exit of nanoparticles and lead to enhanced retention. Here we show that nanoparticles exit the tumour through the lymphatic vessels within or surrounding the tumour. The dominant lymphatic exit mechanism depends on the nanoparticle size. Nanoparticles that exit the tumour through the lymphatics are returned to the blood system, allowing them to recirculate and interact with the tumour in another pass. Our results enable us to define a mechanism of nanoparticle delivery to solid tumours alternative to the enhanced permeability and retention effect. We call this mechanism the active transport and retention principle. This delivery principle provides a new framework to engineer nanomedicines for cancer treatment and detection.

Toward Predicting Nanoparticle Distribution in Heterogeneous Tumor Tissues.

Nanobio interaction studies have generated a significant amount of data. An important next step is to organize the data and design computational techniques to analyze the nanobio interactions. Here we developed a computational technique to correlate the nanoparticle spatial distribution within heterogeneous solid tumors. This approach led to greater than 88% predictive accuracy of nanoparticle location within a tumor tissue. This proof-of-concept study shows that tumor heterogeneity might be defined computationally by the patterns of biological structures within the tissue, enabling the identification of tumor patterns for nanoparticle accumulation.

Nanoparticles Bind to Endothelial Cells in Injured Blood Vessels via a Transient Protein Corona.

Nanoparticles travel through blood vessels to reach disease sites, but the local environment they encounter may affect their surface chemistry and cellular interactions. Here, we found that as nanoparticles transit through injured blood vessels they may interact with a highly localized concentration of platelet factor 4 proteins released from activated platelets. The platelet factor 4 binds to the nanoparticle surface and interacts with heparan sulfate proteoglycans on endothelial cells, and induces uptake. Understanding nanoparticle interactions with blood proteins and endothelial cells during circulation is critical to optimizing their design for diseased tissue targeting and delivery.

Triple-negative breast cancer prevalence in Africa: a systematic review and meta-analysis.

OBJECTIVE: The aggressive triple-negative breast cancer (TNBC) subtype disproportionately affects women of African ancestry across the diaspora, but its frequency across Africa has not been widely studied. This study seeks to estimate the frequency of TNBC among African populations. DESIGN: Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. DATA SOURCES: PubMed, EMBASE, African Journals Online and Web of Science were searched on 25 April 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included studies that use breast cancer tissue samples from indigenous African women with sample size of eligible participants ≥40 and full receptor status for all three receptors (oestrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2)) reported. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias using the modified assessment tool by Hoy et al. (2012) for prevalence studies. A random-effects meta-analysis was performed, and data were pooled using the inverse-variance method and logit transformation. Pooled frequencies were reported with 95% CIs calculated with the Clopper-Pearson method and heterogeneity quantified with I2 statistic. GRADE assessed the certainty of the evidence. RESULTS: 1808 potentially eligible studies were identified of which 67 were included in the systematic review and 60 were included in the meta- analysis. Pooled TNBC frequency across African countries represented was estimated to be 27.0%; 95% CI: 24.0% to 30.2%, I2=94%. Pooled TNBC frequency was highest across West Africa, 45.7% (n=15, 95% CI: 38.8% to 52.8%, I2=91%) and lowest in Central Africa, 14.9% (n=1, 95% CI: 8.9 % to 24.1%). Estimates for TNBC were higher for studies that used Allred guidelines for ER/PR status compared with American Society of Clinical Oncology(ASCO)/College of American Pathologists(CAP) guidelines, and for studies that used older versions of ASCO/CAP guidelines for assessing HER2 status. Certainty of evidence was assessed to be very low using GRADE approach. CONCLUSION: TNBC frequency was variable with the highest frequency reported in West Africa. Greater emphasis should be placed on establishing protocols for assessing receptor status due to the variability among studies.

Why nanoparticles prefer liver macrophage cell uptake in vivo.

Effective delivery of therapeutic and diagnostic nanoparticles is dependent on their ability to accumulate in diseased tissues. However, most nanoparticles end up in liver macrophages regardless of nanoparticle design after administration. In this review, we describe the interactions of liver macrophages with nanoparticles. Liver macrophages have significant advantages in interacting with circulating nanoparticles over most target cells and tissues in the body. We describe these advantages in this article. Understanding these advantages will enable the development of strategies to overcome liver macrophages and deliver nanoparticles to targeted diseased tissues effectively. Ultimately, these approaches will increase the therapeutic efficacy and diagnostic signal of nanoparticles.

Macrophages Actively Transport Nanoparticles in Tumors After Extravasation.

Nanoparticles need to navigate a complex microenvironment to target cells in solid tumors after extravasation. Diffusion is currently the accepted primary mechanism for nanoparticle distribution in tumors. However, the extracellular matrix can limit nanoparticle diffusion. Here, we identified tumor-associated macrophages as another key player in transporting and redistributing nanoparticles in the tumor microenvironment. We found tumor-associated macrophages actively migrate toward nanoparticles extravasated from the vessels, engulfing and redistributing them in the tumor stroma. The macrophages can carry the nanoparticles 2-5 times deeper in the tumor than passive diffusion. The amount of nanoparticles transported by the tumor-associated macrophages is size-dependent. Understanding the nanoparticle behavior after extravasation will provide strategies to engineer them to navigate the microenvironment for improved intratumoral targeting and therapeutic effectiveness.